14.15 – 14.45 B. Štrukelj Razvoj in mehanizem delovanja tarčnih zdravil 14.45 – 15.00 Razprava 15.00 – 15.30 I. Aurer Tarčno zdravljenje limfomov (Target treatment of malignant lymphomas) 15.30 – 15.45 Razprava 15.45 – 16.15 ODMOR 16.15 – 16.45 F. Ciardielllo Tarčno zdravljenje GI tumorjev (Target treatment of GI tumors) 16.45 – 17.00 Razprava 17.00 – 17.30 M. Tiseo Tarčno zdravljenje raka pljuč (Target treatment of lung cancer) 17.30 – 17.45 Razprava 8.00 – 9.00 Skupščina Sekcije za internistično onkologijo 9.00 – 13.20 Predstavitev primerov 9.00 – 10.00 Predstavitev bolnika z nevroendokrinim rakom Mentor: J. Ocvirk Predstavitev: M. Boc, B. Gregorič 10.00 – 11.00 Predstavitev bolnika s hepatocelularnim rakom Mentor: J. Ocvirk Predstavitev: T. Mesti, M. Ebert 11.00 – 11.20 ODMOR 11.20 – 12.20 Predstavitev bolnika z rakom neznanega izvora Mentor: B. Zakotnik Predstavitev: C. Kuhar-Grašič, A. Rusjan 12.20 – 13.20 Predstavitev primera bolnice z rakom dojke Mentor: T. Čufer Predstavitev: K. Vojakovič, M. Humar 13.20 Zaključek 1 TARGET TREATMENT OF MALIGNANT LYMPHOMAS Igor Aurer, MD, PhD Division of Hematology Department of Internal Medicine University Hospital Center and Medical School Zagreb, Croatia LYMPHOMAS • WHO classification of malignant neoplasms – Haematopoietic neoplasms • Lymphoid neoplasms – B-cell neoplasms – T/NK-cell neoplasms – Hodgkin’s lymphoma B-CELL NEOPLASMS • IMMATURE – B acute lymphoblastic leukemia / lymphoblastic lymphoma • PERIPHERAL – Chronic lymphocytic leukemia / small lymphocytic lymphoma – Lymphoplasmocytoid lymphoma / Waldenstroem’s macroglobulinaemia – Follicular lymphoma (grade 1-3) – Mantle-cell lymphoma – Marginal zone lymphoma (nodal, extranodal, splenic) – Large-cell (diffuse, mediastinal, intravascular, primary effusional) –B u r k i t t – Grey zone – Hairy-cell leukemia – Multiple myeloma 2 T- AND NK-CELL NEOPLASMS • IMMATURE – T lymphoblastic leukemia / lymphoblastic lymphoma • PERIPHERAL – (Adult T lymphocytic leukemia, NK leukemia,…) – Peripheral T/NK-cell lymphoma (not otherwise specified, enteropathy associated, angioimmunoblastic, nasal type, hepatosplenic,…) – Anaplastic large-cell (systemic, cutaneous) – Cutaneous T-cell lymphomas (Mycosis fungoides, Sezary syndrome,…) HODGKIN’S LYMPHOMA • Nodular lymphocyte predominant • Classical Hodgkin’s lymphoma – Diffuse lymphocyte predominant – Nodular sclerosis • Type I and II – Mixed cellularity – Lymphocyte depletion NHLs – CLINICAL CLASSIFICATION • INDOLENT – Long survival without treatment – Conventional chemotherapy is not curative – Anthracycline-based chemotherapy does not prolong survival – Repetitive remissions becoming ever shorter – Small cells – Mostly B-cell derived – Mostly correspond to low- grade NHLs • AGGRESSIVE – Short survival without treatment – Conventional anthracycline- based chemotherapy curative in a significant proportion of cases – Mostly large cells – B and T – Mostly correspond to intermediate and high-grade NHLs • VERY AGGRESSIVE – Very short survival without treatment – Very aggressive treatment 3 NHLs – CLINICAL CLASSIFICATION • INDOLENT – Chronic lymphocytic leukemia / small lymphocytic lymphoma – Lymphoplasmocytoid lymphoma – Follicular lymphoma – Marginal-zone lymphoma – (Hairy-cell leukemia) – Mycosis fungoides • AGGRESSIVE – B large-cell – Mantle-cell – Peripheral T/NK-cell – Anaplastic large-cell • VERY AGGRESSIVE –B u r k i t t – B/T acute lymphoblastic leukemia / lymphoblastic lymphoma NHLs - DISEASE COURSE (pre-rituximab era) The good ones 0 20 40 60 80 100 051 0 years % eMZ L FL ALCL The not so good ones 0 20 40 60 80 100 024681 0 years % SLL LPL nMZL The not so bad ones 0 20 40 60 80 100 024681 0 years % B-LCL Burkitt The bad ones 0 20 40 60 80 100 051 0 years % Mantle T-LBL PTCL The non-Hodgkin’s lymphoma classification project. Blood 1997. HODGKIN’S LYMPHOMA • Aggressive B-lymphoma with a good prognosis 4 TARGET TREATMENT OF LYMPHOMAS • Lymphomas are not a single disease • Different lymphomas – different biology, course and response to treatment therefore • Different lymphomas – different target treatment strategies EVIDENCE-BASED MEDICINE • A 1 Randomized controlled trials (Non-randomized trials with dramatic effect) • B 2 Cohort studies • B 3 Case-control studies • C 4 Case series • D 5 Expert opinion TARGET TREATMENT OF LYMPHOMAS Biological basis • Lymphomas are derived from lymphoid cells – Number of strong antigens evolutionary designed to be recognised by immunocompetent cells • Excellent targets for antibodies – Function of B cells can be substituted with ivIg – AIDS epidemic has taught physicians how to deal with T-cell deficient patients – B-cell differentiation has been molecularly dissected • Smart drugs affecting processes important for a specific step in B- cell differentiation 5 TARGET TREATMENT OF LYMPHOMAS drugs • Monoclonal antibodies – Unconjugated, conjugated (to radioactive isotopes or toxins) • Proteasome inhibitors – Bortezomib • Immunomodulators – Thalidomide, lenalidomide • HDAC inhibitors • Antiangiogenic drugs • M-TOR inhibitors, HSP inhibitors… MONOCLONAL ANTIBODIES RITUXIMAB • The big R Rituximab: a chimeric human/mice monoclonal antibody Murine variable regions bind specifically to CD20 on B- cells Human K constant regions Human IgG1 Fc domain works in synergy with human effector mechanisms 6 CD20 molecule • Transmembrane phosphoprotein • Single extracellular loop • Natural ligand unknown • Physiologic function uncertain • Present on most B-cell neoplasms • Resistant to internalization or shedding after antigen binding S Q I S Y C Y Q T S P S N K E S P N A P E C N Y I N I Y P T H A R I F N L S E M K L F H S I K Extracellular Cytoplasm Einfield et al. EMBO J 1988;7:711–7 EXPRESSION OF CD20 IN B-CELL NEOPLASMS 0 100 200 300 400 500 Burkitt’s lymphoma CLL CLL/PLL Follicular NHL Hairy cell leukemia B-LCL LP/Waldenström’s Mantle cell Marginal zone NHL NHL Maloney. Semin Hematol. 2000;37(4 suppl 7):17. Average fluorescence Interaction of rituximab with immunological mechanisms of the host Adapted from Male D, et al., Advanced Immunology 1996: 1.1–1.16 Malignant B-cell Complement Rituximab CD20 CD20 Rituximab Cytotoxic leukocyte 7 RITUXIMAB TOXICITY • Rare infusion reactions – Allergy to murine proteins – Cytokine-relase syndrome • Reduced IgM levels with prolonged use • Hematological toxicity negligible – Ideal for combining with chemotherapy ALEMTUZUMAB antiCD52 • First monoclonal antibody designed for treatment of hematological neoplasia – clinical development hindered by toxicity and incompetence of pharmaceutical industry • CD52 – Present on granulocytes, lymphocytes and most NHLs ALEMTUZUMAB TOXICITY • Severe and frequent infusion reactions – Do not occur with sc administration • Subacute skin reactions after sc administration • Hematological toxicity unpredictable – Occasionally severe granulocytopenia and/or thrombocytopenia in 1st week of treatment • Severe immunodeficiency – AIDS type: CMV, PCP, fungi etc. • Microbiological surveillance, preemptive treatment, early broad-spectrum antibiotic coverage 8 CONJUGATED ANTIBODIES Biological basis • Radioactive isotope or toxin bound to antibody • Antibody targets the tumor • Radioactivity or toxin increases tumor cell kill Anti-CD20 abs conjugated with radioactive isotopes • Ibritumomab with 90 Y (Zevalin) and tositumomab with 131 I (Bexxar) • Toxicity – Prolonged subacute hematological • Not adequate for – pts. with bone marrow infiltration > 25% – reduced bone marrow function 131 I Choice of isotope Properties 90 Yttrium 131 Iodine Half-life 64 hours 192 hours Energy emitter Beta (2.3 MeV) Gamma (0.36 MeV) Beta (0.6 MeV) Path length  90 5 mm  90 0.8 mm Urinary excretion Minimal 7% in 7 days Extensive/variable 46 - 90% in 2 days Dosing Based on weight and platelet count Clearance based dosing using whole body dosimetry Administration Outpatient Inpatient or restrictions to protect family/public 9 HDAC INHIBITORS • HDAC = histone deacetylase – Deacetylation necessary for transcription – Inhibitors inhibit gene transcription • Vorinostat – Toxicity • gastrointestinal, asthenia, hyperglycemia, hematological, respiratory DRUGS REGISTERED FOR MM, USEFUL IN NHL • BORTEZOMIB • Proteasome inhibitor • Intravenous application 4x/3wks. • Toxicity – neuropathy, trombocytopenia, nausea & vomiting, diarrhea… • THALIDOMIDE, LENALIDOMIDE • Mode of action unknown – Immunomodulator, antiangiogenic agent,… • Continuous oral application • Toxicity thalidomide – Neuropathy, DVT, sedation, constipation • Toxicity lenalidomide – Hematological, DVT DLBCL • Front-line treatment – chemotherapy + rituximab • ↑ OS by 15%, PFS and RR by 20% • recommendation grade A • Salvage, R-naive pts. – chemotherapy + rituximab • ↑ RR and PFS by 20%, OS not significant (later treatment?) • recommendation grade A • Salvage, R-pretreated patients – chemotherapy + rituximab • everybody does it but no data • recommendation grade D • Possible indications – Zevalin or Bexxar + BEAM for pretransplant conditioning – Zevalin or Bexxar for salvage treatment – RR 20-50%, TTP 6 mo. 10 •B u r k i t t – Chemotherapy + rituximab • ↑ OS by > 20% • recommendation grade B • Mantle-cell lymphoma – Front-line and salvage in R-naive pts. – Chemotherapy + rituximab • ↑ PFS, OS not significant (later treatment?) • recommendation grade A – Rituximab maintenance • recommendation grade C – Zevalin / Bexxar not very effective • MRD treatment – recommendation grade C – Relapsed / refractory • Bortezomib RR 35%, some responses long-lasting • Thalidomide and lenalidomide RR 50% INDOLENT NHLs •F L – Rituximab monotherapy • Effective, non-toxic alternative to chemotherapy – Rituximab + chemotherapy • ↑ OS 2,5%/year for at least 4 years • recommendation grade A – Zevalin / Bexxar for remission consolidation in R- naive pts. ↑ PFS , OS too early • recommendation grade A • Effect in pts. receiving R+chemo smaller – Zevalin/Bexxar for R+chemo resistant pts. • RR 50%, some responses long-lasting • recommendation grade B • Indolent non-FL – As FL but less evidence MYCOSIS FUNGOIDES / SEZARY • Vorinostat – HDAC inhibitor – RR 50%, toxicity gastrointestinal • Denileukin diftitox – Recombinant protein hybrid of IL-2 and diphteria toxin – RR 35%, toxicity systemic + immunosuppression • Alemtuzumab (anti CD52) – RR 55%, severe cellular immunosuppression • Bexaroten – Retinoid (differentiating agent) – RR 48% TTP 10 mo, hyperlipidemia 11 DRUGS IN TRIALS • Lenalidomide – Maintenance and induction combinations with chemotherapy in indolent and mantle-cell NHL, possibly other B-NHLs •B o r t e z o m i b – Induction treatment in MCL, possibly T-NHL • Anti-CD80 – Combination with rituximab or chemotherapy in B-NHL and HL • Increased potency anti-CD20 – Indolent NHLs failing R, CLL • Zevalin – Remission consolidation in DLBCL • Alemtuzumab – Combination with chemotherapy for T-NHL DRUGS IN TRIALS • HDAC inhibitors – HL and T-NHL • M-TOR inhibitors – Everolimus, tensirolimus – In combination for induction, monotherapy for maintentenance – Indolent NHL, MCL,.. • Bevacizumab – + chemotherapy for induction of DLBCL • Enzastaurin (PKC inhibitor) – Maintenance in B-NHLs • Anti-CD22 + ozogamycin – Indolent NHL, induction DISAPPOINTMENTS • Anti-CD30s • Epratuzumab • FTIs (farnesyl- transferase inhibitors) •… 12 TARGET TREATMENT OF LYMPHOMAS CONCLUSIONS • Rituximab – Revolution in the treatment of B-NHL • Radioimmunotherapy – Here to stay – Probably better for consolidating remissions than as monotherapy • Bortezomib, thalidomide, lenalidomide – Useful for relapsed/refractory MCL • Other drugs – We’ll see whether they’ll live up to the expectations 1 Target treatment of lung cancer Dott. Marcello Tiseo Oncologia Medica Azienda Ospedaliero-Universitaria di Parma Therapeutic paradigms and background in advanced NSCLC • Cytotoxic chemotherapy improves survival in the 1 st and 2 nd line setting •I n 1 st line, 2 drugs (platinum + third generation agent) are better than 1 •I n 2 nd line, docetaxel or pemetrexed are CT registered • Targets of chemotherapy are largely DNA, tubulin and topoisomerases; consequences of inhibiting these targets are broad • Lung cancer is molecularly very complex • The heterogeneity of lung cancer provides opportunity for both one drug/one target as well as one drug/multiple targets Efficacy plateau of cytotoxic chemotherapy in NSCLC Efficacy plateau of cytotoxic chemotherapy in NSCLC Study Drugs # Pts %, St. IV %, ORR MST %, 1-YS Kelly, 2001 SWOG 9503 Vnr/Cis Tax225/Cb 202 208 88 89 28 25 8 8 33 36 Schiller , 2002 ECOG 1594 Tax135/Cis Gem/Cis Txt/Cis Tax225/Cb 292 288 293 290 89 86 86 86 21.3 21 17.3 15.3 8.1 8.1 7.4 8.3 31 36 31 35 Scagliotti, 2002 ILCP Vnr/Cis Gem/Cis Tax225/Cb 201 205 201 81 81 82 30 30 32 9.5 9.8 9.9 37 37 43 Belani, 2002 TAX 326 Vnr/Cis Txt/Cis TxT/Cb 404 408 402 67 67 67 25 32 24 10.1 11.3 9.4 41 46 38 2 How to improve results? How to improve results? • New cytotoxics • Personalized chemotherapy according to the patient’s genetic make-up • Molecular targeted therapies • Drugs to treat biologically homogenous cancer patient population • Tumor specific molecular abnormality • Tumor specific molecular profile • Expression of a specific receptor or antigen • New cytotoxics • Personalized chemotherapy according to the patient’s genetic make-up • Molecular targeted therapies • Drugs to treat biologically homogenous cancer patient population • Tumor specific molecular abnormality • Tumor specific molecular profile • Expression of a specific receptor or antigen Where have the successes been thus far in advanced NSCLC? Recent advances in advanced NSCLC • ECOG 4599 and AVAiL trials – Bevacizumab added to chemotherapy improves clinical outcomes • FLEX trial – Cetuximab added to chemotherapy improves clinical outcomes • BR21 trial – Erlotinib improves clinical outcomes versus placebo in refractory, advanced NSCLC • INTEREST trial – Gefitinib is not inferior to docetaxel in refractory, advanced NSCLC 3 Phase III Trial of Bevacizumab in Non-Squamous NSCLC: ECOG 4599 (PC) Paclitaxel 200 mg/m 2 Carboplatin AUC = 6 (q 3 weeks) x 6 cycles (PCB) PC x 6 cycles + Bevacizumab (15mg/kg q 3 wks) to PD Eligibility: • Non-squamous NSCLC • No Hx of hemoptysis • No CNS metastases No crossover to Bevacizumab permitted Stratification Variables: •R T vs no RT • Stage IIIB or IV vs recurrent • Wt loss < 5% vs > 5% • Measurable vs non-measurable Sandler et al. NEJM 2006 Phase III Trial of Bevacizumab in Non-Squamous NSCLC: AVAiL trial • Cisplatin 80mg/m 2 i.v. every 3 weeks; gemcitabine 1,250mg/m 2 on days 1 and 8 of each 3-week cycle • Primary endpoint: progression-free survival • Secondary endpoint: overall survival and response rate Previously untreated, stage IIIB, IV or recurrent NSCLC (n = 1,150) PD PD CG x 6 + placebo CG x 6 + bevacizumab 7.5mg/kg Q 3 weeks CG x 6 + bevacizumab 15mg/kg Q 3 weeks No bevacizumab after progression PD Manegold et al. ASCO 2007 Manegold et al. ESMO 2008 Overall response rates have increased significantly with Bevacizumab Overall response rate (%) E4599 Avastin 15mg/kg + CP (n=381) CP (n=392) p<0.001 40 30 20 10 0 15% 35% Avastin 7.5mg/kg + CG (n=323) Avastin 15mg/kg + CG (n=332) Placebo + CG (n=324) AVA i L p=0.0023 p<0.0001 40 30 20 10 0 20% 30% 34% Overall response rate (%) CP = carboplatin/paclitaxel; CG = cisplatin/gemcitabine Sandler et al. NEJM 2006 Manegold et al. ASCO 2007 4 Bevacizumab-based therapy significantly improves PFS Time (months) 0 6 12 18 24 30 4.5 6.2 1.0 0.8 0.6 0.4 0.2 0 Probability of PFS Avastin 15mg/kg + CP HR = 0.66 (0.57–0.77); p < 0.001 CP 1.0 0.8 0.6 0.4 0.2 0 Time (months) 0 3 6 9 12 15 18 Avastin 15mg/kg + CG HR = 0.82 (0.68–0.98); p = 0.0301 Avastin 7.5mg/kg + CG HR = 0.75 (0.62–0.91); p = 0.0026 Placebo + CG E4599 AVA i L Probability of PFS Sandler et al. NEJM 2006 Manegold et al. ASCO 2007 CP = carboplatin/paclitaxel CG = cisplatin/gemcitabine; HR = hazard ratio 6.1 6.7 6.5 + 51 days + 18 days 0 6 12 18 24 30 36 42 48 1.0 0.8 0.6 0.4 0.2 0 Months Survival estimate Bevacizumab-based therapy significantly improves OS Sandler et al. NEJM 2006 CP Bevacizumab 15mg/kg + CP HR (95% CI) 0.79 (0.67–0.92) p value <0.003 Median OS (months) 10.3 12.3 Median follow-up: 19 months Bevacizumab in advanced NSCLC Study Regimen N° pts ORR % PFS, months MST, months ECOG 4599 CbT + Placebo CbT + Bev 15 444 434 15 35 p =.001 4.5 6.2 HR =.66 10.3 12.3 HR =.79 p =.003 AVAiL CG + Placebo CG + Bev 7.5 CG + Bev 15 347 345 351 20 34 p =.0001 30 p =.0017 6.1 6.7 HR =.75 6.5 HR =.82 13.1 13.6 HR =.93 13.4 HR =1.03 Sandler et al. NEJM 2006 Manegold et al. ASCO 2007 and ESMO 2008 5 Median survival (months) BSC 2–4 months Cis- based regimens 6–8 months P-based doublets 3rd gener 8–10 months 1970s 1980s 1990–2005 2006 Bevacizumab plus Carbo/Pac (from FDA) or any P-based CTx (from EMEA, 24 Aug 2007) received approvals as 1st-line therapy 2006/2007 G Giaccone, WCLC 2007 0 12 10 8 6 4 2 BEVA + P-based doublet > 12 months 1 ST -line therapy in advanced NSCLC: significant milestones Patient selection for bevacizumab therapy Inclusion Exclusion Non-squamous NSCLC Grade  2 haemoptysis Chemo-naïve Radiological evidence of tumour invasion of major blood vessels Inoperable stage IIIB-IV or recurrent Brain metastases or spinal cord compression ECOG PS of 0-1 Uncontrolled hypertension History of thrombotic or haemorrhagic disorders Therapeutic anticoagulation within 10 days of first dose Sandler et al. NEJM 2006 Manegold et al. ASCO 2007 Sandler et al. NEJM 2006 Manegold et al. ASCO 2007 Severe (grade  3) haematologic toxicity in ECOG and AVAiL trials Placebo + PC n = 440 Bevacizumab 15 mg/kg + PC n = 437 p Neutropenia Thrombocytopenia Anemia 16.8 0.2 0.9 25.5 1.6 0 < 0.002 < 0.04 ns Placebo + CG n = 327 Bevacizumab 7.5 mg/kg + CG n = 330 Bevacizumab 15 mg/kg + CG n = 329 Neutropenia 32 40 36 Thrombocytopenia 23 27 23 Anemia 14 10 10 6 13 (3.1) 0 Proteinuria <.003 13 (3.0) 2 (0.5) Headache 6 (1.4)° 2 (0.4)^ GI 5 (1.1) 1 (0.2) Other <.001 30 (7.0) 3 (0.7) Hypertension 3 (0.7) 0 CNS 8 (1.9)* 1 (0.2) Hemoptysis <.001 19 (4.4) 3 (0.7) Bleeding events p value PCB (%) # 437 PC (%) # 440 Toxicity (grade 3-4) including * 5 deaths, ^1 death, °2 deaths <.001 Sandler et al. NEJM 2006 ECOG 4599: severe (grade  3) non- haematological toxicity AVAiL trial: severe (grade  3) non- haematological toxicity Placebo + CG n = 327 Bevacizumab 7.5mg/kg + CG n = 330 Bevacizumab 15mg/kg + CG n = 329 Bleeding 2% 4% 4% Hypertension 2% 6% 9% Proteinuria – 0.3% 1% Ischaemic events 5% 2% 3% Venous thromb. events 6% 7% 7% Manegold et al. ASCO 2007 AVAiL trial: Pulmonary haemorrhage events • 38% of patients had central lesions, 4/10 patients with severe pulmonary haemorrhage had central lesions • 9% of patients had therapeutic anticoagulation, but none of them had a severe pulmonary haemorrhage Placebo + CG n = 327 Bevacizum ab 7.5mg/kg + CG n = 330 Bevacizumab 15mg/kg + CG n = 329 Pulmonary haemorrhage (all grades) 17 (4.9%) 23 (7.0%) 32 (9.7%) Pulmonary haemorrhage (Gr  3) 2 (0.6%) 5 (1.5%) 3 (0.9%) Fatal pulmonary haemorrhage 1 (0.3%) 4 (1.2%) 3 (0.9%) Manegold et al. ASCO 2007 7 Elderly analysis of ECOG trial • 224 patients aged ≥ 70 years in E4599 • No improvement in survival with PCB vs PC: – PFS: 5.9 m vs. 4.9 m; p = .063 – OS: 12.1 m vs. 11.3 m; p = .4 • More Grade 3/4 toxicity in elderly patients on PCB arm: Ramalingam et al. J Clin Oncol 2008 ≥ 70 y < 70 y p value Neutropenia (G4) 34% 22% .02 Melena/GI bleed 3.5% 1% .005 Muscle weakness 8% 2% .02 Motor neuropathy 3.5% < 1% .05 Tx-related deaths 6% 3% .08 in first-line treatment: conclusions • Two large trials: • One ECOG 4599 with a control arm doing poor, showed and improved RR, PFS and survival • One with a very good control arm showed an improved RR, not clinically meaningful PFS and no benefit on survival • Both with increased risk of toxicity and an increase in cost • On selected patients exploring therapeutic options now and in the future Combination with chemotherapy Adjuvant Combination with erlotinib Neoadjuvant 2005 2006 2007 2008 2009 2010 2011 INNOVATIONS ATLAS TASK BeTa Lung SAiL PASSPORT BRIDGE ABIGAIL E1505 BEACON 8 Recent advances in advanced NSCLC • ECOG 4599 and AVAiL trials – Bevacizumab added to chemotherapy improves clinical outcomes • FLEX trial – Cetuximab added to chemotherapy improves clinical outcomes • BR21 trial – Erlotinib improves clinical outcomes versus placebo in refractory, advanced NSCLC • INTEREST trial – Gefitinib is not inferior to docetaxel in refractory, advanced NSCLC 9 Flex Study: Results • 67% of screened pts (85% EGFR+) eligible • RR: 29 vs 36% (p = 0.012) • PFS: 4.8 vs 4.8 months • TTF: 3.7 vs 4.2 months (p = 0.015) • MS: 10.1 vs 11.3 months • 1-Year survival: 42 vs 47% (HR 0.87, p = 0.044) • Results unaffected by histology • Limited benefit in Asiatics 10 FLEX regimen: Pro and Contra PRO CONTRA Efficacy ● CT regimen ● Toxicity ● Histology ● Patients selection ● Costs ● Phase III Trial of Taxane/Cb ± Cetuximab: BMS-099 Study Design Lynch et al. WCLC 2007 R N = 676 1 st line treatment for advanced NSCLC Primary endpoint: PFS (by IRRC) Secondary endpoints: RR, OS, QOL, Safety Paclitaxel 225 mg/m 2 d1 or Taxotere 75 mg/m 2 d1 + Carboplatin AUC = 6 d1 Q3wk for a maximum of 6 cycles + Cetuximab 400 mg/m 2 d1 wk1; 250 mg/m 2 Paclitaxel 225 mg/m 2 d1 or Taxotere 75 mg/m 2 d1 + Carboplatin AUC = 6 d1 Q3wk for a maximum of 6 cycles Stratification • Site • PS • Taxane IRRC = Independent Review Radiologists Committee Phase III Trial of Taxane/Cb ± Cetuximab: PFS per IRRC MONTHS 0.0 0.2 0.4 0.6 0.8 1.0 0481 21 62 02 4 4.24 mo 4.40 mo Cetuximab + Taxane/Carbo (284 events) Taxane/Carbo (263 events) HR = 0.902 95% CI = 0.761 – 1.069 Stratified log-rank p value = .2358 4.40 mo 4.24 mo IRRC = Independent Review Radiologists Committee Lynch et al. WCLC 2007 11 BMS-099: PFS in Pre-Planned Subsets Subset n Favors cetux combination Favors control arm ECOG PS 0 ECOG PS 1 Paclitaxel Ta x o t e r e Age <65 Age ≥65 Male Female Liver metastases No liver metastases ≥ 4 disease sites < 4 disease sites 214 441 339 337 336 340 396 280 112 557 83 586 HR (95% CI) 0.5 1.0 2.0             IRRC = Independent Review Radiologists Committee Lynch et al. WCLC 2007 Contribution of cetuximab in first-line treatment: conclusions • Two large trials: • FLEX trial, with a not very standard CT arm, showed an improvement in RR and survival (not in PFS) • In BMS-099 difference in PFS and OS did not reach statistical significance (greater PFS improvements in patients on Taxotere) • Survival benefit: same magnitude (1,2-1,3 months) in two trials (but BMS-099 lower power then FLEX trial) • Both with increased risk of toxicity and an increase in cost • Not histology selection, but EGFR IHC + patients (?) . Survival summary in phase III trials with bevacizumab and cetuximab Treatment EXPER. ARM (MS – mos) CONTROL ARM (MS – mos) p value ECOG 4599 (bevacizumab) NEJM 2006 12.3 10.3 0.003 AVAiL (bevacizumab) ESMO 2008 13.6 13.1 NS FLEX (cetuximab) ASCO 2008 11.3 12* 10.1 10.3* 0.044 BMS 099 (Taxane-Cetux) press release 9.7 8.4 NS * Only non-squamous 12 Hirsch et al. J Clin Oncol 2008 Phase II study of cetuximab with cisplatin-docetaxel in the first-line treatment of biologically selected patients with advanced NSCLC: GOIRC trial • NSCLC, stage IIIB-IV, PS 0-1 • availability of tissue specimen for EGFR FISH determination Cetuximab 400 mg/m 2 at the 1st infusion, subsequently 250 mg/m 2 weekly and Cisplatin 75 mg/m 2 and Docetaxel 75 mg/m 2 i.v. on day 1 of a 21 days cycle The primary end-point is RR; this is non-randomized phase II study in which all patients will be accrued and treated with cetuximab-cisplatin- docetaxel and the activity in terms of response rate compared between those with positive biological features (EGFR FISH +,4 0 %o ft h eo v e r a l l population) versus those with negative ones (EGFR FISH -) Recent advances in advanced NSCLC • ECOG 4599 and AVAiL trials – Bevacizumab added to chemotherapy improves clinical outcomes • FLEX trial – Cetuximab added to chemotherapy improves clinical outcomes • BR21 trial – Erlotinib improves clinical outcomes versus placebo in refractory, advanced NSCLC • INTEREST trial – Gefitinib is not inferior to docetaxel in refractory, advanced NSCLC 13 BR.21: Erlotinib versus placebo Overall Survival and PFS Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Survival Time (Months) 0 5 10 15 20 25 30 HR * = 0.70, p < 0.001 Erlotinib Median = 6.7 mo (n=488) Placebo Median = 4.7 mo (n=243) 1-yr Survival = 31% 1-yr Survival = 22% * HR and p-value adjusted for stratification factors at randomization + EGFR status Overall Survival, All Patients Progression-Free Survival, All Patients Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 PFS Time (Weeks) 0 20 40 60 80 100 120 HR * = 0.61, p < 0.001 Erlotinib Median = 2.2 mo (n=488) Placebo Median = 1.8 mo (n=243) * HR and p-value adjusted for stratification factors at randomization + EGFR status Shepherd et al. NEJM 2005 Erlotinib and Gefitinib: BR21 and ISEL trials Shepherd et al. NEJM 2005, Thatcher et al. Lancet 2005 BR21: survival benefit with Erlotinib across all subgroups Shepherd et al. NEJM 2005 14 BR21: survival benefit with Erlotinib across all biological subgroups Tsao et al. NEJM 2005 Prospective trials of EGFR-TKIs in patients with EGFR mutations Author Agent RR (%) PFS OS/1-yr Pas-Ares Erlotinib 31/38 (82) 13.3 NR/81 Morikawa Gefitinib 13/20 (65) 9.7 NR Sunaga Gefitinib 16/21 (77) 13 NR Sutani Gefitinib 21/27 (77) 9.4 15.4/NR Inoue Gefitinib 12/16 (75) 9.7 NR Asahina Gefitinib 12/16 (75) 8.9 NR Sequist Gefitinib 17/31 (55) 11.4 20.8/73 122/169 (72) IPASS: Study Design Gefitinib (250 mg / day) Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # 1:1 randomisation *Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years; # limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression PS, performance status; EGFR, epidermal growth factor receptor Patients • Chemonaïve • Age ≥18 years • Adenocarcinoma histology • Never or light ex- smokers* • Life expectancy ≥12 weeks • PS 0-2 • Measurable stage IIIB / IV disease Primary • Progression-free survival (non-inferiority) Secondary • Objective response rate • Overall survival • Quality of life • Disease-related symptoms • Safety and tolerability Exploratory • Biomarkers • EGFR mutation • EGFR-gene-copy number • EGFR protein expression • Endpoints ESMO 2008 15 IPASS: Results HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001 Gefitinib demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS 609 453 (74.4%) 608 497 (81.7%) N Events Gefitinib Carboplatin / paclitaxel Gefitinib had a more favourable tolerability profile than carboplatin / paclitaxel QoL improvement rate was significantly greater with gefitinib than carboplatin / paclitaxel ESMO 2008 Progression-free Survival in ITT Population 609 453 (74.4%) 608 497 (81.7%) N Events HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001 Gefitinib Gefitinib demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS Primary Cox analysis with covariates HR <1 implies a lower risk of progression on gefitinib Carboplatin / paclitaxel Carboplatin / paclitaxel Gefitinib Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free 5.7 61% 48% 25% 5.8 74% 48% 7% 609 212 76 24 5 0 608 118 22 3 1 0 363 412 0 4 8 12 16 20 24 Months 0.0 0.2 0.4 0.6 0.8 1.0 Probability of PFS At risk : ESMO 2008 Progression-free Survival in EGFR Mutation Positive and Negative Patients EGFR mutation positive EGFR mutation negative Treatment by subgroup interaction test, p<0.0001 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%) Gefitinib (n=132) Carboplatin / paclitaxel (n=129) ITT population Cox analysis with covariates HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib , 88 (96.7%) No. events C / P, 70 (82.4%) 132 71 31 11 3 0 129 37 7 2 1 0 108 103 0 4 8 12 16 20 24 Gefitinib C / P 0.0 0.2 0.4 0.6 0.8 1.0 Probability of progression-free survival At risk : 91 4 2100 85 14 1 0 0 0 21 58 0481 21 62 02 4 0.0 0.2 0.4 0.6 0.8 1.0 Probability of progression-free survival Gefitinib (n=91) Carboplatin / paclitaxel (n=85) Months Months ESMO 2008 16 Recent advances in advanced NSCLC • ECOG 4599 and AVAiL trials – Bevacizumab added to chemotherapy improves clinical outcomes • FLEX trial – Cetuximab added to chemotherapy improves clinical outcomes • BR21 trial – Erlotinib improves clinical outcomes versus placebo in refractory, advanced NSCLC • INTEREST trial – Gefitinib is not inferior to docetaxel in refractory, advanced NSCLC Gefitinib 250 mg / day Docetaxel 75 mg / m 2 every 3 weeks 1:1 randomisation INTEREST study design a Modified Hochberg procedure applied to control for multiple testing CT, chemotherapy; PS, performance status Patients  Age ≥18 years  Life expectancy ≥ 8 weeks  Progressive or recurrent disease following CT  Considered candidates for further CT with docetaxel  1 or 2 CT regimens (≥1 platinum)  PS 0-2 Primary  Overall survival (co-primary analyses a of non-inferiority in all patients and superiority in patients with high EGFR-gene-copy number) Secondary  Progression-free survival  Objective response rate  Quality of life  Disease-related symptoms  Safety and tolerability Exploratory  Biomarkers Endpoints Douillard et al, WCLC 2007 INTEREST study: Overall survival NI, non-inferiority; HR, hazard ratio; OS, overall survival Per-protocol (PP) population Pre-specified NI limit in HR terms (translates to 50% effect retention [Rothmann 2003]) = 1.154 723 593 (82.0%) 710 576 (81.1%) N Events Primary Cox analysis without covariates HR (96% CI) = 1.020 (0.905, 1.150) Median OS (months) 1-year survival 7.6 32% 8.0 34% Gefitinib Docetaxel Conclude non-inferiority in the overall PP population 723 336 225 131 83 50 31 14 0 0 710 339 228 139 89 46 24 7 0 0 518 503 0481 21 62 02 42 83 23 64 0 0.0 0.2 0.4 0.6 0.8 1.0 Months Probability of survival At risk : Gefitinib Docetaxel Douillard et al, WCLC 2007 17 9,1 7,6 0 5 10 15 Gefitinib Docetaxel INTEREST study: objective tumour response OR (95% CI) = 1.22 (0.82, 1.84) p=0.3257 Patients (%) (n=659)( n=657) Evaluable for response (EFR) population OR >1 implies a greater chance of response on gefitinib OR and p-value from logistic regression with covariates OR, odds ratio; CI, confidence interval Douillard et al, WCLC 2007 At risk : Gefitinib 659 77 34 18 9 5 3 0 0 0 Docetaxel 657 42 16 4 2 1 0 0 0 0 194 208 Probability of PFS 0481 21 62 02 42 83 23 64 0 0.0 0.2 0.4 0.6 0.8 1.0 Months INTEREST study: Progression-free survival Evaluable for response (EFR) population; HR <1 implies a lower risk of progression on gefitinib; PFS, progression-free survival HR (95% CI) = 1.04 (0.93, 1.18), p=0.4658 N Events Cox analysis with covariates Median PFS (months) 4 months 6 months 659 593 (90.0%) 657 544 (82.8%) 2.2 32% 19% 2.7 38% 18% Gefitinib Docetaxel Douillard et al, WCLC 2007 Most common AEs (≥ 10% on either treatment) with ≥ 3% difference between treatments 0 20 40 60 80 # Worsening in lab value from baseline * Grouped term (sum of several preferred terms) Gefitinib (N=729) Docetaxel (N=715) Douillard et al, WCLC 2007 18 Quality of life and symptom improvement rates 25,1 17,3 20,4 14,7 10,3 16,8 0 5 10 15 20 25 30 35 Total FACT-L TOI LCS p<0.0001 p=0.0026 p=0.1329 % patients with sustained clinically relevant improvement Gefitinib (N=490) Docetaxel (N=476) Evaluable for quality of life population p-values from logistic regression with covariates. Clinically relevant improvement pre-defined as 6-point improvement for FACT-L and TOI; 2-point improvement for LCS, maintained for at least 21 days EFQ, evaluable for quality of life; FACT-L, Functional Assessment of Cancer Therapy-Lung; TOI, Trial Outcome Index; LCS, Lung Cancer Subscale Douillard et al, WCLC 2007 Overall survival by clinical subgroups all p>0.05 Treatment-by-subgroup interaction test p-value all p>0.05 p=0.0311 for prior regimens Overall Adenocarcinoma Non-adenocarcinoma PS 0 or 1 PS 2 Prior paclitaxel - refractory Prior paclitaxel - received Prior paclitaxel - none 1 prior regimen 2 prior regimens Male Female Asian Non-Asian Aged <65 Aged 65+ Diag to random <6 months Diag to random 6-12 months Diag to random >12 months Best response to prior CT = CR / PR Best response to prior CT = SD Best response to prior CT = PD Best response to prior CT = unknown Prior platinum - refractory Prior platinum - received Ever smoked Never smoked 0.5 1.0 1.5 2.0 HR (gefitinib vs docetaxel) and 95% CI Overall PP population. Cox analysis without covariates Favours gefitinib Favours docetaxel Douillard et al, WCLC 2007 Overall survival by biomarker subgroup 0.5 1.0 1.5 2.0 HR (gefitinib vs docetaxel) and 95% CI Overall High EGFR-gene-copy number Low EGFR-gene-copy number EGFR protein expression positive EGFR protein expression negative EGFR mutation positive EGFR mutation negative K-RAS mutation positive K-RAS mutation negative 0 Favours gefitinib Favours docetaxel ITT population; Cox analysis without covariates (N=1466) (N=174) (N=200) (N=96) (N=44) (N=253) (N=49) (N=226) (N=284) p=0.5163 p=0.8713 Treatment-by-subgroup interaction test p-values p=0.5885 p=0.5120 Douillard et al, ASCO 2008 19 Progression-free survival by biomarkers 0.5 1.0 2.0 2.5 HR (gefitinib vs docetaxel) and 95% CI Overall High EGFR-gene-copy number Low EGFR-gene-copy number EGFR protein expression positive EGFR protein expression negative EGFR mutation positive EGFR mutation negative K-RAS mutation positive K-RAS mutation negative 0 Favours gefitinib Favours docetaxel 1.5 N=1316 N=158 N=179 N=87 N=38 N=229 N=47 N=203 N=258 Douillard et al, ASCO 2008 Objective response rate by treatment and biomarker status 13 7,5 9 15,8 42,1 6,6 0 9,6 7,4 10,1 11 9,8 3,7 6,1 21,1 11,9 0 10 20 30 40 50 Gefitinib Docetaxel p-values from logistic regression with covariates; NC, not calculated EGFR-gene-copy number 77 81 80 99 EGFR protein expression 122 136 38 49 EGFR mutation 19 19 106 123 20 27 109 N = p=0.0361 p=0.3720 p=0.2741 p=0.6560 p=0.2688 p=0.0387 p=NC p=0.6292 ORR (%) Positive Negative High Low Positive Negative K-RAS mutation Positive Negative 94 Douillard et al, ASCO 2008 Exploratory biomarkers summary • Consistent with the overall result, OS was similar for gefitinib and docetaxel irrespective of EGFR gene-copy number, EGFR protein expression or EGFR mutation or K-RAS mutation status • on both treatments, patients with EGFR mutations lived longer than those without • PFS was similar for both treatments in all biomarker subgroups apart from patients with EGFR mutations, where PFS was longer for gefitinib than docetaxel • No differences in ORR between treatments were seen in biomarker subgroups apart from high EGFR gene-copy number and EGFR mutations, where ORR was higher for gefitinib than docetaxel • These findings should be interpreted in the context of exploratory analyses often based on small numbers and the tests performed on archival diagnostic tumour tissue Douillard et al, ASCO 2008 20 Gefitinib versus chemotherapy Stinchcombe and Socinski, The Oncologist 2008 One Drug/One Target • Paradigm validated with ECOG 4599, AVAiL, FLEX and BR.21 • If target is dominant, this strategy can be successful with or without cytotoxic chemotherapy • Likely to be less toxic • The biologic phenomenon of EGFR activating mutations creates a model for success for the one drug/one target approach Randomized Trials with CT+/- Targeted Therapies in treatment-naïve NSCLC: recent failures TARGET AGENT CT OUTCOME EGFR gefitinib PC/CisG No benefit erlotinib PC/CisG No benefit MMP’s AG3340 PC No benefit BMS275291 PC No benefit FT (ras) lonafarnib PC No benefit PKC  ISIS 3521 PC No benefit RXR Bexarotene PC/CisN No benefit 21 377 300 83 34 CPP 462 1 5 13 157 426 354 268 86 47 CPS 464 1 7 16 155 406 ESCAPE: CbP + Sorafenib Overall Survival (ITT Population) HR = 1.16 95% CI: 0.95, 1.43 P = 0.930 Survival Probability 0.25 0.50 0.75 1.00 CPS Median: 10.7 months 95% CI: 9.3, 13.9 CPP Median: 10.6 months 95% CI: 9.7, 12.0 Months 21 01 8 2 0 0 0 Patients at Risk 41 2 61 4 81 6 Scagliotti et al, ESMO IASLC 2008 Sunitinib and Vandetinib: A Model for One Drug/Multiple Targets • Both are multi-targeted RTK inhibitors • Active in a number of solid tumors • Sunitinib: approved for use in renal cell carcinoma and imatinib-refractory GIST • Vandetinib and Sunitinib currently in Phase III testing in NSCLC • Both have tolerable toxicity profiles • Inhibition of which targets account for the activity (and for that matter the toxicity) of these agents? Conclusions • Cytotoxic chemotherapy is targeted therapy but is non-specific relative to our thinking of new agents targeting specific receptor pathways • The One Drug/One Target strategy is effective in combination with cytotoxic chemotherapy (ECOG 4599, AVAiL and FLEX trials) • The One Drug/One Target strategy is also effective as a single agent (BR.21 and INTEREST trials) • The One Drug/Multiple Target strategy may be a more effective strategy when using targeted therapies alone (ongoing clinical trials) 22 True or Not? Avoid bevacizumab in patients with: • Cardiac disease • Hypertension • CNS lesions • Coagulopathy (on anticoagulation) • Peritoneal metastases • Recent surgery • “Central” or “large” chest lesions Safety of bevacizumab treatment in patients receiving full-dose anticoagulation (FDAC) • Patients receiving FDAC for prophylactic purposes are eligible for bevacizumab therapy • In the AVAiL trial, no grade ≥ 3 pulmonary haemorrhage events were reported in patients receiving FDAC Patients receiving FDAC (n=86) Non-anticoagulated patients (n=900) Pulmonary haemorrhage Placebo + CG (n=28) Bev 15* + CG (n=26) Bev 7.5* + CG (n=32) Placebo + CG (n=299) Bev 15* + CG (n=303) Bev 7.5* + CG (n=298) All grades (%) 10.7 19.2 6.3 4.7 8.9 7.0 Grade ≥ 3 (%) 0 0 0 0.7 1.0 1.7 Leighl et al. Eur J Cancer Suppl 2007 *mg/kg Appropriate patient selection for bevacizumab therapy: central tumour • Patients with centrally located tumours are eligible for bevacizumab therapy • Such patients can be successfully treated with bevacizumab October 2007 Before bevacizumab December 2007 During bevacizumab Scans courtesy of Dr Martin Reck 23 Bevacizumab in advanced NSCLC: Efficacy by Gender in ECOG trial Brahmer et al. J Clin Oncol 2006 Parameter Males Females PC (n=230) PCB (n=191) PC (n=162) PCB (n=190) OS, mo 8.7 11.7* 13.1 13.3 PFS, mo 4.3 6.3* 5.3 6.2* RR, % 16 29* 14 41* • No survival benefit for females despite 4-fold increase in RR and statistically significant difference for PFS • A number of potential explanations (statistical chance, imbalance of unmeasured prognostic factors or a true difference) *Statistically significant Biomarker status in patients with evaluable samples 53% 47% High Low 25% 75% Positive Negative EGFR-gene-copy number EGFR protein expression 85% 15% Positive Wild-type 18% 82% Positive Wild-type EGFR mutation K-RAS mutation Evaluable patients N=374 Evaluable patients N=297 Evaluable patients N=380 Evaluable patients N=275 Douillard et al, ASCO 2008 1 NEVROENDOKRINI GASTROENTEROPANKREATIČNI TUMORJI (GPNET) Predstavitev kliničnih primerov Marko Boc, dr.med. Brigita Gregorič, dr.med. Mentor: dr. Janja Ocvirk, dr.med. Lokalizacija primarnega tumorja: • zgornji GIT: želodec, duodenum, pankreas • srednji GIT: jejunum, ileum (23-28%), apendiks, desni hemikolon • spodnji GIT: levi hemikolon, rektum; GPNET heterogena skupina tumorjev • groba incidenca v Evropi 3/100.000 • najpogosteje po 50. letu, razen nevroendokrini tumorji apendiksa, ki največkrat nastanejo okoli 30. leta • bolniki z genetsko predispozicijo za GPNET pričnejo obolevati povprečno 15 let prej kot ljudje s sporadičnim GPNET • MEN-1 (multipla endokrina neoplazija) – mutacija tumor supresorskega gena na 11q k.=>AD dedovanje – prevalenca 2/100.000 – pogostejši predvsem PNET: 45% somatostatinomov, 25-40% gastrinomov, 15% GFRomov in 10% glukagenomov • vHL (von Hippel-Lindau) – prevalenca 1/30-40.000 – mutacija tumor supresorskega gena na 3p k.=>AD dedovanje – za PNET oboli 12-17 % bolnikov • NF-1 (nevrofibromatoza tip 1) – prevalenca 1/3-4.000 – mutacije tumor supresorskega gena na 17q k.=>AD dedovanje • narašča incidenca PNET in NET rektuma Maligni potencial: • dobro diferenciran endokrini tumor (karcinoid) • dobro diferenciran endokrini karcinom (maligni karcinoid), nizko maligni, globoko invazivni ali metastatski • slabo diferenciran endokrini karcinom, visoko maligni • mešani endokrini in eksokrini karcinom • številne redke nevroendokrinsko sorodne lezije Register raka za Slovenijo 1996-2005 0 2 4 6 8 10 12 Želodec TČ DČ Danka Pankreas Lokacija Št. primerov 11 2 4 8 5 2 Tumor Klinični znaki Mesto vznika %mlg Insulinom hipoglikemija, ↑ tel. teža >95 % pankreas > 10 Gastrinom abd.bolečina, diareja, ulkusi, želodčna hipersekrecija duodenum 70%, pankreas 25% 60-90 VIPom diareja, ↓ K, ↓ Cl, metabolna acidoza, rdečica, ↓ tel.teža 90% pankreas > 50 Glukagonom DM, GVT, nekrolitični migratorni eritem, depresija pankreas > 50 Somatostatinom DM, žolčni kamni, ↓ telesna teža, steatoreja pankreas 6%, zg.GIT 44% 70-80 ACTHom AH, DM, oslabelost pankreas 30%, pljuča 50% > 99 PTHrPom hiperkalcemija, nefrolitiaza pankreas > 99 Neurotensinom DM, diareja, rdečica, AH, ↓ tel.teža, edemi pankreas - Calcitoninom pankreas,pljuča > 80% GFRom akromegalija pankreas,pljuča 30 111 73 63 - 3 - 22 14 - - - - - - - Feldman 1987 91 84 75 - 15 - - 33 46 - - 9 87 1 2 Norheim 1987 748 67 78 34 10 - - 33 52 54.5 9-91 33 60 1 6 79 68 74 - 18 5 - 41 64 52 18-80 2 75 8 15 91 32 23 10 4 - - - 46 59 - 9 87 1 2 91 73 65 - 8 2 12 11 59 57 25-79 5 78 5 11 Število bolnikov SIMPTOM/ZNAK (%) Driska Rdečica Bolečina Obstrukcija (pljuča) Pellagra (↓ B 3 ) Brez Karcinoidno srce DEMOGRAFIJA Moški (%) Srednja starost (leta) Razpon starosti (leta) LOKACIJA TU. (%) zgornji GIT srednji GIT spodnji GIT neznano Soga 1999 Thorson 1958 Norheim 1987 Davis 1973 Med potekom bolezni Ob ugotovitvi * Soga J et al. J Exp Clin Cancer Res 1999;18(2):133 Karcinoidni sindrom: • 8% od 8876 bolnikov z karcinoidnim tumorjem, incidenca 1.7%-18.4% v 6 različnih serijah, 92% bolnikov je imelo ↑ aktivnost serotonina (5-HT)* LAB. DIAGNOSTIKA osnovni hemogram in biokemija, Ca, P, B12, folna kislina ščitnični hormoni PTH kalcitonin prolaktin α- FP CEA α in β- HCG PP senzitivni & nespecifični marker kromogranin A specifični markerji ↑ bazalni somatostatin bazalni GIT hormoni Somatostatinom ↑ bazalni PP bazalni GIT hormoni PP-om ↑ bazalni VIP bazalni GIT hormoni VIP-om ↑ serumska vrednost glukagona in enteroglukagona bazalni GIT hormoni, biopsija kože Glukagonom ↑ razmerje inzulin/glukagon, ↑ proinzulin, ↑ C peptid bazalni inzulin, C peptid, stradalni test Insulinom ↑ gastrin bazalno in po testu bazalni gastrin, test z sekretinom Gastrinom ni ↑ 24-h 5 HIAA v urinu Karcinoid sp. GIT ↑ v 70% primerov 24-h 5 HIAA v urinu, neurokinin A in B Karcinoid sr. GIT včasih ↑ 24-h 5 HIAA v urinu Karcinoid zg. GIT Rezultat Test Sindrom 3 OCTREOSKEN • najobčutljivejša metoda za zaznavanje metastatske bolezni • Indij 111 vezan na somatostatinski analog pentetreotid • pozitiven pri 80-90% bolnikih z NET zg. GIT (10-15% tu. brez somatostatinskih receptorjev) • demarkira tako primarni tu. kot tudi zasevke oz. pozitivne bezgavke • omejitev je velikost lezije (< 0.5cm) • pozitiven izvid korelira z odgovorom na zdravljenje z AS endoskopski UZ, kolonoskopija, gastroskopija UZ CT & MRI tankoigelna punkcija lezije SLIKOVNA DIAGNOSTIKA Gradus Število mitoz (10 HPF) a Ki67 Index (%) b G1 G2 G3 <2 2-20 >20 <(=) 2 3-20 <20 a HPF (“high power field”)=2mm 2 , vsaj 40 pregledanih polj na mestu največje gostote mitoz b MIBI protitelo T (primarni tumor) TX T0 T1 T2 T3 T4 neznan brez omejen na pankreas <2 cm omejen na pankreas 2-4 cm na pankreas >4 cm ali invadira v dvanajstnik, žolčni sis. vključuje bližnje organe ali velike žile N (regionalne bezgavke) NX N0 N1 neznano brez zasevkov v reg. bezg. z zasevki v reg. bezg. M (oddaljene metastaze) MX M0 M1 neznano brez zasevkov z zasevki Stadij Stadij I Stadij IIa IIb Stadij IIIa IIIb Stadij IV T1 N0 M0 T2 N0 M0 T3 N0 M0 T4 N0 M0 kkT N1 M0 kkT kkN M1 Stadij in TNM: • nevroendokrini markerji - PGP 9.5, sinaptofizin, kromogranin A • določitev GIT ali pankreatičnih hormonov z imunohistokemijo • vaskularna, perinevralna in limfatična invazija • ekscizijski robovi • infiltracija sosednjih tkiv (seroza, muscularis propria) • status bezgavk in distalne metastaze Kirurško zdravljenje: • preoperativno moramo preprečiti karcinoidno krizo – dolgotrajna rdečica kože, hipo- oz. hipertenzija, hud bronhospazem, motnje srčnega ritma • profilaksa: kontinuirana i.v. infuzija Octreotida 50 mcg/h 12 h pred operacijo in 48 h po operaciji • odstranitev primarnega tumorja – povečanje OS z 69 mesecev na 139 mesecev • odstranitev primarnega tumorja in jetrnih metastaz – klinasta resekcija, delna hepatektomija – možno pri 20% bolnikov, perioperativna mortaliteta <3% – manj simptomov, izboljšanje kvalitete življenja – 5-letno preživetje 61%, brez OP 30% (mediano prež. 3-4 leta) * * Plöckinger U et al.Neuroendocrinology 2004; 80; 394-424 4 Selektivna (kemo)-embolizacija, RFA, krioablacija Tarčna RT (na analog somatostatina vezani izotopi) – Itrij 90 & Lutecij 177 – predvsem izboljšanje kvalitete življenja preko ↓ simptomov • PR 12-34%, MR 12-14%, SD 28-56%* • mediani TTP (Itrij 90) 30 m, mediani OS 59 m 1 • mediani TTP in mediani OS (Lutecij 177) >30 m 1 • indicirani pri bolnikih z pozitivnim oktreoskenom • !!! ledvična funkcija in penije!!! Analogi somatostatina – octreotid, lanreotid • predvsem dobra kontrola simptomov (↓ v 40-80%) 1 • znižanje biokemičnih markerjev (kromogranin, 5-HIAA) v 40% 1 IFN z ali brez analoga somatostatina – enake indiakcije kot analogi somatostatina KT (RR <10%) – monoterapija adriamicin ali 5-FU => RR >20% – DTIC manj učinkovit – streptozotocin & klorozotocin najbolj učinkovita (!!!NEFROTOKSIČNA!!!) – polikemoterapija 5-FU/DTIC/epiadriamicin => PR 50%, SD 25%, PD 3% 2 – bolj učinkovita pri hitro rastočih tumorjih (predvsem cisplatin/etoposid) Tarčna zdravila bevacizumab, sunitinib, sorafenib, m-TOR inhibitor – v raziskavah faze II uspešni pri inhibiciji rasti tu. 1 Plöckinger U et al. Neuroendocrinology 2004; 80; 394-424 2 Bajetta E et al. Ann Oncol 13 (2002):614-621 1. KLINIČNI PRIMER • 58-letna bolnica • glede mlg. družinsko obremenjena • 1957 prebolela hepatitis, drugače zdrava • preiskave 2001: – UZ ugotovljena dilatacija pankreatičnega voda, – CT in endoskopski UZ trebuha pokažeta cc. 2 cm veliko tvorbo v glavi trebušne slinavke, – ERCP potrdi zaporo in razširitev pankreatičnega voda vse do repa trebušne slinavke (zapora in spremembe so kroničnega tipa) • maj 2001 – OP – subtotalna duodenopankreatomija z ohranjenim pilorusom – R0 resekcija – negativne bezgavke (0/29) – H (Inštitut za patologijo MF): endokrini carcinoid • 30% celic poz. na glukagon (glukagunom) – ponujeno zdravljenje z interferonom, ki ga bolnica odkloni – redna spremljava, UZ in nivo kromogranina bp • februar 2007 – UZ pokaže 3 spremembe v jetrih: 1x3 cm v DJR in dve manjši v LJR – MRI: več lezij v jetrih – OCTREOSKEN: potrdi 3 UZ ugotovljene lezije => poz. somatostatinski receptorji (drugje brez kopičenja) – močno zvišan kromogranin (749ng/L, norm <39ng/L) in zvišan 5 HIAA v urinu (5.5, norm 2-8mg/34h) – C 2008 (jetrna lezija-MRI): endokrini karcinom – H 2001 (revizija na OI): endokrini karcinoid • nizka proliferacijska aktivnost • celice poz. na kromogranin in sinaptofizin • 30% celic pozitivnih na glukagon • 20% celic pozitivnih na VIP in PGP 9.5 • ostale reakcije (serotonin, gastrin, insulin, somatostatin, PP) neg. 1. KLINIČNI PRIMER KOMBINACIJA 5 • INTERFERON => enake indikacije kot za somatostatinske analoge, izjema karcinoidna kriza • glede na kontrolo simptomov primerljiv z analogi somatostatina • 13 raziskav (1986-2003), različe doze interferona (TTP 12 mesecev, mediano preživetje 44-80 mesecev) * 10% (29/287) PR 18% (44/243) 73% (185/253) 0 95% (287/302) 302 PD SD CR Št. evaluiranih bolnikov Št. bolnikov * Plöckinger U et al. Neuroendocrinology 2004; 80; 394-424 • prične zdravljenje z Sandostatin LAR in KT po shemi FDE (5- FU (5-fluorouracil) , DTIC (dakarabazin) , epirubicin) • prejme 9. ciklusov (zadnjega 07/2008) • kontrolni MRI (50% regres bolezni) – CR metastaz endokrinega karcinoma – ostajajo 3 metastaze, ki kopičijo octreotid • avgust 2008 – resekcija 3 jeternih metastaz – H (OI): metastaze nevroendokrinega tumorja – histološka slika skladna z prejšnjimi – PROFILAKSA! • številni zapleti po OP • zaključila zdravljenje brez bolezni 1. KLINIČNI PRIMER • ANALOGI SOMATOSTATINA izboljšajo simptome pri bolnikih z karcinoidnim sindromom (anti-sekretorni efekt) • zmanjšanje biokemičnih markerjev pri 40% in izboljšanje simptomov pri 40-80% bolnikov • antiproliferativni učinek neraziskan • učinkovitost lanreotida in octreotida je primerljiva • dozo je potrebno individualno stetrirati • stranski učinki blagi – abdominalne kolike, napihnjenost, steatoreja hujši – nastanek žolčnih kamnov (50%, redko simptomatski), persistentna steatoreja in posledična malabsorbcija 24-57% <10% SD PR+CR Plöckinger U et al. Neuroendocrinology 2004; 80; 394-424 6 trajanje > 6m objektivni RR 53 (73.6%) Bajetta E et al. Ann Oncol 13 (2002):614-621 2. KLINIČNI PRIMER • 60 letna bolnica • družinska anamneza glede mlg. pozitivna • od leta 1996 spremljana na OI zaradi histol. verific. MALT limfoma desne gl. arotis, v povezavi s Sjögrenovim sy, st. po tnzilektomiji, st. po TELA • 2001 - dermoidna cista v predelu trtice • sept. 2001 OP (drenaža in biospija) => H neg. • preiskave: – UZ abdomna & endoUZ - tu. za dist. rektumom, ki iz tega ne izrašča – MRI - tu. pred sakrumom, trtico velikosti 3 x 4 cm – octreoscan - kopičenje v sp. delu sakruma in pred trtico – transrektalna punkcija lezije • C: nevroendokrini karcinoid, ki ga imunohistokemično ne morejo potrditi • H: najverjetneje nevroendokrini karcinom oz. karcinoid • dec. 2001 OP => ekstirpacija tu. z delno resekcijo sakruma in trtice – H: nevroendokrini tu., z dezmoplazijo, nizke stopnje mlg. 2. KLINIČNI PRIMER Zdravljenje: • kirurško – tu. neradikalno odstranjen, kontrolni octreoscan pokaže ostanke oz. recidiv v medenici na dveh mestih – možnost zanosa celic tu. v biopsijski kanal • sistemsko => indicirano zdravljenje z Yttrium 90-DOTEC (prejme 2. aplikaciji v Baslu) • stranski učinki - ↓ ledvične funkcije, pancitopenija Sledenje – UZ, MRI, 5-HIAA v urinu, kromogranin April 2005 (3 leta) => bolečine na mestu prim. tu., ki se stopnjujejo že dalj časa • octreoscan => kopičenje v post.delu sakruma in v jetrih => ponovitev bolezni • UZ trebuha => potrdi številne lezije v jetrih • indicirano zdravljenje z Lutecij 177-DOTEC (aplikacijo prejme v Baslu) • stranski učinki - ↓ ledvične funkcije, pancitopenija 7 Center Agens N CR n/% PR n/% MR n/% SD n/% PD n/% Rotterdam New Orleans Milan Basel Basel Rotterdam Rotterdam [111In-DTPA0]octreotide [111In-DTPA0]octreotide [90Y-DOTA0, Tyr3]octreotide [90Y-DOTA0, Tyr3]octreotide [90Y-DOTA0, Tyr3]octreotide [90Y-DOTA0, Tyr3]octreotide [177Lu-DOTA0, Tyr3]octreotide 26 26 21 74 33 54 76 0 0 0 3/4 2/6 0 1/1 0 2/8 6/29 15/20 9/27 4/7 22/29 5/19 NA NA NA NA 7/13 9/12 11/42 21/81 11/52 48/65 19/57 33/61 29/39 10/38 3/12 4/19 8/11 3/9 10/19 14/18 Kwekkeboom DJ et al. J Nucl Med 2005; 46 Suppl 1:62 2. KLINIČNI PRIMER • dosežena stagnacija zasevkov v jetrih • bolnica brez znakov karcinoidnega sy. Junij 2007 (5 let) • MRI in octreoscan => stagnacija lokalno in progres jetrnih zasevkov • september 2007 => Lutecij 177-DOTEC (prejme v Baslu) • zadnja kontrola sept. 2008 (6 let) – stagnacija, bolnica je brez znakov karcinoidnega sy. REFERENCE: 1. Plöckinger U et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal timours. Neuroendocrinology 2004; 80; 394-424 2. Bajetta E et al. Efficacy of a chemotherapy combination for the treatment of metastatic neuroendocrine tumours. Ann Oncol 13 (2002):614-621 3. Baxter Oncology. Selected schedules. 12th update; 254-260 4. Rihard R et al. Enteroendocrine tumors other then carcinoid: A review oc clinically significant advances. Gastroenterology 2005; 128: 1668-1684 5. Soga J et al. Carcinoid syndrome: a statistical evaluation of 748 reported cases. J Exp Clin Cancer Res 1999; 18(2): 133 6. Garland J et al. Sandostatin LAR (long-acting ocreotide acetate) for malignant carcinoid syndrome: a 3-year expirience. Aliment Pharmacol Ther 2003; 17: 437-444 7. Hematology/Oncology clinics of north America. Neuroendocrine tumors. Junij 2007; volume 21: number 3 8. Siegbert F et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interfeon alfa and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumours – the international lanreotide and interferon alfa study group. J Clin Oncol 2003; vol 21: No 14: 2689-2696 8 9. UpToDate (www.uptodate.com) 10. NCCN - Cancer Guidelines for Patients and Physicians by Cancer Experts 11. (www.nccn.org) 12. Devita et al. Cancer – principles & practice of oncology; 8th edition: vol 2: 1702-1735 13. Kwekkeboom DJ et al. Overwiew of results of peptide receptor radionucleotide therapy with 3 radiolabeled somatostatin analog. J.Nucl.Med. 2005; 46 Suppl 1:62 14. Kwekkeboom DJ et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3] octreotate: toxcicity, efficiency, and survival. J. Clin. Oncol. 2008; 26:2124 15. Valkema R et al. Survival and response after peptide receptor radionucleotide therapy with [90Y-DOTAO,Tyr3] octreotide in patients with advanced GPNET tumors. Semin. Nucl. Med. 2006; 36: 147 16. De Jong M et al. Somatostatin receptor- targeted radionucleotide therapy of tumors: preclinical and clinical findings. Semin. Nucl. Med. 2002; 32: 133 17. Waldherr C et al. Tumor response and clinical benefit in NET after 7,4 GBq (90)Y-DOTATOC. J. Nucl. Med. 2002; 43: 610 1 HEPATOCELIČNI RAK Dnevi internistične onkologije November 2008 Maja Ebert Moltara, Tanja Mesti Mentor: Janja Ocvirk EPIDEMIOLOGIJA: Incidenca:  8.29/100.000 v EU  1,6-3,2/100.000 v Sloveniji Internistični dnevi onkologije, November 2008 Internistični dnevi onkologije, November 2008 DIAGNOZA: Anamneza in status (slabost, utrujenost, slab apetit, hujšanje, bolečine v zgornjem delu trebuha, zlatenica) UZ, MRI ali CT Zvišan AFP 400ng/ml 2 Internistični dnevi onkologije, November 2008 T1 Solitarni tumor brez vaskularne invazije T2 Solitarni tumor z vaskularno invazijo ali multipli tumorji ne večji od 5 cm T3 Multipli tumorji, večji od 5 cm ali tumor, ki zajema večjo vejo portalne ali hepatične vene T4 Tumor ali tumorji z direktno invazijo v sosednje organe razen v žolčnik, ali perforacija visceralnega peritoneja N0 Ni zasevkov v področnih bezgavkah N1 Zasevki v regionalnih bezgavkah M0 Ni oddaljenih zasevkov M1 Oddaljeni zasevki Stadij I T1N0M0 Stadij II T2N0M0 Stadij IIIA T3N0M0 Stadij IIIB T4N0M0 Stadij IIIC TxN1M0 Stadij IVB TxNxM1 TNM klasifikacija Internistični dnevi onkologije, November 2008 123 ascites odsoten blag močan Bilirubin (nmol/l)  34,2 34,2-51,3  51,3 Albumin (g/l) 35 28-35  28 Protrombinski čas (%) do 50 30-50  30 encefalopatija 0 1-2 3-4 Child A 5-6 točk Child B 7-9 točk Child C 10-15točk Child-Pugh klasifikacija Internistični dnevi onkologije, November 2008 Zdravljenje:  stadij bolezni  stanje jetrnega tkiva  splošna bolnikovo stanje 3 Internistični dnevi onkologije, November 2008 Resektabilni tumorji (T1, T2, T3, nekateri T4; N0; M0) Kirurška resekcija ali jeterna transplatacija (ciroza) Kontraindikacije za kirurško zdravljenje:  Izven jeterna bolezen  Multipli ali bilobarni tumorji  Napredovala jetrna biolezen  Zajetje glavnega žolčnega voda  Prisotnost tromboze debla vene porte ali spodnje vene cave 5 letno preživetje: 60-70% - bolniki s solitarnim tumorjem, ohranjeno jeterno funkcijo 20-50% - bolnikih s kronično bolnimi jetrni Internistični dnevi onkologije, November 2008 Transplantacija (Milanski kriteriji):  tumor v cirotičnih jetrih manjši od 5cm, ali 2-3 tumorji manjši od 3 cm v premeru  tumor ne sme zajemati žilnih struktur  ne sme biti prisotne izven jeterne bolezni 5-letno preživetje: do 70% Internistični dnevi onkologije, November 2008 Neresektabilni tumorji (T2, T3 in T4, N0, M0)  transplantacija  operacija - resekcija  kemoembolizacija (pri multifokalnem HCC z zadovoljivo jeterno rezervo)  perkutano etanolno injiciranje - PEI (pri manj kot 3 nodulih manjših od 5 cm)  perkutana radiofrekvenčna ablacija - RFA (za manjše od 5 cm in manj kot 4)  sorafenib  vključitev v klinične raziskave  paliativna oskrba 4 Internistični dnevi onkologije, November 2008 Napredovali tumorji (katerikoli T,N+,M1)  sorafenib  vključitev v klinične raziskave  paliativna oskrba Internistični dnevi onkologije, November 2008 Sorafenib, Nexavar ® Internistični dnevi onkologije, November 2008 SHARP: Sorafenib HCC Assessment Randomized Protocol Trial 5 Internistični dnevi onkologije, November 2008 SHARP: Sorafenib HCC Assessment Randomized Protocol Trial Sorafenib (N=297) Placebo (N=302) Vse stopnje (%) G4/G3 (%) Vse stopnje (%) G4/G3 (%) skupaj 80 52 driska 39 8/0 11 2/0 utrujenost 22 3/1 16 3/<1 roka-noga sindrom* 21 8/0 3 <1/0 anoreksija 14 <1/0 3 1/0 alopecija 14 0/0 2 0/0 slabost 11 <1/0 8 1/0 Izguba TT 9 2 1 0/0 srbenje 8 0/0 7 <1/0 Suha koža 8 0/0 4 0/0 Bolečine v trebuhu 8 2/0 3 1/0 krvavitve 7 1/0 4 1/ <1 bruhanje 5 1/0 3 1/0 hripavost 6 0/0 1 0/0 hipertenzija 5 2/0 2 1/0 NEŽELENI UČINKI SORAFENIBA (SHARP študija) * palmo-plantarne eritodisestezije Internistični dnevi onkologije, November 2008 ZAKLJUČEK: Sorafenib  je multikinazni inhibitor, ki deluje na poti RAF/MEK/ERK in blokira tako celično proliferacijo kot angiogenezo HCC  signifikantno podaljša OS za 44% (46 vs. 34 tednov) 5  za dvakrat podaljša čas do radiolškega progesa (24 vs. 12 tednov) 5  podaljša čas do progresa simptomov (18 vs. 21 tednov, vendar razlika ni signifikantna) 5  najpogostejši stranski učinki: driska, kožne spremembe, alopecija in palmo-plantarne eritodisestezije 5 6 Internistični dnevi onkologije, November 2008 REFERENCEs: 1. Hepatocellular carcinoma: ESMO Clinical Recommendation for diagnosis, treatment and follow-up. P. Parikh, H.Malhotra, S. Jelic and on behalf of the ESMO Guidelines Working Group; Ann. Onc. 19:27-28, 2008 2. NCCN Clinical Practice Guidelines in Oncology 3. Incidenca raka v Sloveniji 2004. Ljubljana: Onkološki inštitut, Register raka za Slovenijo, 2007 4. Prognosis of advanced hepatocellular carcinoma: comparison of three staging systems in two French clinical trials, S. Collete, F. Bonnetain, X. Paoletti, M. Doffoel, O. Bouche, J.L. Raoul, P. Rougier, F. Masskouri, L. Bedenne & J.C. Barbare; Ann. Onc. 19: 1117-1126, 2008 5. Sorafenib in advanced Hepatocellular Carcinoma, J.M. Lovet, S. Ricci, V. Mazzaferro, P . Hilgard, E. Gane, JF. Blanc, A.C. Olivera, A. Santoro and others; N Engl J Med. 2008 Jul 24;359(4):378-90. 1 HEPATOCELIČNI RAK (prikaz primera 1) Dnevi internistične onkologije November 2008 Tanja Mesti, Maja Ebert Moltara Mentor: Janja Ocvirk prikaz primera 51 letni bolnik Razvade: etilik, kadilec Družinska anamneza: oče umrl zaradi raka na prostati, mama zaradi srčnega infarkta Spremljajoče bolezni: • Etilična jetrna ciroza, Child A • Hepatorenalni sindrom • Ledvična insuficienca II stopnje • Erozivna gastropatija • Varice požiralnika I stopnje • Trombocitopenija • Mikrocitna anemija Redna terapija: Ortanol, Aldactone, Edemid, Portalak September 2001: Hospitalizacija v SB Murska Sobota Dekompenzacija etilične jetrne ciroze s ledvično insuficienco II stopnje, ascites, hiperamonemija, hiperurikemija UZ trebuha: 5 cm velika hiperehogena tvorba v V. jetrnem segmentu desno - sum na HCC; CT trebuha: Ekspanzivni proces v jetrih - sum na HCC. Rtg pc: Nekoliko povečano srce na račun levega prekata. V pljučih intersticijske spremembe - najverjetneje posledica kajenja. Ni metastaz. prikaz primera 2 prikaz primera Oktober 2001: Pregled na OI • Status: spider nevusi po koži; palmarni eritem; ginekomastija; sistolni šum nad prekordijem; jetra tipna 3cm pod DRL-jem; vtisljivi edemi goleni in stopala • PS WHO 0-1 • TT 93,5 kg. • Citopatološki izvid: dobro diferenciran HCC • Histopatološki izvid: dobrodiferenciran HCC, glandularni in trabekularni tip. Laboratorijski izvidi: Hb 97 MCV 87,3 Tr 125 Kreatinin 121 Urea 12,7 GFR 84 Urat 633 AF 2,18 PČ 0,60 INR 1,41 AFP 4,16 Kako bi bolnika zdravili? a) Operacija b) Kemoembolizacija c) RFA d) PEI e) Transplantacija f) Sistemska terapija g) Paliativna oskrba prikaz primera 51 letni bolnik z HCC, PS WHO 0-1, etilična jetrna ciroza, Child A, hepatorenalni sindrom, renalna insuficienca II stopnje, trombocitopenija, mikrocitna anemija November 2001 (OI): Prva kemoembolizacija z mitomicinom in lipiodolom. Kontrolni CT trebuha (december 2001): Povečana, grčasta jetra, v V. segmentu desno 4 cm nejasno omejena sprememba. Januar 2002 (OI): Druga kemoembolizacija z mitomicinom in lipiodolom Kontrolni CT trebuha (februar 2002): Lezija v V. jetrnem segmentu desno nekoliko večja, predvsem na račun kolekcije lipiodola. prikaz primera 3 Kako bi bolnika zdravili sedaj? a) Kemoembolizacija b) Operacija c) RFA d) PEI e) Transplantacija f) Sistemska terapija g) Paliativna oskrba prikaz primera Februar 2002 (OI): 51 letni bolnik z HCC PS WHO 0-1 St.po kemoembolizaciji - lezija nespremenjene velikosti. Marec 2002: Opravljena RFA Kontrolni CT trebuha (april 2002): v V. jetrnem segmentu desno lezija velikosti 3,1x 3cm prikaz primera prikaz primera Kako bi bolnika zdravili sedaj? a) Kemoembolizacija b) Operacija c) RFA d) PEI e) Transplantacija f) Sistemska terapija g) Paliativna oskrba Januar 2003: 51 letni bolnik z HCC AFP 10,95 IU/ml Kontrolni UZ trebuha: v V. jetrnem segmentu desno lezija velikosti 4 x 6 cm. 4 prikaz primera Februar 2003: Drugič RFA Kontrolni CT trebuha (marec 2003): v V. jetrnem segmentu desno cirotično spremenjih jeter lezija 4,5 x 5,5cm. 2/3 so po RFA povsem koagulirani. Približno 2,5 x 2,6 cm velik mediokranialni del je videti še aktiven s posameznimi žilnimi signali. prikaz primera Kako bi bolnika zdravili sedaj? a) kemoembolizacija b) Operacija c) RFA d) PEI e) Transplantacija f) Sistemska terapija g) Paliativna oskrba December 2003: 51 letni bolnik z multifokalnim HCC, jetrna ciroza Child C AFP 201,30 IU/ml Kontrolni UZ trebuha: multifokalne spremembe v jetrih- V., VI., VII. in VIII. jetrnem segmentu desno, sled proste tekočine. 1 HEPATOCELIČNI RAK (prikaz primera 2) Dnevi internistične onkologije November 2008 Maja Ebert Moltara, Tanja Mesti Mentor: Janja Ocvirk prikaz primera PRVI PREGLED NA OI moški, 53 let, PS: WHO 0 Dg: primarni jeterni tumor (HCC) v cirotičnih jetrih Potek zdravljenja HCC pred pregledom na OI: 3x kemoemboliziran z Doxorubicinom Spremljajo če bolezni bolezni: • hepatitis C (od l. 1997), • periferna angiopatija • arterijska hipertenzija • st. po holecistektomiji prikaz primera Kako bi bolnika zdravili? a) Operacija b) Kemoembolizacija c) RFA d) PEI e) Transplantacija f) Sistemska terapija g) Paliativna oskrba 2 prikaz primera datum anamneza Status lab doza 17.12. 2007 brez težav WHO 0 AFP 13434 800mg UZ trebuha: 3 seg: 5 cm 7-8. seg: 2,2 cm 28.1. 2008 2x tiščanje v prsnem košu PS: WHO 1 AFP 13172 800mg CT abdomna: več ascitesa, 3 seg: 5 cm z nekrozo 7 seg: nekroza 10.3. 2008 driska PS: WHO 1-2 TT ↓ 4kg znaki ascitesa edemi gležnjev AFP 13206 800mg Dopller ven: izključena GVT 21.4. 2008 2x drenaža ascitesa PS: WHO 1-2 koža: luščenje in rdečina, znaki ascitesa, edemi AFP 6899 800mg prikaz primera datum anamneza status lab Doza 5.6. 2008 splošno dobro počutje, hujšanje, drenaža 1x na 3 tedne PS: WHO 1 TT ↓ 11kg AFP 1593 800mg CT abdomna: obsežen ascites, difuzno spremenjena jetra z žariščnimi hipodeznimi lezijami (L/D), karcinoza? 17.7. 2008 slabost, pogosto bruhal, večkrat driska (5-10x odvajanje) PS: WHO 1-2 ikteričen AFP 928 prekinitev za 4 tedne Drenaža: 3l (19.6.) Koprokultura: neg. 14.8. 2008 hospitaliziran zaradi bruhanja in drisk PS: WHO 1-2 400mg Drenaža 1 Rak neznanega izvora – Predstavitev primerov Rak neznanega izvora – Predstavitev primerov Mag. Cvetka Grašič Kuhar, dr. med. Astrid Lui Rusjan, dr.med. Prof. dr. Branko Zakotnik, dr. med. Definicija raka neznanega izvora VT DeVita et al. Cancer Principles of Oncology, 8th ed., 2008 • Heterogena skupina tumorjev (3-5% vseh rakov): – ob diagnozi so prisotni zasevki, ne uspemo pa ugotoviti mesta primarnega tumorja – nizko preživetje (srednje =5 mes, 1-letno =22%, 5-letno=5%) • Diagnoza: -iz metastatske lezije: citol. punkcija DIBiopsija ekscizijska biopsija; NE odprta biopsija!) -patološka evaluacija: svetlobni mikroskop + -imunoperoksidazno barvanje: določitev celičnih encimov in normalnih tkivnih komponent -elektronska mikroskopija (nevrosekretorne granule, premelanosomi, dezmosomi) -molekularna genetika (i12p, t(15,12), hematološki tumorji, sarkomi) Karcinom Epitel. m. (CK 7, CK 20), EMA+ Vimentin-, CLA-, S-100- Kolorektalni ca. CK 7-, CK 20+ Pljučni ca. -adenoca. -ostali NSCLC -SCLC TTF-1+, Surf-A in Surf-B+ CK 7+, CK 20- TTF-1+, kromogranin+, NSE+ Nevroendokrini ca. NSE, kromogranin, epitel. m. Germinalni tumorji β-HCG, α-FP, Oct4 transkr. f.+, PLAP+, epitel. m.+ Ca. prostate PSA+, epitel. m.+ (CK 7-, CK 20-) Ca. dojke ER, PgR+, Her2+, CK 7+, CK 20-, epitel. m. + Ca. pankreasa CA 19-9+, CK 7+, mezotelin+, trifoil f. + Imunoperoksidazna barvanja v ddg. slabo diferenciranih karcinomov 2 Osnovne histološke skupine raka neznanega izvora (svetlobni mikroskop) SLABO DIFERENCIRAN (ADENO)KARCINOM (29%) PLOŠ ČATOCELI ČNI KARCINOM (5%) SLABO DIFERENCIRANA MALIGNA NEOPLAZMA (5%) KARCINOM Z NEVROENDOKRINOD IFERENCIACIJO (1%) DOBRO/SREDNJE DIFERENCIRAN ADENOKARCINOM (60%) Minimalni nabor preiskav za iskanje origa oz. zamejitev bolezni E. Briasoulis et al. ESMO Clinical Recommendations. Ann Oncol 2008; 19 (Suppl 2): ii106-7. -Anamneza -Fizikalni pregled (vrat, dojke, rektalni pregled, mala medenica) -Hemogram, biokemi čne preiskave, urin, hematest blata -rtg pc; CT toraksa, CT/UZ abdomna, CT/UZ medenice -PET CT pri pove čanih bezgavkah na vratu in solitarni metastazi -dg. primar. mesta: -pri slabo dif. ca. v 40% -pri ploš čatocel. ca. v 75% -ženske z zasevkom v mamografija aksilarni bezgavki -moški z adenokarcinomom in PSA kostnimi zasevki -zasevki v retroperitonealnih β-HCG, α-FP, in/ali mediastinalnih bezgavkah, LDH pljučih: -zasevki karcinoma v bezgavkah CT glave in vratu na vratu (ploščatocelični, adenoca.) CT prsnega koša ali PET CT -simptomi ali znaki za prizadetost endoskopske preiskave votlih organov: -zasevki v jetrih: CEA, CA 19-9, α-FP Ciljane preiskave pri raku neznanega izvora 3 Zdravljenje karcinoma neznanega izvora Podtip karcinoma Predvideno zdravljenje Slabo diferenc. karcinom (pretežno v bezgavkah, mlajši, kemosenzitivni) Osnova je cisplatin Slabo diferenciran nevroendokrini karcinom Cisplatin/karboplatin + etopozid Karcinoza peritoneja ali serozni adenokarcinom pri ženski Kot ovarijski karcinom: optimalna kirurška citoredukcija, nato KT na osnovi platine Izolirane metastaze v aksilarnih bezgavkah pri ženski Kot rak dojke za enak stadij Ploščatocelični karcinom v: bezgavkah na vratu zg. 2/3 bezgavke spodnja 1/3 ingvinalnih bezgavkah Kot rak glave in vratu Kot rak pljuč Vulva, cervix, anus, penis Kostne, jetrne ali multiple metastaze adenokarcinoma -nizko toksična KT ali -simptomatsko zdravljenje KT in tarčna zdravila za karcinom neznanega izvora -prognostično ugodna skupina je le 10% adenokarcinomov (GI-II) in 20% slabo diferenciranih karcinomov (mlajši, v bezgavkah): -veliko kompletnih remisij -potencialno ozdravljivi tumorji! -zadnja leta: tudi prognostično neugodna skupina ima z novimi KT shemami in biološkimi zdravili izboljšano prognozo (taksani, gemcitabin, vinorelbin, irino-/topotekan; bevacizumab, erlotinib); -izboljšano preživetje (srednje=9 mes, 1-letno=20%, 5-letno= 5%) Klinični primer 1/1 -moški, 65 let -FA, OA: bp. -sedanja bolezen: -pol leta hude bolečine v predelu desne rame (ojačajo se pri ležanju; olajšajo se, če sklonjen naprej): prejemal NSAR; -09/2006: protibolečinska ambulanta: nevropatska bolečina v desnem kostovertebralnem kotu, ki izžareva v desno ramo (th: Morfij in Xylocain po epiduralnem katetru) -CT abdomna (09/2006): velik ekspanziven proces v ležišču d. nadledvičnice, infiltrira zg. pol in hilus d. ledvice ter odriva jetra -UZ vodena aspiracijcka biopsija tumorja: maligen proces, najverjetneje metastaza slabo diferenciranega karcinoma. V kolikor gre za bezgavko, prihaja ddg. v poštev tudi germinativni tumor (embrionalni karcinom). Dodatna IHC barvanja za germ. tumor niso razrešile dileme. 4 Klinični primer 1/2 -KO za urologijo UKC Lj - eksplorativna laparotomija (13/09/2006): inoperabilni proces v področju d. nadledvične lože, vrašča proti hrbtenici, diafragmi, v precejšnji del desnih jeter, infiltrira v. cavo inf., širi se proti želodcu in pankreasu -Urološki konzilij (19/09/2006): predlaga paliativno obsevanje -Obsevanje (22.09.-05.10.2006): 10x3 Gy -Laboratorij 20.09.2006: BLR (52/29), kre 124 -protibolečinska th. po epiduralnem katetru -amb. internista onkologa (23/10/2006): določitev tumorskih markerjev: α-FP 15 740, β-HCG, LDH normalen, CA 19-9 38, NSE 57, UZ testisov: v spodnjem delu d. testisa 2-3mm kalc. -ddg. dilema: germinalni tumor/hepatocelularni karcinom -th. možnosti pri napredovalem germinalnem tumorju dobre, pri HCC zelo omejene poskus zdravljenja s KT po shemi BEP (bleomicin, etopozid, cisplatin) Klinični primer 1/3 -KT po shemi BEP x 4 (08/11/2006-10/01/2007) -dober upad tumorskega markerja (slika) -pancitopenija po 1. ciklusu -ob pričetku 2. ciklusa brez kakršnekoli protiboleč. th. -UZ trebuha po 3. ciklusu: odlična parcialna remisija -po 4. ciklusu: tumorski marker normalen alfa-fetoprotein 15740 11980 4092 217 26 0 5000 10000 15000 20000 135 ciklus KT Klinični primer 1/4 -21/02/2007: operacija ostanka tumorja: ‘en bloc’ d. nefrektomija + 6., 7. segment jeter + dorzalna muskulatura + del diafragme; (operacija trajala 10 ur, izguba krvi 18 l) -histološki izvid: nodusi popolnoma nekrotičnega retroperitonealnega tumorja z nekrotičnimi zasevki v jetrih in hilusu ledvice. Sence nekrotičnih tumorskih celic nakazujejo možnost, da je šlo za germinalno-celični tumor -kontrola 06/2007: bp., pričel z delom -kontrola 09/2008: bp. 5 Zaključek klinični primer 1: Karcinom neznanega izvora – posebna klinično-patološka entiteta -‘izgoreli primarni tumor’ –”burned out” (germinalni tumor) (UZ testisov!) -iz ostankov embrionalnih epitelijskih celic -iz odraslih nediferenciranih pluripotentnih matičnih celic (so v vezivnem tkivu) -specifične genetske spremembe v vseh celicah • Ženska, 39 let • Napotna diagnoza: NHL, visoko maligni (citologija iz bezgavke scl levo) • Družinska anamneza: bp • Razvade: kadi 20 let, 10 cigaret /dan • Sedanja bolezen: 10 dni dizurične težave, bolečine ledveno, subfebrilna, herpetični izpuščaj pod nosnico, tri meseca napetost v trebuhu, B-simptome zanika • Status: scl levo 3 bezgavke ( 2-premera 0.5 cm, 1 premera 1 cm); ostali status b.p. Klinični primer 2/1 Klinični primer 2/2 • Punkcija bezgavke: slabo diferecirani adenokarcinom • Biopsija bezgavke: slabo diferenciran adenokarcinom (dojka? pljuča?), ER 30%, PR 30%, HER2 neg. • Biopsija KM: bp (Napotna dg!) • Laboratorij: hemogramu, biokemija, ščitnični hormoni b.p.; Ca 125 77.77, Ca 15-3 145.26, CEA, Ca 19-9 bp • Ginekološki pregled in PAP test: b.p • Mamografija: ostanki žleznega tkiva v obeh dojkah, brez vidnih jasnih tumorskih jeder, brez vidnih polimorfnih kalcinacij • UZ dojke: 4 mm cista v zgornjem kvadrantu desne dojke 6 Klinični primer 2/3 • RTG pc: b.p., CT toraksa: patološko povečane bezgavke v poteku desnega mamarnega žilja, v obeh kardiofreničnih kotih in v spodnjem posteriornem mediastinumu • RTG obnosnih votlin: b.p. • ORL pregled: b.p. • UZ trebuha: patološko povečane bezgavke retroperitonealno, v l. Ingv. regiji ena bezg. prmera 1.1 cm • CT abdomna: uterus v celoti nekoliko povečan, nejasno razmejen proti okolici in obema ovarijema. Maščevje v okolici uterusa strukturno nehomogeno, prisotno malo proste tekočine- izgled v smislu peritonealne karcinoze. V jetrih 3 < kot 1 cm formacije susp. za zasevke. Patološk do 1,5 cm velike bezgavke v retroperitoneju • Sken skeleta: bp Klinični primer 2/4 • Hematest: negativen • Gastroskopija (?), kolonoskopija (?): bp • DDg: slabo diferencirani adenoca: 1 – dojka? 2 - ovarij? -> KT CAP Klinični primer 2/5 • 6x KT po shemi CAP • 04/2006, CR (klinično CR, Ca 125 bp, Ca 15- 3 pa ob 6 ciklusu iz 33 -> 38) • ER+,PR+ -> Tamoxifen (brez mensesa, FSH, LH v menop. območju) -> normalizacija Ca 15-3 7 Klinični primer 2/6 • PI 1,5 let, porast Ca 15-3 . • Ginekološki pregled in UZ male medenice: 10 mm lezija na zadnji steni uterusa. • MR medenice: manjši miom v uteruseu, drobna cista d. ovarija. • Mamogrefija, sken skeleta, Rtg pc: b.p. • UZ trebuha: cista v jajčniku večja kot ob zadnji kontroli ( 4.5 cm). Klinični primer 2/7 • Ginekolog: vaginalna histerektomija z obojnimi adneksi ter parcialna omentektomija. • Hisologija: slabo diferenciran endometrioidni adenokarcinom jajcevoda desno z metastazo v omentumu ( z ozirom na morfološko skladnost in podoben imunofenotip, je šlo primarno najverjetneje za zasevek karcinoma jajcevoda v bezgavko na vratu) Klinični primer 2/8 • Bolnica je prejela šest ciklusov KT: Paclitaxel, Carboplatin (do 05/2008) • 28.08.2008 zadnja kontrola: Ginekološki pregled, UZ trbuha, markerji: b.p. • Pričela s 4-urnim delavnikom 8 Klinični primer 2/9 tumorski markerji 0 20 40 60 80 100 120 140 160 nov.05 jan.06 mar.06 maj.06 jul.06 sep.06 nov.06 jan.07 mar.07 maj.07 jul.07 sep.07 nov.07 jan.08 mar.08 maj.08 jul.08 CA 15-3 CA -125 1 RAK DOJK - vloga genskega podpisa pri odlo čitvi o sistemskem zdravljenju Ksenija Strojnik, Mojca Humar Mentorica: prof.dr. Tanja Čufer, dr.med., višja svetnica RM, ♀ 34 let • Družinska anamneza: brez posebnosti • Ginekološka anamneza: menarhe 11 let, rodila 2x (prvič pri 27-ih), dojila skupno 2 leti; brez hormonske kontracepcije; konizacija dec. 2007 • Dosedanje bolezni: brez posebnosti • Sedanja bolezen: pred 3 meseci si je zatipala 2 cm veliko zatrdlino v levi dojki retromamilarno; bezgavke v levi aksili tipno niso bile povečane DIAGNOZA: - mamografija: 2cm maligno jedro z okolnimi mikrokalcinacijami - tankoigelna biopsija: karcinom dojke - preiskave za oddaljene zasevke: negativne MASTEKTOMIJA s takojšnjo rekonstrukcijo ter SNB 2 PATOHISTOLOGIJA: • masivni DCIS solidnega, komedo in kribriformnega tipa premera 7 cm z več žarišči invazivnega duktalnega karcinoma BDO, največji 1.5 cm; kirurški rob oddaljen 0.8 cm od karcinoma; SNB 0/2. • G3 (tubuli 3, jedrni polimorfizem 3, mitoze 2), brez LVI, ER 100%, PR 100%, HER-2 neg. (IHC 0, FISH količnik 1.0). • Revizija: obe komponenti rasti invazivnega dela hormonsko visoko odvisni ter Her2 negativni. SISTEMSKO ZDRAVLJENJE? ZNAČILNOSTI BOLNIKA Z DOKAZI PODPRTI PODATKI ZNAČILNOSTI TUMORJA RAZPOLOŽLJIVA TERAPIJA U ČINKI ENDOKRINEGA ZDRAVLJENJA IN KEMOTERAPIJE PRI ZGODNJEM RAKU DOJK • Dopolnilno hormonsko zdravljenje s tamoksifenom (pri ER+ bolnicah) – 40% zmanjšanje tveganja za ponovitev – 32% zmanjšanje smrtnosti zaradi raka dojk • Polikemoterapija (pri vseh bolnicah) – 33% zmanjšanje tveganja za ponovitev – 17% zmanjšanje smrtnosti zaradi raka dojk EBCTCG Lancet 2005 3 Randomized trials Trial Size Stage Treatments Outcome (DFS/OS) Comments Pomenopausal patients SWOG trial Rivkin SE, JCO 1994 892 N+,HR+ TAM 1 y +/- CMFVP No signif. difference in DFS and OS IBCSG IX IBCSG, JNCI 2004 1669 N- HR+/- TAM 5y +/- CMF No signif. difference in DFS and OS of adding ChT in ER+ subgroup of pts Initial stratification according ER status NCIC CTG Pritchard K, JCO 1997 705 N+, HR+ TAM 2y +/- CMF No signif. difference in DFS and OS Premenopausal patients IBCSG 11-93 IBCSG, Breast Cancer Res 2008 174 N+, HR+ (OA + TAM 5 y) +/- AC No difference in DFS and OS Premature closure of the trial due to low accrual Premeno- and pomenopausal Patients NSABP B-20 Fisher B, Lancet 2004 788 N-, HR+ TAM 5y +/- CMF Signif. difference in DFS and OS for premeno- but not pomenopausal pts PROSPEKTIVNE RANDOMIZIRANE ŠTUDIJE O DODATKU KEMOTERAPIJE K HORMONSKEMU ZDRAVLJENJU 10 U ČINKOVITOST ADJUVANTNE KEMOTERAPIJE GLEDE NA ER STATUS: CALGB ŠTUDIJE (N+, pre- in pomenopavzne bolnice) ! MUCH GREATER IMPACT FOR ER- DISEASE ! Berry D, et al.JAMA 295: 1658-67 2006 Trial INT 0148 Trial 8541 Trial 9741 Low, int CAF vs high dose CAF AC vs AC P Q3wk vs q2wk Control arm Experim arm, ER+ Experim arm, ER- 1.0 1.0 1.0 0.91 0.92 0.88 0.77 0.75 0.79 9 Hazard reduction for relapse 4 ST. GALLEN 2007 - priporo čila ASCO 2007 PRIPORO ČILA ZA UPORABO TUMORSKIH MARKERJEV PRI RAKU DOJK Drugi multiparameterski testi genske ekspresije Določanje prognoze pri ženskah, ki bodo prejela dopolnilni tamoksifen Oncotype DX BREZ PRIPOROČILA PRIPOROČENI DIAGNOZA Določanje prognoze in vodenje uporabe dopolnilne kemoterapije s CMF uPA/PAI-1 test Novoodkrit invazivni rak dojk, negativne bezgavke in ER in/ali PR pozitiven Napoved odgovora na trastuzumab in napoved odgovora na dopolnilno kemoterapijo z antraciklini HER-2 test / Napoved odgovora na dopolnilno hormonsko zdravljenje ER/PR test Novoodkrit invazivni rak dojk TEST NAMEN IME TESTA 5 ER- ER+ Bazalne mioepitelijske celice Luminalne celice Luminal-like A Luminal-like B Basal-like HER-like GENSKI PODPISI – NAPOVEDNIKI PROGNOZE PRI ZGODNJEM RAKU DOJK • 21-genski podpis (Oncotype DX TM ); Breast Cancer Res 2006 • 70-genski podpis (MammaPrint ® ); JNCI 2006 • 76-genski podpis; J Clin Oncol 2006 Proliferacija Ki-67 STK15 Survivin Ciklin B1 MYBL2 Estrogen ER PgR Bcl2 SCUBE2 Invazija Stromolizin 3 Katepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 Referenčni β-aktin GAPDH RPLPO GUS TFRC CD68 • 16 rakavih in 5 referenčnih genov iz 3 študij Kategorija RS (0-100) Nizko tveganje RS < 18 Srednje tveganje RS ≥ 18 and < 31 Visoko tveganje RS ≥ 31 21-GENSKI PODPIS RS = + 0.47 X HER2 group score - 0.34 X ER group score + 1.04 X Proliferation group score + 0.10 X Invasion group score + 0.05 X CD 68 - 0.08 X GSTM1 - 0.07 X BAG1 6 Načrt Cilj Določitev velikosti dobrobiti kemoterapije kot funkcije 21- genskega RS (RECURRENCE SCORE) podpisa DOBROBIT KEMOTERAPIJE PRI ER+ N- RAKU DOJK GLEDE NA 21- GENSKI PODPIS NSABP B-20 študija: dobrobit kemoterapije pri N-, ER+ bolnicah Paik S, et al. ASCO 2005. Abstract 510. N-, ER+ Tamoksifen + MF Tamoksifen + CMF Tamoksifen Paik S, et al. ASCO 2005. Abstract 510. Permission granted to print. DOBROBIT KEMOTERAPIJE PRI ER+ N- RAKU DOJK GLEDE NA 21- GENSKI PODPIS 024 6 81 01 2 Leta 0 0.2 0.4 0.6 0.8 1.0 DRFS Ta m + K T Ta m 10 let P = .71 89% 90% P = .001 60% 88% 10 let P = .76 N 218 135 96% 95% Nizko tveganje (RS < 18) Srednje tveganje (RS 18-30) Visoko tveganje (RS≥31) 10 let Dogodki 11 5 0 0.2 0.4 0.6 0.8 1.0 DRFS 0 2 4 6 8 10 12 Leta Ta m + K T Ta m N 117 47 Dogodki 13 18 0 0.2 0.4 0.6 0.8 1.0 DRFS 2 4 6 8 10 12 Leta 0 Ta m + K T Ta m N 89 45 Dogodki 9 8 DFS Stratified log-rank p = 0.033 pri 10 letih Tamoksifen (n=47, 26 dogodkov) CAF-T (n=71, 25 dogodkov) Leta od registracije 1.00 0.75 0.50 0.25 0.00 0 2 4 6 8 10 Visoko tveganje (RS ≥ 31) DFS DOBROBIT KEMOTERAPIJE PRI ER+ N+ POMENOP. BOLNICAH Z RAKOM DOJK SWOG 8814, INT0100 študija Stratified log-rank p = 0.97 pri 10 letih Tamoksifen (n=55, 15 dogodkov) CAF-T (n=51, 26 dogodkov) Leta od registracije 1.00 0.75 0.50 0.25 0.00 0 2 4 6 8 10 Nizko tveganje (RS < 18) DFS Stratified log-rank p = 0.48 pri 10 letih Tamoksifen (n=46, 22 dogodkov) CAF-T (n=57, 20 dogodkov) Leta od registracije 1.00 0.75 0.50 0.25 0.00 0 2 4 6 8 10 Srednje tveganje (RS 18- 30) Albain K, et. al. SABCS 2007.Abstract 10 Pomenopavzne bolnice z N+ HR+ rakom dojk (n = 1470) TAM CAF-T CAFT 7 AMSTERDAMSKI 70-GENSKI PROGNOSTI ČNI PODPIS • Nadzirana klasifikacija je odkrila 70-genski ekspresijski podpis, ki je močno napoveden za kratek interval do oddaljenih zasevkov pri N- bolnicah mlajših od 55 let. • Slab prognostični podpis je sestavljen iz genov za regulacijo celičnega cikla, invazijo, zasevanje in angiogenezo. 78 nezdravljenih N- primarnih tumorjev Pri 44 brez ponovitve po 8 letih sledenja Pri 34 ponovitev bolezni v roku 5 let 5000 genov 231 genov 70-genski podpis, ki napoveduje slabo prognozo Van‘t Veer et al. Nature 2002, 31: 530-536. 8 70-GENSKI PODPIS IN KT • 70-genski podpis izboljša oceno tveganja v primerjavi z Adjuvant! Online in identificira nizko rizične skupine z odlično prognozo brez KT. 1-3 N+, Vse bolnice (N = 241) 8-let OS, % Events, n Dober podpis (n = 99) 95 5 Slab podpis (n = 142) 73 34 Kemoterapija (n = 128) 8-let OS, % Events , n Dober podpis (n = 39) 95 2 Slab podpis (n = 89) 69 24 Brez kemoterapije (n = 101) 8-let OS, % Events, n Dober podpis (n = 57) 94 3 Slab podpis (n = 44) 77 10 Mook S, et al. 2007 SABCS. Abstract 50. ONCOTYPE vs. MAMMAPRINT Oncotype DX TM MammaPrint ® RT-PCR test Genski čip na tkivu, fiksiranem s formalinom ter vklopljenem v parafin na sveže zamrznjenem, nefiksiranem tkivu prognostičen test za bolnice z ER+ N- rakom dojk, zdravljene s tamoksifenom prognostičen test za bolnice z ER+/- z N- in N+ rakom dojk ASCO in NCCN priporočilo za klinično uporabo Nizozemska priporočila za klinično uporabo High-risk 21-gene RS or high-risk 70-gene signature + high-risk Adjuvant! Online TAILORx (N = 10,500) IN MINDACT (N = 6000) PROSPEKTIVNI RANDOMIZIRANI ŠTUDIJI Pre- in pomenopavzne bolnice z MINDACT: HR-/+ N-/+(1-3) TAILORx: HR+ N- rakom dojk Chemotherapy  Randomize chemo: yes or no (TAILORx)  Randomized for the decision-making tool (MINDACT) Endocrine therapy Medium-risk 21-gene RS or discordant risk group (mostly low-risk 70-gene signature but high risk adjuvant on line) Low-risk 21-gene RS or low-risk 70-gene signature + low-risk Adjuvant! Online Potencialno prihranimo KT pri 20-30% bolnic 9 • Družinska anamneza: negativna. • Ginekološka anamneza: menarhe pri 11-ih; rodila 2x (prvič pri 27-ih); menstruacije redne; brez hormonske kontracepcije. • Sedanja anamneza: bolnica si je zatipala zatrdlino v desni dojki. • Status: notranji zg. kvadrant desne dojke 3x3 cm velika okrogla zatrdlina z retrakcijo kože, lokoreg. bezgavke niso bile tipno povečane. M.C., ♀, 38 let • Mamografija: na meji notranjih kvadrantov desne dojke, 3.5 cm, mestoma neostro omejen. • Tankoigelna biopsija: karcinom dojke • Laboratorijski izvidi: bp • Preiskave za oddaljene zasevke: negativne DIAGNOZA: KVADRANTEKTOMIJA in SNB • Invazivni duktalni karcinom BDO, največji premer 3 cm; izrezan v zdravo; SNB 0/1; • G 3 (tubuli 3, jedrni polimorfizem 3, mitoze 3),izrazita LVI, ER 30%, PR 0%, HER-2 negativen (IHC 0, FISH količnik 1.3) ; PATOHISTOLOGIJA: 10 SISTEMSKO ZDRAVLJENJE? ZNAČILNOSTI BOLNIKA Z DOKAZI PODPRTI PODATKI ZNAČILNOSTI TUMORJA RAZPOLOŽLJIVA TERAPIJA St. GALLEN 2007 - priporo čila 11 Ocena klini čno – patološkega tveganja in tveganja glede na 70-genski podpis Klini čno-patološko in 70-gensko VISOKO TVEGANJE Neskladni primeri Klinično-patološko VISOKO 70- gensko NIZKO Klinično-patološko NIZKO 70-gensko VISOKO Klinično-patološko in 70-gensko NIZKO TVEGANJE Uporabi klini čno-patološko tveganje za odlo čitev KT da/ne Uporabi 70-gensko tveganje za odločitev KT da/ne 55% 32% 13% R1 KEMOTERAPIJA N=3300 N=780 HORMONSKO ZDRAVLJENJE Microarray In Node-negative and 1-3 positive lymph node Disease may Avoid ChemoTherapy 6,000 N- in N+ (1-3) bolnic N=1920 22 PRIMERJALNA TABELA ZNA ČILNOSTI OBEH BOLNIC RM, 34 let MC, 38 let 1,5 cm tumor 3 cm tumor G3 (mitoze 2) G3 (mitoze 3) Brez LVI Izrazita LVI ER 100% PR 100% ER 30% PR 0% Adjuvant! online: 44% tveganje za ponovitev Adjuvant! online: 45% tveganje za ponovitev Genski podpis??? MammaPrint: visoko tveganje za ponovitev Ocena klini čno – patološkega tveganja in tveganja glede na 70-genski podpis Klini čno-patološko in 70-gensko VISOKO TVEGANJE Neskladni primeri Klinično-patološko VISOKO 70- gensko NIZKO Klinično-patološko NIZKO 70-gensko VISOKO Klinično-patološko in 70-gensko NIZKO TVEGANJE Uporabi klini čno-patološko tveganje za odlo čitev KT da/ne Uporabi 70-gensko tveganje za odločitev KT da/ne 55% 32% 13% R1 KEMOTERAPIJA N=3300 N=780 HORMONSKO ZDRAVLJENJE Microarray In Node-negative and 1-3 positive lymph node Disease may Avoid ChemoTherapy 6,000 N- in N+ (1-3) bolnic N=1920 22 Randomizirati ali ne ? Izvedbo so finančno podprli: Merck Roche GSK Pfizer Novartis Oncology Shering – Plough Jansen – Cilag Amgen Abbot laboratories Pharma Swiss MSD LEK Bayer Sanofi Aventis Astra Zeneca Medis Pharmadab