o Onkološki Inštitut Ljubljana Institute of Oncology Ljubljana m Onkološki inštitut Ljubljana Sektor za internistično onkologijo SLOVENSKO ZDRAVNIŠKO DRUŠTVO Sekcija za internistično onkologijo EM) GOOD SCIENCt BFTTEfi MFOICIME BF51 PRACTICf LUiC'poön S o c. lo: nlsoic.ii OUcóloív Annual Meeting of the Slovenian Society for Medical Oncology ARI TUMORS ročki predavan] 'in datum srečanja: davalnica stavba C, Ljubljana, .11,2010 d>; 2-010 6th Annual Meeting of the Slovenian Society for Medical Oncology Organizacijski in strokovni odbor: Simona Borštnar, MD, PhD Prof. Tanja Čufer, MD, PhD Asist. prof. Barbara Jezeršek-Novakovič, MD, PhD Tanja Južnic, MD, Msc. Erika Matos, MD, Msc. Asist. prof. Janja Ocvirk, MD, PhD Breda Škrbinc, MD, PhD Assoc. prof. Branko Zakotnik, MD PhD Izdajatelja: OIL in Sekcija za internistično onkologijo pri SZD VSEBINA STANDARDS AND FUTURE PERSPECTIVES IN SYSTEMIC TREATMENT OF OESOPHAGO-GASTRIC CANCER (Cervantes) THYROID CANCER (Elisei) GERM-CELL TUMORS (Skrbinc) METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (Seruga) NEUROENDOCRINE TUMORS. LUNG NET (Cufer) LYMPHOMAS IN PATIENTS WITH HIV INFECTIONS (Gregoric, Horvat, Mesti, Jezersek Novakovic) MALIGNANT PLEURAL MESOTHELIOMA (Unk, Ribnikar, Golicnik, Zakotnik) MALIGNANT PLEURAL MESOTHELIOMA. CLINICAL CASE REPORT (Ribnikar, Golicnik, Unk, Juvan, Zakotnik) ADRENAL GLAND TUMORS (Devjak, Ovcaricek, Strojnik, Borstnar) r UltótJ I1 izumim Fundación Investigación Clínico de Valencia iriciiva Andres Cervantes Associate Professor of Mcdicine Hematolog)- and Medical Oncology Dept. University Hospital Valencia Spain STANDARDS AND FUTURE PERSPECTIVES IN SYSTEMIC TREATMENT OF OESOPHAGO-GASTRIC CANCER CLASSICAL APPROACH TO LOCALISED GASTRIC CANCER • Surgical resection • Pathology assessment and estimation of risk • Treatment based upon classical TNM stage • Postoperative Chemotherapy of limited value • Postoperative Chemoradiation 1 META-ANALYSIS OT TRIALS INVOLVING ADJUVANT CHEMOTHERAPY VERSUS SURGERY ALONE FOR GASTRIC CANCER-1 Meta-analysis Year No. Trial s No. Pts Odds Ratio 95% CI Conclusions Hermanns J Clin Oncol 1993 11 2096 0.88 0.78-1.08 No benefit Earle Eur J Cancer 1999 13 1990 0.80 0.66-0.97 Small survival benefit In N+ patients Mari Ann Oncol 2000 20 3658 0.82 0.75-0.89 Small survival benefit Januger Eur J Surg 2002 21 3962 0.84 0.74-0.96 Very heterogeneous group of trials Western 0.96 0.83-1.12 Asian 0.58 0.44-076 META-ANALYSIS OT TRIALS INVOLVING ADJUVANT CHEMOTHERAPY VERSUS SURGERY ALONE FOR GASTRIC CANCER-2 Meta-analysis Year No. Trial s No. Pts Odds Ratio 95% CI Conclusions Zhao et al Cancer Investigation 2008 15 3212 0.90 0.84-0.96 Marginal, though significant benefit P: 0.001 Liu et al Eur J Surg Oncol 2008 19 2286 0.85 0.80-0.90 Marginal, though significant benefit P< 0.0001 Gastric Group JAMA 2010 17 3871 0.82 0.76-090 P< 0.001 2 Figure 3. Overall Survival Estimate After Any Chemotherapy or Surgery Atone Truncated at 10 Years Timo From Randomization, y No. at risk Any charnosrwfnpy 1924 1868 1385 1217 1080 029 709 526 380 287 243 Suraotynlaie 1857 1568 1300 1092 952 782 683 407 267 172 138 The GASTRIC GROUP JAMA. 2010; 303:1729 RECENTLY PUBLISHED TRIALS OF ADJUVANT CHEMOTHERAPY FOR LOCALIZED GASTRIC CANCER FROM WESTERN COUNTRIES Trial CT Nr. Pts Control Nr. Pts CT 5-year Survival Control Median Survival CT HR (CI at 95%) Di Constanzo JNCI2008 PELF 128 No CT 130 48.7% 47.6 % 0.90 0.64-1.26 Cascinu JNCI2007 PELFw 196 FU-LV 201 50% 52% 0.95 0.70-1.29 De Vita Ann Oncol 2007 ELFE 113 No CT 113 43.5% 48% 0.91 0.69-1.21 Bajetta Ann Oncol 2002 EAP 5FU-LV 137 No CT 137 48% 52% 0.93 0.65-1.34 3 POSTOPERATIVE CHEMOTHERAPY IN LOCALIZED GASTRIC CANCER • LIMITED VALUE, IF ANY • HRs BY 0.90 • NON SIGNIFICANT EFFECT IN MOST SINGLE TRIALS • BUT... -NONSTANDARDIZED SURGERY -MANY SINGLE TRIALS UNDERPOWERED -HYPOTETIC BENEFIT OVERESTIMATED -STRATIFIED BY MANY AND DIFFERENT CLINICAL OR PATHOLOGICAL FACTORS -HETEROGENEOUS POPULATION ACCRUED -N NEGATIVE PATIENTS PREDOMINATE -SELECTED POPULATION OF PATIENTS WELL ADAPTED TO TOTAL OR PARTIAL GASTRECTOMY -BIOLOGICAL PREDICTIVE FACTORS UNKOWN AND THEREFORE NOT APPLIED TO STRATIFICATION D2 LYMPHADENECTOMY ALONE OR WITH PARA-AORTIC NODAL DISSECTION FOR GASTRIC CANCER Table 2 Sit« of First Tumor Recurrence.* Sita D2 Lymphadenectomy Alone (N=109) D2 Lymphadenectomy plus PAND (No 106) no. (%) Peritoneum 43 (39.4) 39 (36.8) Lymph nodes 24 (22.0) 23 (217) Liver 21 (19.3) 24 (22.6) Others 21 (19.3) 20 (18.9) * In nine patients in the group assigned to D2 lymphadenectomy alone and seven patients in the group assigned to D2 lymphadenectomy plus para-aortic nodal dissection (PAND), more than one site was involved at the time of first recurrence. Sasako et al. N Eng J Med 2008; ; 359; 453 4 D2 LYMPHADENECTOMY ALONE OR WITH PARA-AORTIC NODAL DISSECTION FOR GASTRIC CANCER "3 i a «/) 1 01 > O 1009080706050403020100- — D2 lymphadenectomy --■ D2 lymphadenectomy plus PAND 10 "1 11 Years Sasako et al. N Eng J Med 2008; ; 359; 453 ADJUVANT CHEMOTHERAPY FOR GASTRIC CANCER WITH SI: AN ORAL FLUOROPYRIMIDINE TRIAL DESIGN SURGERY N= 1059 \ STRATIFIED ^N. STAGE II, IIIA, IIIB SI 40 MG/M2 BID 4 OUT OF 6 WEEKS ONE YEAR Sakuramoto et al N Eng J Med 2007; 357:1810_ 5 ADJUVANT CHEMOTHERAPY FOR GASTRIC CANCER WITH SI: AN ORAL FLUOROPYRIMIDINE Tables Site offlrst Relapse, According to Treatment Group.* Hazard Ratio for Relapse in S-l Surgery Only the SI Group Site (N = 529) (N-530) (95% CI) P Value no. of patients (%) Total no. of relapses 133 (25.1) 188 (35.5) Local 7 (1.3) 15 (2.8) 0.42 (0.16-1.00) 0.05 Lymph nodes 27 (5.1) 46 (8.7) 0.54 (0.33-0.87) 0.01 Peritoneum 59 (11.2) 84 (15.8) 0.64 (0.46-0.89) 0.009 Hematogenous 54 (10.2) 60 (11.3) 0.84 (0.58-1.21) 0.35 Sakuramoto et al N Eng J Med 2007; 357:1810 ADJUVANT CHEMOTHERAPY FOR GASTRIC CANCER WITH SI: AN ORAL FLUOROPYRIMIDINE £ 1 i 3 1/1 I ill 100 90 SO 70 60 50403020100- — ^-ii. J S-l tMif > '»iiianniL Surgery only P<0.001 1 1 '1- i i 12 3 4 Years since Randomization Sakuramoto et al N Eng J Med 2007; 357:1810 6 ADJUVANT CHEMOTHERAPY FOR GASTRIC CANCER WITH SI: AN ORAL FLUOROPYRIMIDINE 100 90 SO 70 60 SO 40 30 20 10 0 P-0.003 Surgery only Years since Randomization Sakuramoto et al N Eng J Med 2007; 357:1810 POSTOPERATIVE CHEMORADIOTHERAPY FOR LOCALISED GASTRIC CANCER TRIAL DESIGN SURGERY N= 556 STRATIFIED T 1-4 NODES 0,1-3, >3 ChT+ ChRT + ChT McDonald JS et al (N Engl J Med 2001;345:725-30.) 7 POSTOPERATIVE CHEMORADIOTHERAPY FOR LOCALISED GASTRIC CANCER 21 4B 72 96 121) Months after Registration Figure 1 Overall Survival among All Eligible Patients, According to Treatment-Group Assignment Chemoradiotherapy ^ ... Surgery only ""'"^Ltj il 1« 72 96 Months after Registration ■i 120 Figure 2. Relapse-free Survival among All Eligible Patients, According to Treatment-Group Assignments. * Clear benefit in disease free and overall survival with median follow-up of 6 years. Risk reduction of death by 24%. ■ Type of surgery: D2 resection less than 10% ■ Planning of Radiation to be modified after central review in 35% of cases due to minor/minor deviations McDonald JS et al (N Engl J Med 2001;345:725-30.) DISADVANTAGES OF POST-OPERATIVE TREATMENT ■ Efficacy of treatment used is unknown ■ Treatment appears to be less well tolerated after major surgery ■ Commencement of post-operative treatment may be delayed by slow recovery from surgery or peri-operative morbidity ■ Important morbidity related with total gastrectomy, specially altered nutritional status 8 LOCALISED GASTRIC CANCER: Estimated median survival 10-14 months STAGING AND RESECT ABILITY SATUS RESECTABLE LOCALISED UNRESECTABLE ADVANCED OR METASTATIC I MEDIAN SURVIVAL 30 MONTHS 5-Y-SURVIVAL: 30% 1 R0 RESECTION RATE 50% RESECTION IS R1-R2 MEDIAN SURVIVAL 8 MONTHS 5-Y-SURVIVAL:<5% RATIONALE FOR PRE-OPERATIVE TREATMENT ■ Tumour downstaging/downsizing prior to surgery ■ Reduction of microscopic marginal involvement with tumour ■ Increase likelihood of curative resection ■ Eliminating disseminated micrometastatic disease and achieving systemic control ■ Demonstrates in vivo sensitivity to systemic treatment * Improvement of tumour related symptoms ■ Better tolerated than post-operative therapy ■ More patients may benefit from therapy 9 DISADVANTAGES OF PRE-OPERATIVE TREATMENT ■ Risk of progression of disease during preoperative treatment * ?lncreased risk of peri-operative morbidity ■ Pathological staging is difficult after a response to pre-operative treatment ■ Need for alternative prognostic or predictive factors * Definitive surgery may be delayed if significant toxicity occurs * Patients must be referred for treatment prior to surgery Perioperative chemotherapy in operable gastric and lower oesophageal cancer: a randomised controlled trial (the MAGIC trial, ISRCTN 93793971) D Cunningham, W Allum, S Stenning and S Weeden on behalf of the UK NCRI Upper Gl Clinical Studies Group. Conducted by the UK Medical Research Council CTU. NEJM 2006, 355(1): 11-20 10 PRE-OPERATIVE CHEMOTHERAPY AND SURGERY TRIAL PROFILE CSC N=250 Commenced pre-operative chemotherapy N=237 (95%) Completed pre-operative chemotherapy N=215 (86%) Proceeded to surgery N=219 (88%) N=253 Proceeded to surgery N=240(95%) Cunningham et al NEJM 2006 11 Cunningham et al NEJM 2006 REASON FOR NOT COMMENCING POST-OPERATIVE CHEMOTHERAPY N= % Early death/ progression of disease 34 52% Never had surgery 15 Surgery but did not complete pre-op chemo 10 11% Patient request 11 12% Post-op complications 9 10% Toxicity from pre-op chemotherapy 6 6% Hickman line complications 4 4% Other 5 5% TOTAL 94 100% Cunningham et al NEJM 2006 12 GRADE 3/4 TOXICITIES Preop Postop Granulocytes 24% 28% Lymphocytes 20% 17% WBC Count 12% 11% Haemoglobin 5% 1% Platelets < 1% 3% Haemotological other < 1% 2% Preop Postop Nausea 6% 12% Vomiting 6% 10% Neurological maximum 4% 4% Skin 3% 2% Stomatitis 4% 4% Diarrhoea 3% 4% No significant difference in toxicity between pre-operative and post-operative treatment. Cunningham et al NEJM 2006 POSTOPERATIVE MORBIDITY/MORTALITY CSC S Postoperative deaths 6% 6% (14/219) (15/240) Postoperative complications 46% 46% Median duration of 13 days 13 days post-operative hospital stay Cunningham et al NEJM 2006 13 PATHOLOGY STAGING FOLLOWING SURGERY CSC S p-value Maximum tumour diameter Median (IQR) 3.cm 5.0cm <0.001, Mann- (2.0-5.0) (3.5-7.5) Whitney U test Extent of tumour (gastric only) T1/T2 52% 38% 0.009, %2 test (trend) T3/T4 48% 62% Nodal status (gastric only) N0/N1 84% 76% 0.01, X2 test (trend) N2/N3 16% 29% Cunningham et al NEJM 2006 Y PFS* Logrank p-value = 0.0001 Hazard Ratio = 0.66 (95% CI 0.53 - 0.81) Eve nls Total 163 250 CSC 190 253 .....S \ Overall Logrank p-value = 0.009 Hazard Ratio = 0.75 (95% CI 0.60 - 0.93) EventaTotal 149 250 CSC 170 253 .....S Months from randomisation 2 year survival 5 year survival Median survival CSC 50% 36% 24 mo s 41% 23% 20 mo Benefit to CSC arm 9% 13% 4 mo •Included relapse, PD and death from any cause. Months from randomisation On multivariate analysis, treatment effect unchanged after adjustment for age, performance status, site of primary and gender Hazard ratio for death ■ Adjusted: 0.74 (95%CI: 0.590.93) ■ Unadjusted: 0.75_ Cunningham et al NEJM 2006 14 MAGIC: Conclusions In operable gastric and lower oesophageal cancer, perioperative chemotherapy: • leads to downsizing of primary tumour • significantly improves progression-free survival • significantly improves overall survival Cunningham et al NEJM 2006 CAN MAGIC BE COMPARED TO INT0116? MAGIC1 (N=503) INT1162(N=556) Peri-op chemo + surgery N=250 Surgery only N=253 Post-op chemoRT + surgery N=282 Surgery only N=277 2 year survival 50% 41% 58%* 50%* 5 year survival 36% 23% 40%* 26%* Median survival 24 months 20 months 35 months 27 months Hazard ratio (96% CI) 0.75 (0.60-0.93) P=0.009 0.76 (0,62-0.93) P-0.006 Direct comparison of results is difficult due to different inclusion criteria and different time of randomization. 1 Cunningham NEJM 2006 2 MacDonaid NEJM 2001; 2004 Gl Cancers Symposium *Estimated from curve 15 PERIOPERATIVE CHEMO: FNLCC 94012-FFCD 9703 TRIAL r CT + S Randomization N=224 _i i__ FP <*> x 2/3 every 28 days ~r 4-6 weeks I Resection 4-6 weeks _\_ FP x 3/4 or no treatment I "5-Fluorouracil 800 mg/m2 d1-5* + Cisplatin 100 mg/m2 day 1 Within 4 weeks Resection Follow-up Trial accrual 1995-2003 Median FU 5.7 yrs BÖIGE et al ASCO 2007 PERIOPERATIVE CHEMO: FNLCC 94012-FFCD 9703 TRIAL 111 67 111 77 2 3 4 5 6 36 28 21 14 11 63 44 34 !6 17 Logrank p value = 0.0033 Hazard Ratio = 0.65 (95% CI 0.48-0.89) S — CT + S years 0 40 0 20 Logrank p value = 0.021 Harartt Ratio = 0.69 S (95% CI 0.50-0.95) -CT+S loflmiii: p>o*n 2 year survival 5 year survival Median survival Perlop CT 58% 38% 29 mo Surgery 47% 24% 20 mo Benefit to CSC arm 10% 14% 9 mo On multivariate analysis, treatment effect unchanged after adjustment for age, performance status, site of primary and gender Prognostic variables In Cox multivariate analysis: ■ Preoperative CT ■ Gastric location 16 SUMMARY OF TRIALS OF PERIOPERATIVE CHEMOTHERAPY FOR LOCALIZED GASTRIC CANCER Trial CT Nr. Nr. 5-year 5-year HR Pts Pts Survival Survival (CI at Control CT Control CT 95%) Cunningham ECF 253 250 23% 36% 0.75 NEJM 2006 No CT 0.60-0.93 p=.O09 Boige CDDP 111 113 24% 38% 0.69 ASCO 2007 5-FU No CT 0.50-0,95 p=.021 FUTURE DIRECTIONS IN THE TREATMENT OF LOCALISED GASTRIC CANCER - More active systemic treatment combinations, including targeted therapies - Defining role of radiotherapy in relation to systemic therapy - Diagnostic/assessment - Assessing response to treatment (i.e. role of PET) - Translational: prognostic and predictive markers TAILORING TREATMENT: METABOLIC RESPONSE 66 patients with locally advanced adenocarcinomas of the gastroesophageal union C is plat in-based chemo pre-op FDG-PET at baseline and day 14 PET Response cut-off ¿35% Predictive of response and survival Metabolic response Responder Non-responder Path Responder (<10% viable cells) 8 2 Path Non-responder (>10% viable cells) 10 36 X2 p=0.0002 jo so M Tim (monta) Ott et al JCO 2006, 24 PET TO ASSESS EARLY METABOLIC RESPONSE AND TO GUIDE TREATMENT OF ADENOCARCINOMA OF THE GASTROESOPHAGEAL JUNCTION: THE NUNICON PHASE II TRIAL PIT il*y» ft Ítíilíwci Rtucttan F^i.stujydrtgn_Lordick F. et al Lancet Oncol 2007:8:797 18 PET TO ASSESS EARLY METABOLIC RESPONSE AND TO GUIDE TREATMENT OF ADENOCARCINOMA OF THE GASTROESOPHAGEAL JUNCTION: THE NUNICON PHASE II TRIAL Rt^pond^i (r>-$0> Noo m^xKVtk'r (n-54) p Resection IIUKJIIV n (H.) HO 4S06) 4(T/4) n 00: W) 2(4! 14(26) M.-. 1.11 KHporttc' . rtCM Vex 1 '.nlil 29 (58) 0 0-001 Scorn 2 It) (20) 2(4) SiOfC 3 11 (22) 52(96) - p~ c«trqury. pTO 8(1,6) 0 <0-0001 pTl 13(26) 3(G) - pT2 B(lS] Mil) w pT2b or pT3 21(42! 44(81} - pT4 0 1(2) pH category, n l*> pNO 31(62) 11(20) 0-001 pNl 19 IW) 43 (80) ' nwporvn wof*vf *#dby Btcfcei *r«d ** «or* 1* 4tvdlc*h» complflii remlwJort and o*i**idu*l tumour.mch« ib imlhcatn I«» than 10% mifduil tumour: «or* 2 ihdicatn 10-50* re*idu»l tumour; andsccr« J u-tdicat« mem tl-wn residual tumour Tofci* SunjicAl and histopathologic al outcome-In patient* who showed a metabolic re*pOrt*evern» thov who did not «how a metabolic mponwto ncoAdjuv^nt thcmollwwpy _Lordick F. et al Lancet Oncol 2007:8:797 PET TO ASSESS EARLY METABOLIC RESPONSE AND TO GUIDE TREATMENT OF ADENOCARCINOMA OF THE GASTROESOPHAGEAL JUNCTION: THE NUNICON PHASE II TRIAL PET rwpondtrs PET non-r«pondirs Number tut ilsk PETreipaoderi' 54 PETncrtvr«pcntkT5t 56 12 24 Tin» ee> «writ (morUta) 38 29 24 13 11 2 to* NoriJwi Jtrhfc pETrssponduir 54 PET niio-iespondersf 12 Survival tlmt(monthi) 46 45 30 21 13 4 Lordick F. et al Lancet Oncol 2007:8:797 19 TAILORING TREATMENT: GENE EXPRESSION PROFILING 18 patients with gastric cancer undergoing D2 gastrectomy cDNA microarray-based gene expression profiling Identification of 3 genes for survival prediction model Validated by RT-PCR and tested in inHononHnnt toet nmi ir» n—"3A A ¿"Ofl n — IMMwkMfMrHM I» IX Survival Tim« (months) tBMln of turn» jralnMil urna UBiiejfeirnicnHir» tlr.»v tn Suwifl > to mrjLn n»J .27) Test tor overall effect: Z = 3.28 (P = .001) 0.1 0.2 0 5 Favors Combination 1.0 2.0 5.0 Favors Single Agent Wagner A, et al. JCO 2006. 28 What are the active drugs that have shown superiority in randomized trials? 5-FluorouraciI Oral Fluoropirymidines (capecitabine, S1, UFT) Anthracyclines? Cisplatin Oxatiplatin Docetaxel CPT-11 Transtuzumab SPIRITS: Study Design Central Randomization (dynamic balancing) Adjustment Factors: • Institute • PS • Unresectable vs Recurrent AGC No prior Chemo. V \l S-1 alone S-1: 40-60 mg BID for 28 days q6wks S-1 + CDDP S-1: 40-60 mg BID for 21 days q5wks CDDP: 60 mg/m2 iv on day 8 Koizumi W, et al. Lancet Oncol 2008 29 S-l plus cisplatin versus S-l alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial Koizumi W, et al. Lancet Oncol 2008 Docetaxel-based chemotherapy in advanced gastric cancer: Phase III trial Measurable/evaluable metastatic or measurable locally recurrent gastric adenocarcinoma Age >18 years KPS>70 Adequate haematological/ biochemical parameters No prior palliative chemotherapy DCF Docetaxel 75 mg/m2 over 1 h, Day 1 Cisplatin 75 mg/m2 over 1-3 h. Day 1 5-FU 750 mg/m2/day over 5 days. q3w (n=227)_ Treatment until PD. consent withdrawn or unacceptable toxicity: tumour assessments q8w Cisplatin 100 mg/m2 over 1-3 h. Day 1 5-FU 1000 mg/m2/day over 5 days, q4w (n=230) Van Cutsem E, et al. J Clin Oncol ¿006 30 Docetaxel-CF vs CF in advanced gastric cancer: Overall survival 31 Docetaxel-CF vs CF in advanced gastric cancer: Time to 5% definitive Global Health status deterioration 100- 90- 80- O 70- .t; 60- S 50 PH BCIRG 006 AC->DH BCIRG 006 DCarboH FinHer» VH / DH->CEF 1-0—1 h I- 0 Favors Trastuzumab Median follow-up, years 1 2 2 2 3 1 Favors no Trastuzumab HR Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2005; Joensuu et al 2006 TRASTUZUMAB-RELATED CARDIAC DYSFUNCTION IN EBC TRIALS EBC trials [1-year Herceptin] Arm n Asymptomatic LVEF decline, %a Severe CHF, % Cardiac death, n HERA" H 1 year 1678 3.0 0.6 0 NSABP B-31 ACDPH 947 NR 3agcum [5 yr] 0 NCCTG N9831 ACDPH 570 NR 3.3cum Œ yr) 0 BCIRG 006 ACDDH 1068 18.0 1.9 0 DCarboH 1056 8.6 0.4 0 EBC, early breast cancer; LVEF, left ventricular ejection fraction; CHF, congestive heart failure; cum, cumulative incidence; Carbo, carboplatin Slamon et al 2006; "Data not comparable due to different Rastogi et al 2007; assessment criteria; b1-year median follow-up Smith et al 2007; Perez et al 2008 35 Efficacy: OS by HER2 status Pre-planned analysis Exploratoiy analysis IHL: : - IISH > im : Median OS (months) Hazard 95 . CI St 7î YS 10= ~Q 102 vs 07 159 10È TI U 5 256 IS Ï ,s KU 13.1 8.r lis 100 J4t net! w o Oh lit 1 Ï 1 .! FdvOlsT Risk fcltio f J. .I ' I OPTIMAL THRESHOLD DEFINING HER-2 STATUS - In the exploratory pooled analysis of patients with ICH 3+ and ICH 2+ with FISH +ve, median overall survival increased to 16 months from 11.8 months - Those criteria are similar to those recommended in breast cancer guidelines1 - In ToGA, only 5% of eligible patients had ICH 2 or 1+ with FISH negative2 - Magnitude of the benefit of trastuzumab could be greater than observed in ToGA trial if those guidelines to define HER2 status were applied to gastric cancer _1 Wolff et al., JCO 2007; 2 Bang et al., ASCO 2008 36 OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) Event 1 0 09 Median Events OS Ó 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) 228 218 196 170 142 100 04 GD 51 28 218 198 li'O 141 112 95 75 53 39 28 2D 13 HER2: LESSONS FROM BREAST CANCER - HER2 is over-expressed in 15-25% of patients and indicates poor prognosis - HER2 status is defined by ICH or FISH - In HER2 positive patients, transtuzumab is active as single agent and in combination with CT1, in advanced disease and in the adjuvant setting2 3 - Transtuzumab, when given concurrently with anthracyclines, increases cardiotoxocity to 27%, but can be given after anthracyclines with a better safety profile3"4 -IVogel et al., JCO 2002; 2Slamon et al., NEJM 2001; 3Smith et al., Lancet 2007; 4Romond et al., NEJM 2005; 37 ToGA TRIAL: TOXICITY DERIVED FROM THE ADDITION OF TRANSTUZUMAB - No increase in hematological or GI toxicity - No increase in clinicaly detected cardiac events, but a higher rate of asymptomatic decrease of LVEF (4.6% vs 1,1 %) - The median duration of transtuzumab treatment is shorter than in breast cancer trials ( 4.9 months) - Cardiotoxicity might be more prevalent when used in other settings (perioperative, with anthracyclines or after second line therapy) The HERs, a dysfunctional family of receptors The epidermal growth factor family of receptors comprises 4 transmembrane proteins with distinct properties, which all regulate cell proliferation NRG1 NRG2 HER2 HEH3 HER4 HER1 Extracellular Intracellular Adapted from Tzahar and Yarden Biochim Biophys Acta 1998;1377:M25 38 Ligands Receptoi idlmers Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol 2001;2:127-37 The HER signalling network Adaptors and enzymes Cascades Signal- \ processing layer The HER signalling network (cont'd) Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol 2001;2:127-37 39 Transcription factors The HER signalling network (cont'd) Yarden Y. Sliwkowski M. Nat Rev Mol Cell Biol 2001;2:127-37 Apo ptosis Migration Growth Adhesion Differentiation The HER signalling network (cont'd) Yarden Y, Sliwkowski M Nat Rev Mol Cell Biol 2001;2:127-37 40 HER2: LESSONS FROM BIOLOGY - MECHANISMS OF RESISTANCE TO TRANSTUZUMAB • PRESENCE OF HER2 C TERMINAL FRAGMENTS (p95HER2) • INCREASED SIGNAL FROM EGFR/ERBB3 • PTEN LOSS OF FUNCTION AND ACTIVATION OF THE PI3K AKT m-TOR PATHWAY • LATERAL SIGNALING BY OTHER RECEPTOR FAMILIES BASELGA J AND SWAIN SM CANCER NAT REV 2009 HIGH EXPRESSION OF HER3 IS ASSOCIATED WITH A DECREASED SURVIVAL IN GASTRIC CANCER HER1 1050 300(1 300U Time after surgery (days) HER3 iooa 2000 soda Time after surgery (deys) HER2 low expression (n=94) high expression (n«40) p-0.0753 high expression (n=24) low expression (n-110) p-0.6288 1000 2000 30QQ Time after surgery (daye) law expression (n=55) high expresêlon (n-70) pxQ.0000 low expression (n°19) p=0.6148 1000 2000 3000 Time after surgery (days) HAYASHI M, et al. Clin Cancer Res 2008 41 HIGH EXPRESSION OF HER3 IS ASSOCIATED WITH A DECREASED SURVIVAL IN GASTRIC CANCER C HER3 100 IV—■■ „ 80 vP 8s Will -H- -»*-f-t-»- L low expression (n=55) r 60 CD > E 40 X.......... CO high expression (n=79) 20 p=0.0000 0 1000 2000 3000 Time after surgery (days) HAYASHI M, et at. Clin Cancer Res 2008 What are the active drugs that have shown non inferiority in randomized trials? 5-Fluorouracii Oral Fiuoropirymidines sCapecitabine, SI, UFT) A n t h r a c y c! i n e s ? Cis.pi latin Oxaliplatin Doc-staxei CPT-11 Trasiuzuniab REAL-2: First line phase 3 trial in oesophagogastric cancer IT r=1002 PPP = 961 ECF ECX EOF EOX Primary end point of demonstrating non-inferiority in both PPP comparisons for survival was met (upper limit of CI of HR<1.23) Arm No. (ITT) OS ORR, % Med, mo lyr EOX 244 11.2 46.8% 47.9% Cunningham et al, NEJM 2008 REAL-2: Overall survival fluoropyrimidin comparison Cunningham etal, NEJM 2008 43 REAL-2: Overall survival platinum comparison B Platinum Comparison iOU- [X. HR for ITT population = 0.91 (0.79-1.04) £ 80- V p=0.159 n \ i 3 60- \ l/l \ O \j g 40- Oxaliplatin IS 1 200- Cis pi ati n ¿-2W. i i. S-' ta ( 1 I I I » < I l 1 i J l 1 II 1 I 1 1 1 I j i i j i i { i i i1 1 2 i i | i ■ r—i 3 Years since Randomization No. at Risk Cisplatin 490 187 41 10 Oxaliplatin 474 198 48 10 Cunningham etal, NEJM 2008 REAL-2: Overall survival: ECF vs EOX comparison Cnnnirmham ft al NF.IM 5nnit 44 5-FU CDDP VERSUS CAPECITABINE-CDDP. A RANDOMISED PHASE III NONINFERIORITY TRIAL (ML17032) Estimated probability 1.0 XP (n=139) FP(n=137) Median OS months (95% CI) 10.5(9.3-11.2) 9,3(7.4-10.6) HR=0.85 (95% CI: 0.64-1.13) Compared to HR upper limit 1.25, p-0.006 ■"""■-I___ T--f-1-1 ' i' i-1-r-1-1-1-1-1-1-1-1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Months Kang YK et al, Ann Oncol 2009 5-FU VERSUS CAPECITABINE A META-ANALYSIS OF REAL2 AND ML17032 Overall Survival by Treatment (ITT) — 5FU — Cape HR:0.87 (95% CI: 0.77-098, p=0.006) Sis 5 Time Since RmuUmrisation (years) Okines AFC et al, Ann Oncol 2009 5-FU. LV, Oxaliplatin (FLO) vs. 5-FU, LV; Cisplatin (FLP) in Advanced Gastroesophageal Adenocarcinoma 220 palicnls with advanced uaslrie cancer: k A M Ssi 5-11 ' 2,000m- in 24hr / 1 euco\ orin 200m- m' y O 2 Weeks / ( Kaliplalin fv^my 'in' / J 1) 0 \ \'1 1 N 5-1 U 2.000my m- 24hr 1 Leuco\ orin ZOOmy m: y Q 2 weeks /. r: Cisplatin 50my m: i.. Al-Batran SE et al, J Clin Oncol 2009 OXALIPLATIN VERSUS CISPLATIN A RANDOMISED PHASE III TRIAL OF FLO VS FLP PROGRESSION FREE SURVIVAL Al-Batran SE et al, J Clin Oncol 2009 46 OXALIPLATIN VERSUS CISPLATIN A RANDOMISED PHASE III TRIAL OF FLO VS FLP OVERALL SURVIVAL 47 Irinotecan and Gastric Cancer CPT11 usually done in CRC (FOLFIRI): Well known and managed drug Many phases II studies: ■ Anti-tumoral activity in gastric cancer ■ Usually combined with 5FU > Good safety profile One large randomized phase II study (LV5FU2 vs LV5FU2 - Platine vs FOLFIRI): ■ In favour of FOLFIRI regimen (RR, PFS, OS, tolerance) One large phase III study (IF vs Platine-5FU): ■ Non inferiority of IF vs PF Bouché O et al J Clin Oncol 2004 22 4319-4328 Dank Metal Ann Oncol 2008 19(8)1450-7 Curran D et al Quai Life Res 2009 18 853-61 Stratification : Mesurable or not PSWHO0-1 or 2 Adj (R)CT or not Linitis or not Cardial or gastric Center < A: ECX until progression ; then FOLFIRI 2d line B: FOLFIRI until progression ; then ECX 2d line ECX : D1 = Eplnjbfcln 50 mfl/m1 (15 min.), Clsplaün 60 mg/m2 (1 h) ; D2 to 15 : Capecrtablne 1 g/m1 x 2/d. Dl = D21 CtHmÉataâ dose of EfUnjbtdn < 900 mg/m* (max 18 curts) FOLFIRI : D1 = Irtnotecan 180 mg/m1 (90 min) + LV 400 mg/m1 (2h), 5FU b 400 mg/ma, 5RJ c.l. 2400 mg/m1 (46h). Dl = D14 Time between Objective 1: 1st line Time to Treatment Failure (TTF) — Randomisation and • Objectives II : - pfs, os, (ttf 2d line) - Toxicity, - Response rate, QoL* 1/ Progression Or 2/ tt discontinuation Or 3/ Death ■ QLQC30 et STO-22 • Data not shown R Guimbaud et al, ESM0 2010 95 Primary end point: 1st line Time To Treatment Failure 1.0 0.8 0.6 u_ t 0.4 0.2 0.0 p (Log-rank)= 0.008 HR (Arm B vs Arm A)= 0.77 [0.63;0.94] Events Arm A Arm B Arm A (ECX 1st line) : 4.24 m [3.46; 4.65] Arm B (FOLFIRI 1st line) : 5.09 m [4.53; 5.66] Time (months) Bras A 209 108 33 8 4 2 1 1 1 Bras B 207 123 50 19 6 3 2 1 0 96 48 Progression Free Survival and Overall Survival Arm A (ECX 1" line) : 5.29 m. [4.53;6 31] Arm B (FOLFIRI 1" line) : 5.75 m. [5.19; 6 74] p (Log-rank)= 0.96 HR (B vs A)= 0.99 [0.81; 1.21] Arm A (ECX 1st line) : 9.49 m. [8 77; 11.14] Arm B (FOLFIRI 1sl line) : 9.72 m. [8.54; 11.27] p (Log-rank)= 0.95 HR (B vs A)= 1.01 [0.82; 1.24] 1.0 209 207 PFS Events Arm A 191 Arm B 197 129 135 8 12 16 20 24 28 32 Time (months) 57 26 17 9 7 3 3 65 26 11 8 0.4 OS Events Arm A 175 Arm B 180 0 6 12 18 24 30 36 42 48 Time (months) 209 135 69 35 18 9 5 207 142 79 38 14 7 2 3 2 0 0 97 HAVE WE MADE ANY PROGRESS IN THE TREATMENT OF ADVANCED GASTRIC CANCER? ^^^^^^ 13.8 months 11.2 months 10.7 months 10.S months 9.2 months 5-FU'monotherapy1 7 months Best ■ supportive 4 months MEDIAN OVERALL SURVIVAL IN ADVANCED GASTRIC CANCER 1. Wagner A, et al. JCO 2003, 2. van Cutsen E, et al. JCO 2006. 3.Kang YK et al, Ann Oncol 2009. 4. Al Batran SE, et al. JCO 2009. 5. Cunningham D, et al. NEJM 2007 6.van Cutsen E, et al. ASCO 2009. 49 HAVE WE MADE ANY PROGRESS IN THE TREATMENT OF ADVANCED GASTRIC CANCER? 2.7 months 1.2 months 1.9 months 1.2 months 0.6 months 2.0 months 1,0 months 6.0 months ABSOLUTE INCREASE IN MEDIAN SURVIVAL IN ADVANCED GASTRIC CANCER 1. Wagner A, et al. JCO 2003. 2. Kaizumi W,et al, Lancet Oncol 2008. 3 van Cutsen E, et al. JCO 2006. 4.Kang YK et al, Ann Oncol 2009. 5. Al Batran SE, et al. JCO 2009. 6. Cunningham D, et al. NEJM 2007. 7.van Cutsen E, et al. ASCO 2009. HAVE WE MADE ANY PROGRESS IN THE TREATMENT OF ADVANCED GASTRIC CANCER? HR: 0,74 p=0.0046 HR: 0.80 p=0.02 HR: not shown p=0.56 HR:0.85 p=0.008 I HR:0.77 p=0.02 | Combination vs monotherapy' HR:0.83 p=0.001 Chemotherapy vs BSC1 HR:0.39 p<0.00001 - w RISK OF DEATH REDUCTION IN ADVANCED GASTRIC CANCER 1. Wagner A. et al. JCO 2003, 2. van Cutsen E, et al JCO 2006 3 Kang YK et al, Ann Oncol 2009. 4 Al Batran SE, et al. JCO 2009. 5. Cunningham D, et al. NEJM 2007. 6.van Cutsen E, et al. ASCO 2009. 50 AVAGAST: first phase III randomised trial with bevacizumab in gastric cancer_ Stratification factors 1. Geographic region 2. Chemotherapy backbone 3. Disease status 5-FU also allowed Capncitabme 1.000 mg/nr bid days 1-21 Clsplatln 80 my/nr day 1 Maximum of 6 cycles of cisplatin Capccltabme and bcvacizumab/placebo until PD • Primary endpoint: OS • Secondary endpoints: PFS, TTP. ORR, duration of response, safety, QoL, biomarkers XP - capocitabinci'cisplatin; GEJ - gastroesophageal junction Available at: http://clinicaltri.ils gov/ct2/show/NCT00548548 51 Primary endpoint: OS Irinotecan versus best supportive care (BSC) as 2nd-line therapy in gastric cancer Arm A Irinotecan 250 mg/m2 q3w (1st cycle) to be increased to 350 mg/m2, depending on toxicity * Arm B BSC 120 patients planned to he included Trial closed due to poor accrual (40 patients in 50 months) Thuss-Patience PC et al, ECCO/ESMO 2009 abstr 6504 Overall survival (ITT-Population) £ «04 Irino: n = 21, 21 events, median = 4.0 mths BSC: n = 19, 19 events, median = 2.4 mths Logrank test: p = 0.023 HR: 0.48 (95% CI: 0.25 - 0.92) "I—[—I—r i 1—1—i—I—I—I—1—r—T—I—T—¡—I—n B0 120 160 200 240 280 320 330 400 Aid 4fi0 ¡20 560 MO days Thuss-Patience PC et al, ECCO/ESMO 2009 abstr 6504 Recommended approach to advanced gastric cancer patients Select patients with PSO-1 to participate in clinical trials CT should have a palliative role Patient reported otcomes of value Assess the risk of toxicity vs benefit TCF, ECF, EOX, XP or similar schedules of value Consider second line therapy for selected patients. More trials on this point are needed 53 Recommended approach to improve results on gastric cancer patients Design better clinical trials within academic and community centers International Cooperation Biological agents should be studied in randomized trials Further studies on better predictive and prognostic biomarkers MULTIDISCIPLINARY TEAM FOR GASTROESOPHAGEAL CANCER UNIVERSITY HOSPITAL VALENCIA • Radiology: Marta Rausell • Pathology: Samuel Navarro • Surgery: Fernando López, Roberto Marti, Blas Flor, Salvador Lledó, Vicente Tarrazona • Radiation Oncology: Ana Hernández, Pepe López Torrecilla • Medical Oncology: Desamparados Roda, Alejandro Pérez-Fidalgo, Susana Roselló, Andrés Cervantes 54 6° Annual Mi eetirtg of Slovi enian Medical On cology Assoc ia+io Lj jubljana 12-13 N lovember, HO Klimi] Rossella Elisei Department of Endocrinology, University Hospital, Pisa, Italy THYROID CANCER IS RARE TUMOR AND REPRESENTS ONLY 1% OF ALL HUMAN TUMORS EQUENT CANCER AMONG ALL ENDOCRINE TUMORS !!! 1 THYROID CANCER HISTOTYPE (Department of Endocrinology, Pisa) 70 TS H »APILL,\P££ FOl.L'K'UL/l t MORPHOLOGY VARIANTS: a) CLASSIC b) FOLLICULAR a) souD dj TRABECULAR S; i®L-UMNÄ& f) TALL. g) warthin like VARIANTS: PAPILLARY FOLLICULAR a) MINIMALLY INVASIVE; fc>) WI'Dfc'LY INvASTVg 2 PAPILLARY THYROID CARCINOMA TYPICAL NUCLEAR FEATURES Nuclear pseudoinclusions Chromatin clearing margination along nuclear membrane Oval cells Grooves ^ GOOD CVTOLOGICAL DIAGNOSIS ^ Widely invasive Minimally invasive ONLY HYSTOLOGIC/\L DIAGNOSIS FOLLICULAR CARCINOMA AND CAPSULAR INVASION 3 THYROID TUMORIGENESIS: MOLECULAR EVENTS Meta-analysis (2003-2007) of in thyroid tumors: prevalence in different hystotypes Benign FA nodules FTC PTC PDC and ATC RET/PTC + BRAF + H-Ras + Jp/\X-8/PPARg + 5-10% 5% <1% <1% 5% 34% 0 7% 0 30% 5% 1 ] 0 45% 20% 45% 15%* 5% 30% 11 % 0 w V /U A A f V v dus mutations as prognostic factirs Survival of thyroid carcinoma patients with (n=35) and without (n=72) ras mutation i 1 ^ I 0.50 RAS- \ 72 patiente. 23 DOO RAS+ 1 0.00 35 patiente, 26 DOD p < 0.001 5 0 48 96 144 1«? 240 288 Months Modified from Garcia-Rostan et al J Clin Oncol 2003 5 RADIATION AND THYROID CANCER Thyroid cancer in Belarus before and after the Chernobyl accident Age 1971-1985 1986-2000 Fold of increase 0-14 8 703 87.8 15-18 21 267 12.7 >19 1465 6719 4.6 Total 1494 7689 5.1 7 Estimated risk of developing thyroid cancer after radiation dose of 1 &y, by level of soil iodine and potassium iodide supplementation at the time of Chernobyl accident OR at 1 Gy (95% CI) Consumption of potassium iodide Highest two tertiles Lowest tertiles of soil iodine of soil iodine No 3.5 (1.8 to 7.0) 10.8 (5.6 to 20.8)* Yes 3.3 (1.0 to 10.6) * Lowest r^sk "^Highest risk From Cordis E et ol J Natl Cancer Inst. 97: 724-32. 2005 PREVALENCE OF THYROID NODULES AND THYROID CANCER IN 2 SICILIAN AREAS WITH DIFFERENT IODINE CONTENT IODINE DEFICIENT AREA (IDA) IODINE SUFFICIENT AREA 1 _(ISA) CANCER (n.) NODULES (n.) CANCER (inc) PAP/FOL ratio 27 (3.0%) 911 (4.3%)* 127/105/yr 1:1 139 (5.5%) 2537 (1.7%) 93/105/yr 3.7:1 *IDA > ISA 2.5 from Belfiore A, Cancer 1987 PTC AND FTC PREVALENCE BEFORE AND AFTER IODINE PROPHYLAXIS IN AUSTRIA 1952-59 1970-75 1984-89 1990-95 From Lind, Thyroid 2002 9 PAPILLARY AND FOLLICULAR HYSTOTYPES IN PISA SERIES 1969-2004 SEX DISTRIBUTION IN PAPILLARY AND FOLLICULAR THYROID CANCER p= ns and 6.2 % per year In females and males respectively. Laurence Leenhardt et at, Thyroid, 2004 Evidence of significant increase of thyroid cancer incidence but not of mortality cf Incidence \j/ Incidence Mortality _»_ Mortality Trends in SEER Incidence by Primary Cancer Site 1992-2001 Trends in SEER Incidence Rates Thyroid Liver & IBO ^mm - 4* Melanoma of ttra Shin Kidney & Renal Pelvis HI; 4* Teetto Hi Breast (Female) lQ.fi* Esophagus los NciiVrUxi&hin Lymphoma 00 Urinary Bladder -Ol Corpus & Uterus, NOS -CU Lung 1 Bronchus (Female) -02 1 Pancreas >0.« 1 Hodflkln Lymphoma -OS 1 All Except Lung -o e* a Al Cancer Sites ¿r a Bfain&ONS 0,* 1 Myeloma 07 a Colon & Rectum •flff* ■ Leukemia -10' ■ Ovary 10' ■ stomach -t.C* HI Oral Cavity & Pharynx •2 0" ■■ Lung & Bronchus (Male) iy BH Prostale -2 5* I^H Cervix Uteri Larynx 20- WV 1 | 1 | i' J Jl 1 1 1 1 1 I"'1 Soüfce: SEER 12 areas and NCMS ptible im .TUbapc¡wTSiiftmp ^rwipt The AI II t&twW nnp: 01 II ton) wo ID- »]. -4 -2 0 2 4 6 B APC, 1992-2001 Be for ttieIfiUI US RMeeenpar100.0fl0Me0e-edMtedta11w30UIUSMen 1991 1991 19SF 2000 Ftticuiar PoalyairerenlfatW *MTC and ATC Davies L and Welch G, JAMA, May 10, 2006 modified with the data of the Italian Network of Cancer Registries Papillary thyroid cancer Follicular variant Increased incidence up to 173% according with Semsenjager E. et al, Swiss Med Wkly 131:157, 2001. / «A.*® * I • 'h ■>*» » .a * iNcmewce or PAPILLAHV CABCJNOHA ONLT «KO We FOLLICULAR VARIANT - seen Ilil'llHIMI ¿p -¡r-f s spiffs? YHAK P%- 2 Increau in p^iiltay caittnofTM iinj the (bllkuhr varim over lOyan (Jprt|g AlftvTCF-SnnvDdras et II. Ëjtdttcr Pflthul, Trend incidence of papillary thyroid cancer by size in USA (1988-2002) Davies L and Welch &, JAMA, May 10, 2006 Percentage distribution of mPTCs on the overall CTDs (793/4108) diagnosed in Pisa between 1972-2003 Possible reasons to explain this increase of thyroid cancer incidence Thyroid nodule prevalence 70 60 • • Autopsy or v—/ jf Neck ultrasouru ft) o DU / c ft) 40 • jf a ft) ou / S— a. 20 ■ t/ 10 • / • n / • U ( ) 10 20 30 40 50 60 70 80 90 Age (yrs) (Mazzaferri et al. 1993) About 50% of all thyroid nodules escape detection on clinical examination Thyroid Nodule Prevalence at Autc » jpsy Author Subjects (n) Prevalence (%) Age Rice, 1932 Hellwig, 1935 Mortensen,1955 390 100 821 57 51.3 49.5 11-75 5-85 All ages Burg uera and Sharib 2000 20 Thyroid Nodule Prevalence by Palpation Author Subjects Prevalence Age (n) (%) Van der, 1968 5127 4.2 30-59 Tunbridge, 1977 2979 3.2 18-75 Wang and Crapo 1997 In the '80s: neck ultrasound 21 Thyroid nodule: not visible, not palpable Number of cases per year of PTC in relationship to the tumor size (Rhone-Alpes region tumor registry) >2-4 cm 1998 1999 2000 2001 2002 2003 2004 2005 2006 Years Sassolas G. et a! Eur J Endocrinol 160: 71, 2009 Are the Clinical and Pathological Features of Differentiated Thyroid Carcinoma Really Changed over the Last 35 Years? Study on 4187 Patients from a Single Italian Institution to Answer this Question Rossella Elisei,* Eleonora Molinaro,* Laura Agate, Valeria Bottici, Lucio Masserini, Claudia Ceccarelli, Francesco Lippi, Lucia Grasso, Fulvio Basolo, Generoso Bevilacqua, Paolo Miccoli, Giancarlo Di Coscio, Paolo Vitti, Furio Pacini, and Aldo Pinchera J Clin Endocrinol Me tab, 2010 Changing features of thyroid tumors Total 1969-1989 1990-2004 P series Group1 Group2 N of patients 4187 1215 2972 (29.0%) (71.0%) Sex Female 3166 944 2222 0.04 (75.6%) (77.7%) (74.8%) Male 1021 271 750 (24.4%) (22.3%) (25.2%) Age at diagnosis 42.5 +14.4 42.2+15.8 42.6+13.9 NS (0.56) (5-88) (5-84) (7-88) Median 42 Median Median 42 aa 41aa aa Histotype Papillary cancer 3684 979 2705 <0.0001 (PTC) (88%) (80.5%) (91.0%) Follicular cancer 503 236 267 (FTC)* (12%) (19.5%) (9.0%) 23 Changing features of thyroid tumors Total series 1969-1989 Group 1 1990-2004 Group2 P N of patients 4187 1215 2972 Coexisting thyroid diseases None 2661 (63.6%) 882 (72.6%) 1779 (59.8%) <0.0001 Nodular Goiter 1089 (26%) 271 (22.3%) 818 (27.5%) 0.0006 Autoim Thyroiditis 24 (2.0%) 292 (9.9%) <0.0001 Graves' disease 91 (2.2%) 25 (2.1%) 66 (2.2%) NS (0.8) Toxic Adenoma 30 (0.7%) 13 (1.1%) 17 (0.6 %) NS (0.1) Neck irradiation 119/3898* (3.2%) 63/1021* (6.1%) 56/2877* (1.9%) <0.0001 ' Information on the radiation exposure was not available in 289 patients: 194 of Group 1 and 95 of Group 2 Changing features of thyroid tumors Total series 1969-1989 Group 1 1990-2004 Group2 P N of patients 3997* 1175* 2822* Presenting symptoms thyroid nodule 2670 (66.8%) 772 (65.7%) 1898 (67.3%) NS (0.3) incidental finding 657 (16.4%) 94 (8.0%) 563 (20.0%) <0.0001 cervical 396 200 196 <0.0001 nodes (9.9%) (17.0%) (7.0%) local symptoms 134 (3.4%) 58 (5.0%) 76 (2.6%) 0.0005 hyperthyroidism 104 (2.6%) 30 (2.5%) 74 (2.6%) NS (0.9) distant 36 21 15 0.0003 metastases (0.9%) (1.8%) (0 5%) 24 Changing features of thyroid tumors Total series 1969-1989 Sroupl 1990-2004 Sroup2 P Tumor size: N* 3996 1100 2896 1 cm (mPTC) 923 (23.1%) 87 (7.9%) 836 (28.7%) <0.0001 >1 cm 2 cm 1132 (28 3%) 389 (35 4%) 743 (25.8%) <0.0001 >2 cm <4 cm 1409 (35.3%) 432 (39.3%) 977 (33.7%) 0.002 4 cm 532 (13.3%) 192 (17.4%) 340 (11.8%) <0.0001 Local extension: N* 3625 824 2774 No extrathyroid 2967 (81.8%) 673 (81.7%) 2267 (81.7%) NS (0.4) Extrathyroid 658 (18.2%) 151 (18.3%) 507 (18.3%) T3 (micro-invasion) 545 (15.0%) 93 (11 3%) 452 (16.3%) 0.002 T4 (macro-invasion) 113 (3.1%) 58 (7.0%) 55 (1 9%) <0.0001 Changing features of thyroid tumors Lymph nodes metastases: N* 4184 1213 2971 1081 (25 8%) 415 (34 2%) 666 (22 4%) <0 0001 Distant Metastases: N* 4184 1213 2971 127 (3%) 66 (5 4%) 61 (2%) <0 0001 Clinical Classes (De Groot's classification): N* 3995 1102 2893 I 2450 (61.3%) 542 (49 2%) 1908 (65 9%) <0 0001 II 764 (19 1%) 332 (30 1%) 432 (14 9%) <0 0001 III 655 (16 4%) 163 (14 8%) 492 (17 %) NS (0 1) IV 126 (3 2%) 65 (5 9%) 61 (2 2%) <0 0001 Multifocality: N* 3726 896 2830 1354 (36 0) 283 (31 5%) 1071 (37 8%) 0 0008 Bilaterality: N* 3662 873 2789 730 (19 9%) 134 (15 3%) 596 (21 4%) 0 0001 25 2 major considerations: Finding of small papillary thyroid cancer (and of other changing features) as consequence of the widespread use of neck ultrasound anticipation of diagnosis Increased percentage of less advanced tumors (both for lymph nodes and distant metastases) SURVIVAL OF DTC PATIENTS (N=4187) AFTER A LONG TERM FOLLOW UP OF 35 YEARS (Elisei R et al, JCEAM, 2010) THERAPEUTIC STRATEGY 80-85% "CURED" 1% RISK OF RECURRENCE UP TO 20 YEARS 27 MULTIVARIATE ANALYSIS OF PROGNOSTIC FACTORS IN THE TOTAL SERIES, GROUP 1 (1969-1989) AND GROUP 2 (1990-2004) \ Aim HI I S to I \ '-I Kit s BE I'OKM I'/iJil \f ll It 199» u SE i> tlH H M ! i> Ol* P SE |l (III fruiter! malt i> Immlr 11.41 11.26 it.uo; \.ff (Pifi li,3rp i II, 1U Ii?? 11.4.1 11.42 tun (>jr»»):< •Vi VAU «1411 ^fiQ vi < 40 2. J J i.fto 11.62 II. i.l - o.i iiiiii ii.finni 11,Hi 41.111 Ml 4.5.1 1.1)4 P.IU 0.11115 ii.i mill Hilfl «&» i.ta MI n.mi 11.7 V ii.fliti o.oobi ft.DI 21.52 I'M v*rr< 41.0? i|47 it, m> i II,.III -1.44 lljf Ii. um il II. 2 J ii,i u.j/c (» in|: 1-2 v* 1 2+4 iv i _ 4 v* 1 -Mi .11,14 1.71 lU? <1.41 IP..»1! U.tltJ It*.! DJOtS IU2 II.'K 1.IH -11.41 j -0.1 it (P.07 ().<>), 11,ft) 11,(1(1 11.54 J n.s:« 0 1114 U.ftll li. i.oi 0.01 11.70 il.»,i o.i") IWWi fl III.'' 11.17» O.PII 0,12 I.UI J.« 1 «t-rtl fMrnilm<4uliil ritrnviiiii hvilli n tt if twill) I i'i a,fit IM145 iu.t .II.S1 0,119 <1.11(1 tl.411 /1.045 «¡12 I 1-Mil[ill lllliic Hii'linMisf* ft* Ith v* «nliiiiiii i.tii . II.UOM) 4.51 I,IUI ll.fl <1,(141 1') I. IJ !6 1MII4 4,1 l)i"(inKil't(!liitt! Jn i ■i"L_ II. N 1.1» iww 0,5V U.,1* it.'i'^ 0,'IIIJ IP.HI HI P I.III i.TO m.ii- (Ii 4$ I.Dil Iii« |l;74 ii.i.d H r U.iJS ii,(i If ii.uiiiii Ii» n.nf IH.K4 n.24 1.21 i.Olt II.»7 0.11; (l.-J II. TVS II ill 15 ii.dliill >.27 0.1" M.iJ Yftir Iii ill.i^M mi; I'DOlli-, .. |Wll .II.JU) Mi 11.11 111 11.41 Survival of DTC patients with and without distant metastases at the diagnosis Department of Endocrinology, University of Pisa 4187 DTC from 1969 to 2004 100 80 TO 60 > 'e 40 Cfl 6- 20 o- 0 p=<0.0001 10 15 20 25 30 Follow up (years) 28 29 POORLY AND/OR DE-DIFFERENTIATED THYROID TU/ * $ 20-30% of thyroid carcinomas lose the capacity to uptake iodine NIS ^Ooooo 131-1 useless i No Uptake of Iodine to do? DE-DIFFERENTIATED THYROID TUMORS ARE CANDIDATE TO CHEMOTHERAPY 10-year survival after chemotherapy, external Rx or both °L inn (Dept. of Endocrinology, Pisa) /O I Mil ■in k 1-n Chemo (n=15) Ml 70 — Chemo+Rx (n=19) (ill Rx (n=10) >11 \ \ \ ; \ \ \ 411 t \ \ .ill \ 211 1 ., 1 III JL \ • ■-V, 1 ™T 1 r n 1 r 1 T T ^S? < 1 1 J t .1 5 1. 7 S '1 III II 30 OVERALL RESULTS OF CHEMOTHERAPY VARIOUS COMBINATIONS OF DIFFERENT DRUGS PRODUCE SIMILAR RESPONSE RATES (20-30%), WITH SYMPTOMATIC IMPROVEMENT IN SOME PATIENTS BUT NO BENEFIT ON THE SURVIVAL RATE THE RESPONSES ARE USUALLY PARTIAL AND SHORT-LIVED. THE TOXICITY OF THE DRUGS IS USUALLY VERY HIGH OTHER THERAPEUTIC TARGETS Aii|»:>gcitc%it mmmiT OCN 10.1007/s 1M56 -009-9 IftÖfi I REVIEW PAPER Anti-angiogenic tyrosine kinase inhibitors: what is their] mechanism of action? KrLsty .1. C^jllnk - Hcnk M. W. Vcrheull |Sunhinih (SU1124«; Sulent) HSnrafenib (BAY439006; Neu va r) I Pazopanib (GW7 86034; Vot rient) || Vandetonib (ZD6474; Zactima) I Axitinib (AGO 13736) |Cediranib (AZD2I71; Recentin) IV Wulm i h (PTK7R7; ZK2225R4) |Motesanib (AM0706) Target Clinical activity andfor study Phase ofdevebpment VEGFR-l, -2, -3, PDGFR, KIT, FLT3, CSF-IR, RET VEGFR-2, -3, PDGFR, Raf, KIT VEGFR-l, »2, -3, PDGFR, KIT VEGFR-2, EGFR, KIT, RET VEGFR-l, -2, -3, PDGFR-ß, KIT VEGFR-1, -2, -3. PDGFR- fi, KIT VEGFR-l,-2, .3, PDGFR-pt KIT VEGFR-l,-2, -X PDGFR, KIT, RÊT Kidney, breast, prostate, lung, liver, ovarian, colorectal, thyroid, head and neck, gastric, bladder, cwvical and pancreatic c«ice\ GIST, mdanoma, glioblastoma, myeloma, lymphoma Kidney, liver, breast, prostate, limg, ovarian, colorectal, thyroid, head and neck, gastric and pmcreXic canco-, GIST, melanoma, glioblastoma, lymphoma, leukemia KiAiey, breast, lung, cervital, liver, thyroid, prostate and colorectal cancer, melanoma, glioblastoma Lung, kidney, thyroid, head and neck, prostate, ovvian, breast and colorectal cancer, glioma, neurobl&floma KiAiey, lung, thyroid, paicreaic, colorecinl and breast cancer, melanoma Ki { f > \ V / 3rs * * * » \ il/ Kindly provided by Or Wells S, büke University, USA BRAIN/BONE METASTASIS FROM UNTREATABLE FOLLICULAR THYROID CANCER 34 Follicular thyroid cancer: primary tumor r WiiiÈM Follicular thyroid cancer: brain/bone metastasis ANAPLASTIC THYROID CANCER BEFORE THERAPY AFTER 10 DAYS AFTER 20 DAYS OF THERAPY CONCLUSIONS Thyroi cancer ¡s a rare tumor but is the tumor with the highest rate of increase in incidence With the exception of a significant increase of small tumors, all the other epidemiological features have been maintained over the years The vast majority is curable with conventional therapy (i.e thyroidectomy and 131-1 radiometabolic therapy) New therapeutic strategies with TKI are under investigation for the treament of advanced/radioiodine refractory cases (15-20% of all cases): very promising results!! 36 LZ GERM-CELL TUMORS B . BredaSkrbinc, MD, PhD Institute of Oncology Ljubljana TAILEl Ouamcjüon or khe Ph«B Tv oca of Germ-Cefl Turoon (Oortirhu»» nd looljtwfla, ZQD5). 5« Text for Purtlwr Pwfrlto tiiia/O-K»/ iacral reg-on,' retro perito- mediastinum/ neck/nu'dflne braln/other rare Testis pysgirrrmamai non seminoma Dwgermuwma/ Dysgerelfc mediastinum (ttiyrrus) MHPne brain [p'neal gland/ f*>poi)*aiafmjs) Test* Ptocenta/ulcius HytJatrfo'm md« »Of/ (median age 35 and 2S itars) Congenital AdoteiCTnli OiMrei (median age 1J years) PGC/gonocyle PGC/gonorytc PGC/gonocyte PGQ9 ovocyte Fraud Erased E.-ased Erased OiWreti/adulB Spermatogonium/ Papally 5(>erroatocv(« compete palcral ■» 5D years OogoilaAxWe Partially complete matemil C^twaasnwi turnrr |i of lq, D(Mn>nj ion. •rMlSiASf IM wlbq AiienJo« (i/-bn'pbld) gam of X, 7. 8, Up, and Aneuptoid Dijiofd/'e rap laid (Near) dlpkiW, drytoU/tiireploti. oet wpk)!d [gain o; x, 7, 12, and IS) 1 Epidemiology * Germ-cell tumor type II - most common solid malignancy of Young Caucasian men between 15 and 40 years of age « The incidence in Europe rising, with doubling every 20 years ■ Current incidence 6.31100 0001 year ■ Highest incidence in Northern European Countries 6.81100 000 I year Byology of GCTII -1 2 Byology of GCT II - 2 Samlnltaroua tubula (cross sactlon) Epididymis Teatl* Sftmlnlfaroui tubule CPrimordial \ germ cell J "--T--- spermatogonium (gj> ^ (diploid) i Mitotic division «rs Primary opormniocyto (diploid) (in prophase of meloals 1) / \ First melotlc division »» Secondary spermatocyte ** * (haploid) v ^ Second melotlc division 2 (f\ 6/ Spermatid» Spermatids (haploid) (at two stag ot differentiation) Spann call a (haploid) wvv- ¿ia. Byology of GCT II - 3 ICM @ w ® • Spermatocytes Spermatids Neoplastic development Biology of GCT II - 4 s e? # 0 20 f"^ Carnegie Stages Byology of GTC II - 5 Preinvasive cis/iecNu o 200 considered a non-seminoma Extrygonadai tumor syndrom □ high tumor markers □ biopsy Diagnosis I staging I risk assessment 2 Extrygonadai tumor syndrom □ retroperytoneal or medistinal mass □ high tumor markers □ biopsy n undifferentiated (adeno)carcinoma of unknown primary ■ tipical TM elevation m elevated copy number of cromosome i12p (specific for germ cell tumore ) ■ 1/3 CIS In testis ■ 1/3 burned out tumor (scar In testicular tissue ( a 1/3 defflnltlveprlmary extragonadal GCT without affecting the testicle Diagnosis I staging / risk assessment 1 • blood tests ► differentiation of stage and IGCCCG prognostic group: TM determined • before orhiectomy • 7 days after orhiectomy Diagnosis / staging / risk assessment 4 Testicular sonography of both testicles mandatory it Diagnosis I staging I risk assessment 5 CT scan abdomen, pelvis mandatory mm. m. Diagnosis 1 staging 1 risk assessment 6 Ct scan of chest mandatory exeption pure seminoma stage I 12 Diagnosis I staging / risk assessment 7 In case of borderline lymph node size, CT scan should be repeated in 6 weeks to define definitive treatment strategy If imaging is normal TM decline monitoring until normalization MRI of CNS only in advanced stages or with symptoms Bone scan in case of symptoms PET scan - no contribution in early stages a possible option in seminoma stage II / III for defining treatment strategies in case of residual leseions n staging of seminoma according to UICC/AJCC and IGCCCG classification Cfll»iiç*i TMM (UlCC/AJQCiltOWy SartM igcccg pTAQUiHliC gfoup* """ r X w « LO»»4 (»Si' AFP WW « ntiwtubular germ cell inopMa hiO MO n a. » oT1 ■inn« \o am nra itpkfldpr*, without jaecularf lymphatic nvaelon; tumour may nv»da Ink) 0» Uwikca >ilbuglnaa but not lite tunica nglnda NO MO 6-n iny level .iny level Donnai na. «1 oT2 iHTUwa io Maw ana itpkfldyrrtfa. with vascular/ lymphatic Invaaion or lumour «tending through Ihe lurks afcugtnM WHh involvement of tha tunica tasinaBa NO MO uny (aval norme n a pTS invaaion of aparrreMc cord PT* invaaion of acratum I1A N1 |i2mi) MO tny lavd iny lavai nom»! n.a tin N2 (>2-5 cm) MO iny laval any IBV* normal NC r„ N3 (>s em) MO 3« •ny levai «6«i*J ----— — nir^utiular IF"" oaU naopiaaia N HO u MO ■ so*/ ax' pTi p-cs— ciwni 4A umour mmy Invda' Ms tn* tunlo* <*<«lrM but una* Itintaa v^nM 1« MO ■o bwiM (sao*) Ta «E^r^^Mii,*.^!!«.* Of ttt no MO •0 — — «V rt* (HOft) Hb<4jkiM wWi Inviihnini of na unka - ~ # * BO — — — iflCCíO -- ._ . _, - -—■■■ —- T«ny MO MO da....... »1 KB ¿«3 ■ '^BTO' «mi. u«t Chmtlmw .FBuScyeh« .¿A IMmnwC -RspnanftagM HMnrycta PEilCj*. * AtMlúr Mar V f pvrion mMNnpy: dWTVtnr^y M Mp I1CM a dHMlNfm i FEB K 3 epfct * 1 H^UMM igaM Uauiif.kt: PE x 4 o/o "Hi" II1 X •¿A ulMQt (JWMtmipy; conrtvmMlwqiyFor locrtnd^M cfMHttwipy * Good pn^Mtb OtvnHUwipr * CT • Fctewvp (BCCCQ): Ft ncphi I <3em: PETopM ¡«I^wocÍSmmj • PUT dMMmpjK fntWUp «H*pwfiwiCM«D ICV f ' ooHddtr Mtcüon wÉhiMy • Into up > •Muwia« ■ vmUm FBdatwapy «Pragm^n nwUffeiw H), widMÉ. ran i hbtmdlfc pMQtnk (OCCCO): PEB¡Mon*»(5d| ^iJAi-igkU tAMUk/r^r PET IKWIMKM • roPETficn« Ma»q>orm>dion • PET i*n» (iw ip • PETOwmiWflpMl*»; xrwjBmmjir ) - Mtnga dwKtmvf tooal^ralMlm Treatment algorithm for non-seminoma stage I Clinical stngo Clinical prognostic classified Ion T»t choice îrtiimnt Irai choice 3rd choke IA 'Low risk" (no vascular Invatlon) Surveillance Adjuvant cherttolfwrapy * (PEBx 2 óyeles) Only for very restricted cases (e.g. If chemotherapy or >- surveillance declined by the patient): nerve spertng-RPLND IB ■High risk" (vascular Invasion) 2 comparable ojillons with 9am« finHl outcome (> 98% survival) will i différent treatment/ follow up burden • adjuvant chemotherapy (PEBx 2 cycles) or • surveillance • Survaillnrra or • ad|uvant chemotherapy (PEBx 2 cycles) ---a " Treatment algorithm for non-seminoma stage II A / B Clinical slago Treatment Result I Further management IIA marker + Chemotherapy »CR Follow up il s marker+/- • standard: PEB x 3 cycles • option: PE x 4 cycles • Residual tumor (»1 cm) Reseotlon and follow up • PD, and marker © PEB x 3 cycles (or PE x 4 cylces, In case of residual tumour (> 1 cm): resection Strategy 1* follow up only q 6 weeks • PD, marker remains 0 PEB x 3 cycles (or PE x 4 oycles) or* Nerve sparlng-RPLND • NC Nerve sparlng-RPLND II A marker- • Regression Further follow up Btrategy 2* active treatment: biopsy or nerve aparing-RPLND • Pathological stage I Surveillance (Independent of vascular Invasion) •Pathologloal stage IIA/B • Follow up or* • PEB it 2 cycles or* • PE * 2 cycles ■ ftrnlva^nn miittinti 15 Treatment algorithm for advanced non-seminorna stage tfC - III m » HD • 3 tn* () v í A hleerryw p£ 1 4 ioi*it«rpí IMX* a>1S ■» fn HI Ham Hi ■ n>. ra «Huma • ML«kMniip«M<1ffi •» htmv • «.Mm ■» Fotow •tlErntdicB am f R?. iadMfiMdsftiM0N J (•« WJicn««) - v , s /¿Uvto-HI 4 F<2« •» tmtmmf m 1 • <12w Í g^MMMIIB. ÜMlflNUn) 'tart* Irtw »frdtolng^wln^ 'dfcitahrtíifcWH ni; npta^ÉÉÉ Folow-up for seminoma Clinical stag o Strategy investigations (year) 1 2b 3 4 S1" 6 to 10" 1 Surveillance Exam/markers* 4x 4x 3x 2x 2x. 1x Chest X-ray 2x 2x 1x IX 1x - CT abdomen 2x 2x 1x 1x 1x - Csrboplatiri Exam/markers* 4x 3x 2x 2x 2x dx)?0 Chest X-ray 2x 2x 2x 1x 1x (1x)?° CT abdoman 2x 2x 1x - 1x fix)?0 Radiotherapy Exam/markers* 4x 3x 2x 2x 2x Chest X-ray 2x 2x 2x 1x 1x CT abdomen/pelvis 2x 2x 1x - 1x IIAJB Radiotherapy Chemotherapy Exam/markers" 4x 3x 2x 2x 2x Chest X-ray 3x 1x 1x 1x 1x CT abdomen/pelvis 2x 1x - - 1x 110/111 good ION Intermediate Chemotherapy Exam/markers" 6x 3x 2x 2x 2x Chest X-ray 3x 3x 1* 1X 1x CT abdomen/pelvis CT 1 -4x until CR with or without surgery, than according to chest X-ray plan *AFP, HCG, LDH b Determination of late effects: Urea and electrolytes, fasting cholesterol (HDL, LDL), triglycerides, fastln glucose, FSH, LH, Testosterone 0 Policies vary among oountrles and hospitals and there is no definitive evidence. 16 J! i I lil í > jI I III 11 11111 11 ! 11 s lí> Iii c P ? M ill ü ill ï * s t I i • • •i H! I Id III I i } i tli H! il 4 S s \Û ilà íihillí CIS Follow-up scheme for patients with [ yes Tetticular Blopty — negativ« -■-( SdfEiaminrton [ positive ) An«r facility pre»rvtfran Int J Androl. 2009 Aug;32(4):279-87 --1-r- tin I j loi mill' SlDlllnlll L 1)1)1' + Surilllnlb Clin Cancer Res 2009;15(10) May 15, 2009 18 new agents Phase II trial of sunitinib in patients with relapsed or refractory germ cell tumors Darren R. Feldman & Stefan Turkula & Michelle S. Ginsberg & Nicole Ishill & Sujata Patll & Maryann Carousso & George J. Bosl & Robert J. Motzer Invest New Drugs (2010) 28:523-528 • all patients progressive disease within three cycles of sunitinib • some marker decline during the active treatment period with subsequent marker rise during the twoo-week off peroid —> dosing scedule of sunitinib 37.5 mg I day cintuinously • in general sunitinib well tolerated ( no grade 4 toxicity) EUROCARE study TatblprfiMtiqidlS-Wrwiitdvoilir rjnlriçiillk. MwJ. Eunpwimwi I m 19 Metastatic castration-resistant prostate cancer (mCRPC) t- Boštjan Šeruga, MD Sector of Medical Oncology Institute of Oncology Ljubljana November 12, 2010; Ljubljana Outline ■ How "rare" is CRPC? ■ Biology of CRPC and mechanisms of resistance to standard therapies ■ Current drug development in CRPC i 1 Incidence and mortality rates for prostate cancer (World) Prostate cancer GLOBOCAN, 2008 4 Mas Incidence and mortality rates for prostate cancer (Slovenia) ost frequent cancers in males Non-Hodgkin i.rrphiim q Brain, Miwgityttôn ;tt jrj ai ASR (W) rale per 100,000 Mortality 919(26 3%)- ■ Prostate ■ Lung Colorectum I Stomach ■ Bladder ■ Kidney I Melanoma of skin M Pancreas H Lip, oral cavity Other 209 gra)' 419(13 4%) • 367 men died of prostate cancer in Slovenia In 2008 • ASR (W): 19/100,000 • In Europe Denmark, Estonia, Lithuania, Latvia and Sweden have higher mortality rates GLOBOCAN, 2008 2 Current definition of CRPC ■ Castration-resistant prostate cancer (CRPC): ■ Castrate levels of testosterone (< 0.50 ng/mL, 1.7 nmol/L) ■ Evidence of cancer progression (PSA or imaging) ■ It is not Hormone-resistant prostate cancer (HRPC)! 1 i What are the goals of any cancer treatment? ■ To allow the patient to live longer and/or ■ To allow the patient to live better 3 iPivotal phase III clinical trials with Mitoxantrone in mCRPC Author/Year (Journal) Experimental arm Control arm Results Tannock/1996 (JCO) Mitoxantrone + Prednisone Prednisone t Quality of Life Kantoff/1999 (JCO) Mitoxantrone + Prednisone Prednisone t Quality of Life Mitoxantrone allowed patients with mCRPC to live better Pivotal phase III clinical trials with I Docetaxel in mCRPC Author/Year (Journal) Experimental arm Control arm Results Tannock 2004 (NEJM) Docetaxel +Prednisone Mitoxantrone +Prednisone t Survival t Quality of Life Petrylak 2004 (NEJM) Docetaxel +Estramustine Mitoxantrone +Prednisone t Survival Docetaxel allowed patients with mCRPC to live longer and better 4 ^ Outcome of patients with mCRPC RCT (Drug) Patient population Median OS (mo) NCIC (Mitoxantrone) Tannock,1996 Symptomatic 10.8 TAX327 (Docetaxel) Tannock, 2004 Symptomatic/ Minimally symp. 18.9 IMPACT (Provenge®) Kantoff, 2010 Asymptomatic/ Minimally symp. 25.8 How many patients with mCRPC ^ do we treat with docetaxel? ~ 370 men die of prostate cancer in Slovenia annually Year No. of patients treated with docetaxel 2007 16(4,3%) 2008 17(4,6%) 2009 43 (11,6%) 2010 (until 09/2010) 60(16,2%) Are our patients undertreated? Courtesy of mag. Petra Tavcar & Samo Rozman 5 Mechanisms of drug resistance in CRPC Drug-real stant suboopulntlons or cancer celts (stem calls, NE cells) {Oil b Activated RTK d Aberrant aneloeenesls AitivatMt AH osteoblast Osteoclast f Mlcroenvlron merit Dooetaxel c Antlapoptoilc meoha nlsms g Increased drug efflux Seruga, Ocana & Tannock, Nat Clin Pract Oncol, 2010 Mechanisms of drug resistance in CRPC Seruga, Ocana & Tannock, Nat Clin Pract Oncol, 2010 B Druil militant aubpo I Jul alio ns 01 cancer cells (stem cells, NE cells) b Activated RTK c Antlapoptotlc mechanisms ° | g incrstraad dme afflux] :iIk-ii1s w lio pni^ivwil ;ilk-i I ix- :i I il ti- il I »¡111 ;i (l<>a-l;i\rMi;iM- riiil|>iiiiil: ( is NvmiiJan r i k 11 minis: '. ■ ; > ii-Ikv sima i\ i 11 'I Si k Njii'iisc i ak and ~aki v Ii mil ;in:il\<.is: Niaiilkan^ Ic\lI I,.I i Mini*: I" ;iiv 'mil I' M mlci mi Jll.lK • I'- 2010 Genitourinary Cancers Symposium i Priman Midpoint: Overall Sun ival (I I I Analysis) rni|)iiii inn li>6 «I osen h motilh 12 m um lu Nil tlllíl'í W Ul'lHi- lll/V ¡JÜ10 Çwml on rili .'ti v Cancers Symposium 10 Tol;il IX ;ilhs I>11111«: Study Sulciv Population Mi'in .n) (li/i'in .rn 17-1 I ",,i Ml i(I I K.X I 1' 7 I > l"ni 7 i I '»"„i I X i I >r„i I ^ 14 ii".,I IJ i ' :",.i liilnl (l( ;illis timing sludv Diir In |)iii^ivssiiin Due In Ms Due III UllU'l IV;IS(Hlv Toxic deaths due to infections and diarrhea! 2010 Genitourinary Cancers Symposium i * Targeting AR-associated signalling in CRPC li Jch ■M Molecular determinants of resistance to antiandrogen therapy Charlie D Chen1'5'8, Derek S Welshie3'5'8, Chris Trnn' '4, Sung Hee Bnek4'«, Randy Chen1, Robert Vessella7, Michael G Rosenfeld4'6 & Charles L Sawyers'"5 AR over-expression causes hormone refractory progression AR expression is necessary for hormone-sensitive to hormone-refractory progression AR-mediated progression occurs by a ligand-dependent mechanism Increased AR expression converts antagonists to agonists nature,. . medicine 2004 i AR is over-expressed in CRPC 9000080000 70000 60000 50000 40000 30000 20000 10000 Androgen Receptor Expression D 1577 at M23263 ■ 1S7B at M23263 li I fit iL I il 1IU Ikl 111 Ml Silt I ü I Ik m Hi m.n lUlalh a Ik a Ü» 1... _ Ik Untruttd primary prostata cancar Nao adjuvant androgan ablation traatad primary prostata cancar Mataatatlc prostata cancar Androgan ablation rsalatant mataatatlc proatata can oar Holzbeierlein, Am J Pathol, 2004 12 AR-associated signalling in CRPC CjjVPlT^» j ^ ^ ^pv t] AUienai iiiidiciuofi B --X ^ ^ a Ovwiiiwassea AR IX) novo loc.lil gyiitnesis □cocH^g— ( AIllvmiOriOfAfi D/BIK fj^ui m is? £& BIWll 11 IB Hilda Progestins b Muiaiaufi Seruga, Ocana &Tannock, Nat Clin Pract Oncol, 2010 Targeting AR-associated signalling in CRPC i®® (f^ d Attrsnal an tiroes ns a OroiexureKiW) AH Abiraterone acetate EQFR cnn-o-ay^—-«AR^ f AeUvailon of AR by flTK upfeauuteo c nuclear «■Gctivators b MLtaieijAfi Proliferation antlaoontotlc effect Seruga, Ocana & Tannock, Nat Clin Pract Oncol, 2010 13 CYP17, MDV3100 - De nom lucaf synttwsls of andioflons iypi7A> Targeting AR-associated signalling in CRPC -I^Abiraterone acetate Ç^f*1 d Adrenal andiouans a OuerexprasseO AH .«"»J il f Activation of AR by RTK Unregulated c nuclear coactlvators Blcalutamlde progestins * Prolireration antlapoptotlc effect b Mutated AR Seruga, Ocana & Tannock, Nat Clin Pract Oncol, 2010 RCTs evaluating agents targeting AR-associated signalling in mCRPC Phase III RCT Experimental a. Control a. Primary endpoint Results Drug X pre-docetaxel COU-AA-302 Abiraterone+P Placebo+P OS N=1,000 Recruitment complete Drug X post-docetaxel COU-AA-301 De Bono, 2010 Abiraterone+P Placebo+P OS N=1,185 Positive AFFIRM MDV3100 Placebo OS N=1,170 Recruiting OS: Overall Survival; P: Prednisone 14 1 Abiraterone acetate: Inhibitor of Androgen Synthesis i I j— ACTH 5 I Positive drive Pr«anenolon« D«wycorrl(oiiori>n« f x 10-» Cortloolleron» "J". S)-» Aldosierorm 1.6 HvPOkaîernï« HYpe-'.ention Fluid ovetfafld Suppression of Rufiin Negative feedbnck 17j ii7QHff»Sr«)i>bn» -► 1 l-daojtyeonliot f. H Cortlwl ,|rx2 — — — — — — cwrtwfwa ........i -■TWBStamnp i 24 27 64 47 Denosumab 950 758 582 472 361 259 168 U5 70 39 Fizazi K et «1,, ASCO 2010 24 New immunoherapeutic strategies in CRPC Whole-Cell Prostate Cancer Vaccine (GVAX®) ■ GVAX prostate cancer vaccine is a GM-CSF secreting whole-cell vaccine composed of prostate cancer cell lines (PC-3 and LN-CaP) genetically modified to secrete GM-CSF ■ GM-CSF (sargramostim) can expand and activate APCs ■ Whole-cell vaccines, unlike peptide vaccines, express multiple tumor antigens and are capable of eliciting a broad immune response; especially important if the "best" antigen target is unknown 25 4 1 An Autologous Cellular immunotherapy Sipuleucel-T (Provenge®) d A J Week 0 T 1 RCTs evaluating L new immunotherapies S m Phase III RCT Experimental a. Control a. Target Primary endpoint Results 1 Drug X pre-Docetaxel VITAL-1 GVAX® D+P Multiple Antigens OS N=626 Negative IMPACT Kantoff, 2010 Provenge® Placebo PAP OS N=521 Positive Drug X + Docetaxel II VITAL-2 GVAX® +D+P D+P Multiple Antigens OS N=408 Negative 26 i Phase III IMPACT Trial Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512/) Primary endpoint: Secondary endpoint: Treated at Physician discretion and/oi Salvage Protocol Overall Survival Time to Objective Disease Progression I IMPACT Overall Survival: Primary Endpoint — Placebo (n = 171) ,. Median Survival: 21.7 Mos. ' ■ i Kantoff, NEJM, 2010 27 The cemetery of dead drugs in struggle against CRPC Negative RCTs Inactive drugs? Inappropriate target? Lack of appropriate patient selection? j/ Mê WW ^ CABAZITAXEL W^ ^Ji J A BI RATE RONE ACETATE % SIPULEUCEL-T Ê ¿J? 28 6Z Neuroendocrine tumors Lung NET Tanja Cufer, MD, PhD University Clinic Golnik, Slovenia Medical Faculty, University of Ljubljana, Slovenia Incidence of NET is Increasing 1.40 0.20 NET Site — Lung — Colon — Small intestine — Rectum Pancreas j i J i.I j J J i J" J 'JiJ i J 1 J. i.i i j 'J IJ Year SEER = Surveillance, Epidemiology, and End Results; Approximate 5-fold increase between 1975 and 2004 Approximate 7-fold increase also evident in Norwegian registry Yao J, Hassan M, Phan A, et al J Clin Oncol. 2006;26:3063-3072 NET Vary by Primary Tumor Site ■ Generally characterized by their ability to produce peptides that may lead to associated syndromes (functional vs nonfunctional) 1. Modlin IM, et al Lancet 2006;9:61-72 2 Modlin IM, et al Gastroenterology 2005;128:1717-1751 f Foreaut • Thymus • Esophagus • Lung • Stomach • Pancreas • Duodenum Midgut • Appendix • Ileum • Cecum . * Ascending colonj f--\ Hindaut • Distal large bowel • Rectum Historically classified based on embryonic origin □ Foregut tumors Midgut tumors □ Hindgut tumors Today, primary tumor location is recommended for NET classification Diversity of NET Has Impacted Nomenclature ■ Although some commonalities exist, NET include a diverse family of malignancies ■ Range of behaviors/aggressiveness Poorly vs. well differentiated Tumor grade (G1, G2, G3) Benign vs. malignant ■ Extent of disease □ Local vs. distant metastases ■ Location of primary tumors □ Lung, colon, small intestine, rectum, pancreas, etc ■ Symptomatic vs. asymptomatic □ Symptoms due to hormonal syndromes vs tumor mass 1 Klimstra DS, et al. Am J Surg Pathol 2010;34(3):300-313 2 Modlin IM, Gastroenterology. 2005;128:1717-1751 3 Modlin IM, etal Lancet Oncol 2008;9(1):61-72 Correlation of Primary Tumor Site with Survival Known prognostic factors include: □ Location of primary tumor □ Extent of disease □ Tumor stage □ Degree of differentiation/ proliferative index (PI) □ Tumor grade □ Patient age □ Performance status Advanced disease Colon - Lung Pancreas Rectum — Small bowel 12 24 36 48 60 72 84 96 108120 Time (months) 65% of patients with advanced NET will not be alive in 5 years I Yao JC, et al. J Clin Oncol. 2008;26 3063-307;; New Treatment Modalities PROMID: Octreotide LAR in advanced Midgut tumours 1.0 p, Octreotide LAR vs placebo P = 0.000072 HR = 0.34 [95% CI: 0.20-0.59] Octreotide LAR (n = 42) Median 14.3 months — Placebo (n = 43) Median 6.0 months Based on conservative ITT analysis 6 12 18 24 30 36 42 48 54 60 66 72 78 Time (months) Rinke A, Barth P, Wied M, et al. J Clin Oncol. 2009;27:4656-4663. Pulmonary NET Classification ■ Low grade □Typical carcinoid ■ Intermediate grade □Atypical carcinoid ■ High grade □ Large cell neuroendocrine carcinoma (LNEC) □ Small cell carcinoma (SCLC) Lung NET Frequency Non-NE Carcinomas 75-80.0% Atypical Carcinoid 0.1-0.2% Carcinoid 0.1-2.0% LCNEC 3.0% SCLC 15-20.0% Lung NET: Clinical Features: Japanese Registry TC AC LCNEC SCLC Age: Mean 52 63 67 65 (Range) yr (17-83) (38-73) (40-84) (17-88) Sex: % M 58,2 44,4 89,4 79,7 Paraneo- 1,8 0 0 2,7 plastic % % smokers 54,6 55,6 98,6 93.8 Asamura H et al: J Clin Oncol 24: 70,2006 Lung NET Pathologic Differential TC AC LCNEC SCLC Mitoses per 10 HPF <2 2-10 >11 (mediart-70) >11 (median-80) Necrosis No Yes Yes Yes Histologic heterogeneity No No Yes Yes IHC tumor markers Neuroendocrine* NSE CD56 TTF1 Yes Yes Yes/No No Yes Yes Yes/No No Yes Yes Yes Yes (40-70%) No No Yes Yes (70-80%) * Chromogranin A, synaptophysin Typical and Atypical Carcinoid Diagnostic Criteria ■ Typical Carcinoid □ Less than 2 mitoses per 10 HPF (2 mm2) and no foci of necrosis □ Centrally located tumors, endobronchial growth ■ Atypical Carcinoid □ 2-10 mitoses per 10 HPF (2 mm2) OR □ Foci of necrosis □ Peripheral lessions Travis WD, et al: Am J Surg Pathol 22: 934-44, 1988_ Atypical Carcinoid Pulmonary NET Survival rates of surgically resected disease 5 %-yr Survival TC: 87% AC: 56% LCNEC: 27% SCLC: 9% Asamura H et al: J Clin Oncol 24:70,2006 Typical and Atypical Carcinoid ■ Most patients with TC are diagnosed with limited disease c Conventional surgery represents a standard treatment, with 5-year survival of 92%-100% ■ AC patients have a significantly worse prognosis with reduced 5-year survival of61%-88% □ Most of the patients are diagnosed in advanced stage □ Conventional chemotherapy has limited efficacy for patients with advanced NET ■ Octreotide LAR, historically used for symptom control in Gl-NET, prolongs time to progression and improves QoL ■ New agents, like bevacizumab, sunitinib, everolimus might be beneficial in pts with in low intermediate grade NET tumors ■ Rationale for Combining Everolimus and Octreotide LAR ■ NET have been linked to genetic ■ mTOR is a central regulator of ■ Octreotide downregulates IGF-1, ■ Everolimus inhibits mTOR alterations that activate the and angiogenesis growth, proliferation, metabolism, an upstream activator of the mTOR pathway PI3K/AKT/mTOR pathway XKMXDi ■ Everolimus + octreotide LAR has shown activity in a phase II trial RADIANT-2: Study Design Phase III Randomized, Double-Blind, Placebo-Controlled, Multi-Center Trial Patients with advanced well,-moderately differentiated NET with a history of carcinoid syndrome, N = 429 Lung N= 40 1:1 Everolimus 10 mg/d * octreotide LAR 30 mg/28 days n =216 Crossover zr Placebo + octreotide LAR 30 mg/28 days n =213 Treatment until disease progression Multi-phasic CT or MRI performed every 12 weeks Primary endpoint: • PFS (RECIST) Secondary endpoints: • OS • Safety and tolerability Cllnlcaltrials gov: NCT00412061 RADIANT 2: PFS by Central Review 100 80 <1) > o> ro 60 8 40 a) a. 20 Total events = 223 Censoring times E + 0(n/N = 103/216) P + 0(n/N = 120/213) Kaplan-Meier median PFS Everolimus + Octreotide LAR: 16.4 months Placebo + Octreotide LAR: 11.3 months Hazard ratio = 0.77; 95% CI [0.59 -1.00] P-vaiue = 0.026 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 Time (months) No. of patients still at risk E + O p + o 216 202 167 129 120 102 61 69 63 56 50 42 33 22 17 11 4 1 1 213 202 155 117 106 84 72 65 57 50 42 35 24 18 11 9 3 1 0 Pavel Metal,; ESMO 2010 RADIANT 2: Treatment Related Adverse Events Occurring in >10% ¡Stomatitis* Eve roll m us + OctfeOtitieLAR n = 216 Placebo + Octreotide LAR n s 211 All Ql*dM (%) 62 Grade 3/4 {%) 7 All Grades (%) 14 Grade 3/4 (%) 0 Rash 37 1 12 0 Fatigue 31 7 23 3 Diarrhea 27 6 16 2 Nausea 20 1 16 1 Infections* 20 5 6 ï I Dysgeusla 17 1 3 0 Anemia 15 1 5 0 Weight decreased 15 1 3 0 Thrombocytopenia 14 5 0 0 Decreased appetite 14 0 6 0 Peripheral edema 13 0 3 0 Hyperglycemia 12 5 2 1 Dyspnea 12 2 1 0 Pulmonary events* 12 2 0 0 Vomiting 11 1 5 1 Pruritus 11 0 4 0 Asthenia 10 1 7 1 •Related toxicities grouped for calculations m Large Cell NE Carcinoma Diagnostic Criteria ■ NE Morphology: Organoid nesting, trabecular, palisading, rosette-like patterns ■ Increased Mitoses (11 or more per 10 HPE or mm2) ■ NE differentiation by immunohistochemistry or EM ■ v "'.V • : ' v 1 ' " * '..i' ■i; ' 'i11.. i*'.!'1 * • "A j • ty ' r •. ■ ■ !v| ; ' , n . . . , . Î. Wi v. ; I ;v. ■■ ■ ■ ■ ■ ^ r ' ■■, .'■ ■ : : • . .. ■ • - i .¿' v.• •• • -, - :„& . . . " ' • ¿M -m* "..»'; ,.••.*< ' ,-,V. • 'if,''»; w« >v< LCNEC: NCC Research Institute, Tokyo ■ 87 cases (3,1% resected lung cancers) ■ Sex: 77M (89%); Mean age 68 yr (37-82) ■ Smoking: 98%; No paraneoplastic syndromes ■ 5-yr survival - overall: 57% □ Stage I: 67%; II: 75%; III: 45%; IV: 0% □ Stage I LCNEC: 67%; PD NSCLEC: 88%; LCC: 92% (p=0,003) □ No difference between Stage I SCLC and LCNEC Takei H et al: J Thorac Cardiovasc Surg 24: 285, 2002 LCNEC: Chemotherapy Adjuvant Setting (piatinum/etoposide vs Gemcitabine/taxanes) Metastatic Setting (Piatinum/etoposide vs Gemcitabine/taxanes) Rossi G eta al: J Clin Oncol 23: 8774,2005 LCNEC: Chemotherapy ■ lyoda A: JTCVS 138: 446, 2009 □ 79 LCNEC; 36 recurred; Pts receiving platinum based chemo -significantly better DF survival (p>0,001) ■ Saji H et al: Anticancer Drugs 21: 89-93, 2010 □ 45 LCNEN pts; 23 (41%) perioperative chemotherapy (mostly platinum based) - better survival (p=0,04) ■ Igawa S et al: Lung Ca 68: 438-45, 2010 □ 14 HG NE carcinoma c/w LCNEN; clinical efficacy of chemo comparable to ED-SCLC SCLC Radiologic Criteria Bulky, widespread mediastinal disease Courtesy of I Pozek m ^m SCLC- Progress in Therapeutic Outcome - Radiotherapy - ChT + PCI \ ^VK Surgery - ChT + RT ChT \ ^ 20% \ -- 15% \ —--10% ('- ^-* 1 -HI- 1 2 3 years Courtesy of J Jassem Cisplatin / Etoposide Versus CEV Cis/Etop CEV N 218 218 OS (all) 2-year 5-year 5% 2% OS (LD) 2-year 15% 8% > Cisplatin/Etoposide is superior to CEV > Subset analyses revealed Cisplatin/etoposid superiority only in LD Sundstram S etal. J Clin 0nco/2002; 20(24): 4665-4672 Unmet Medical Needs in SCLC ■ Topotecan improves survival and symptom control vs. BSC in second line therapy, thus representing a standard SL therapy ■ New platinum based combinations (irinotecan/platinum, pemetrexed/carbo) failed to show superiority to cisplatinum/etoposide schema ■ Amrubicin is a new agent of promising efficacy in relapsed SCLC, phase3 trial comparing amrubicin vs topotecan is underway ■ So far, numerous targeted agents failed in SCLC > To improve treatment results molecular predictor of response to either ChT or targeted agents need to be explored more profoundly in a near future (ERCC1, topo2, VEGF,...) Pulmonary NET Treatment Pulmonary NET - Progress in Therapeutic Outcome HISTOLOGY SURGERY SYSTEMIC THERAPY RADIATION TC Primary approach Not proven Not proven AC Primary approach (N evaluation !) Not yet proven Experimental approaches are encouraged Not proven LCNEC If resectable Probably needed Effective íocally SCLC Controversial Primary approach Effective locally ESMO guidelines, Ann Oncol 2010; 21:v220-222; NCCN guidelines ■ In Summary ■ Pulmonary NET include a wide spectrum of tumors, from low-grade TC, intermediate-grade AC to high-grade LCNEC and SCLC. ■ Most of pulmonary NET express neuroendocrine markers, while paraneoplastic symptoms are quite rare. ■ Nowadays, a proper anatomical staging (according to UICC7 edition) and sophisticated pathomolecular tumor classification are of upmost importance for effective therapy. « Surgery, irradiation and chemotherapy still represent the mainstay of therapy. However, new treatment approaches based on better molecular markers identification and new targeted therapies are supposed to further improve survival rates and Qol of patients. Multidisciplinary teams should take care of pulmonary NET patients! Lymphomas in patients with HIV infection Clinical cases Doc.dr. Barbara Jezeršek Novakovič.dr.med Gregorič Brigita, Matej Horvat, Tanja Mesti Clinical case 1 • M, 37 years old • HIV-1+ patient; otherwise healthy and did not take any medications • Presenting history: Upper abdominal pain and obstructive icterus since April 1998 Despite the ERCP with an insertion of a stent into the dilatated d.choledochus there was no improvement • Physical examination: PS (WHO) 3, icterus, no enlarged lymph nodes, ascites 1 INITIAL INVESTIGATIONS: • Leu 9,19; Ery 5,5; Hb 164; Ht 0,46; MCV 83,7;Plt 619; neutro 77%; lymph 19%, mono 3%, eoz 0%, baso 0%; biochem.- pathologic liver tests (bilirubin 349; AP 12,30; gamaGT 32,48; AST 6,81; ALT 4,49); creatinine 137; urea 15,4; uric acid 849; LDH 25,58; CRP 6 • HIV-1 RNA (PCR) 8902 copies/ml, CD-4 count 114/mm3 • CXR: minimal pleural effusion in right interlobar fissure • XR of paranasal sinuses: normal INITIAL INVESTIGATIONS: • CT of abdomen: extensive ascitic fluid (3-4 L), infiltration of peritoneum, atrofic left hepatic lobe probably due to the occlusion of the left branch of venae portae and left hepatic vein. Larger tumor mass in the left hepatic lobe and in porta hepatis, marked dilatation of intrahepatic ducts, stent in d.choledochus • CT of thorax showed minimal pleural fluid left and hiatal hernia, but was otherwise normal OTHER INVESTIGATIONS: • Ascites - cytology: diffuse large B cell lymphoma (CD10+, FMC7+, CD52+, CD38+, MIB-1 50%) • Biopsy of bone marrow: no lymphoma infiltrates Conclusion: diffuse large B-cell lymphoma, cytological diagnosis, stage IV.A.E. Involved regions: liver (left lobe), peritoneum, ? pleura left, IPI 4. • Diagnosis of lymphoma and HIV infection was made simultaneously TREATMENT: • Treatment in April 2008: methylprednisolone in increasing dosages (16 mg-»125 mg) from the first day of hospitalization; an attempt to treat the patient with modified CVP on the day 4 (50% dosages) • However, the patient's condition was irreversible, his hepatic and liver function progressively deteriorated (hepatorenal syndrome) during hospitalization and the patient died on day 6. 3 Clinical case 2 • M, 54 years old • HIV-1 + patient, otherwise healthy and did not take any medications • Presenting history: Swelling in the right parotid region for the last 2 months growing rapidly to a mass with 15 cm in diameter (spreading down to neck, behind the ear and up to the temple), headache, troubles with opening of his mouth, weight loss of 4 kg, no constitutional (B) symptoms • Physical examination: PS (WHO) 1, large mass in the right parotid region (15 cm), other lymph nodes not enlarged, white coating of tongue _I INITIAL INVESTIGATIONS: • Leu 5,9; Ery 4,95; Hb 158; Ht 0,433; MCV 87; Pit 365; neutro 69%; lymph 22%, mono 8%, eoz 1%, baso 0%; biochem.- gamaGT 1,1, s-proteins 100, otherwise normal biochemistry (LDH 3,28) • HIV-1 RNA (PCR) 250.000 copies/ml, CD-4 count 231/mm3 • CXR: normal • XR of paranasal sinuses: normal • ORL examination: protrusion of pharyngeal wall on the right side • US of abdomen: normal OTHER INVESTIGATIONS: • Cytology of the tumor under the right ear: morphologically and immunocytochemically Burkitt's lymphoma • Biopsy of bone marrow: no lymphoma infiltrates, moderate to marked siderosis Conclusion: Burkitt's lymphoma, cytological diagnosis, stage I.A.X, risk group (Murphy) 2. Involved regions: lymph nodes in the right parotid region extending down to the right side of the neck. • Diagnosis of HIV infection was made prior to the diagnosis of lymphoma TREATMENT: • Treatment from May 1998: Cytoreduction (5 days) with methylprednisolone and cyclophosphamide according to BFM protocol • First A cycle (MD MTX, Ifosfamide, VP-16, Ara-C and dexamethasone) and prophylactic intrathecal chemotherapy from day 5 onwards Complication: 9 days after the first cycle the patient developed febrile neutropenia and stomatitis (Leu 0,42; Hb107; Pit 66) and needed to be hospitalized • Clinically CR after the first cycle, US (neck) showed lymph node in parotid region (14X7mm) and on the right side of neck (15x6 mm) 5 TREATMENT: • Second B cycle (MD MIX, Cyclophosphamide, Adriamycin, Vincristine) and prophylactic intrathecal chemotherapy in June 1998 Complication: 6 days after the second cycle the patient had to be hospitalized because of febrile episode and stomatitis (Leu 1,9; neutro 75%, Hb 85, Pit 146) • The third and the last fourth B cycle with prophylactic intrathecal chemotherapy were applied in July 1998 Complication: stomatitis after third and fourth cycle • No prophylactic antimicrobial therapy during chemotherapy • Prophylactic G-CSF (3 -5 days) after every chemotherapy cycle FOLLOW UP: • The control US of neck in September 1998 showed reactive lymph nodes on the right side of neck (0,7 cm) • In September 1998 the patient refused to take antiretroviral medications adviced by the infectologist and would not start them until 1999 • The patient was followed by regular medical examinations for the first 5 years, no relapse of lymphoma had been confirmed (since July 1998) 6 Retrospective clinical trial • Inclusion criteria: diagnosis of malignant lymphoma diagnosis of HIV infection or AIDS • Patients treated at the Institute of Oncology Ljubljana • Period 1998-2009 • 9 consecutive patients Patients • 9 male patients, 0 female patients • Mean age at the discovery of lymphoma 48,0 years (range 24,0-59,5) • Mean age at the discovery of HIV infection 47,2 years (range 20,0-59,5) • 4 patients diagnosed with HIV infection at the time of diagnosis of lymphoma • 5 patients diagnosed with HIV infection prior to the diagnosis of lymphoma 7 Patients • 8 diagnosed with NHL: 5 diffuse large B cell lymphoma (DLCBL) 2 Burkitt's lymphoma 1 plasmoblastic lymphoma • 1 diagnosed with HL: mixed cell type Type of lymphoma 1 1 ™ ■ ■ DLCBL Burkltt lymphoma Plasmoblastic lymphoma Hodgkin lymphoma 8 Patients • Clinical stage of lymphoma: Stage I: 3 Stage II: 3 Stage III: 1 Stage IV: 2 Clinical stage 3,5 3 2,5 2 1,5 1 0,5 0 Stage I Stage I I Stage I I Clinical stage Stage IV 9 Patients • Involved regions: Head and neck region: 7 Thoracic involvement: 4 Spleen: 3 Liver: 2 Abdominal involvement: 2 Bone marrow: 0 CNS: 0 Involved regions i Involved regions cF 10 Patients • Mean CD4 count: 153,3 cells/mm3 (all 9 patients, range: 17-501 cells/mm3) • Mean number of HIV RNA copies: 48,408 copies/ml (7 patients, range: 40-255,000 copies/ml) CD-4 count 600 500 400 300 — — -CD4 count 200 100 h III 0 ™ ■ PI P 2 P 3 P 4 P 5 P 6 P 7 P 8 P9 11 I HIV RNA - number of copies 300000 250000 200000 150000 —■ ■ HIV RNA-number of copies 100000 50000 0 PI P2 P3 P4 P5 P6 P7 Treatment • All 9 received chemotherapy: 3 patients CHOP 2 patients R-CHOP 1 patient COP 1 patient R-BFM 1 patient BFM 1 patient ABVD 2 patients prophylactic i.t. chemotherapy • Median number of chemotherapy cycles 4,5 (range: 1-8) 12 Type of chemotherapy I Type of chemotherapy II I I CHOP R-CH0P COP R-BFM BFM ABVD Treatment • Radiotherapy: 4 patients had additional radiotherapeutical treatment with 30,6 Gy • HAART: 8 patients received HAART, 7 simultaneously with chemotherapy, 1 after chemotherapy 13 Comorbidities • 1 reactivation of CMV infection • 1 latent TBC infection • 3 hepatitis B infection in their clinical history • 1 patient had 2 other types of cancer (invasive papilary carcinoma of urothelial epithelium, laryngeal carcinoma) 14 Supportive treatment • 6 patients received prophylactic antibiotics and antimicotics (combination of trimetoprim-sulfamethoxazol and fluconazole) • 6 patients received prophylactic granulocyte colony-stimulating factor Complications • 7 had febrile neutropenia • 1 had stomatitis • 1 had CMV pneumonitis • 1 had Streptococus bovis sepsis • 1 had DVT Complications I "J ■ ■ ■ I Complications Febrile Stomatitis CMV Strep, bovis DVT neutropenia pneumonitis sepsis Conclusion • 8 patients completed planned chemotherapy treatment • 4 patients received additional radiotherapy treatment • 7 patients who completed planned chemotherapy treatment achieved CR • 1 patient died after 1st cycle of chemotherapy • 1 patient died after completed chemotherapy treatment 16 Conclusion • 7 patients are still in CR on regular follow up, mean time of their survival is 65 months (range 16-150 months) • Mean time of survival of all patients is 52 months (range 0-150 months) • 1 patient died after 1st cycle of chemotherapy, because of spread of lymphoma • 1 patient died after completed chemotherapy treatment, because of an opportunistic infection Conclusion • Patients were treated with the same chemotherapeutic regimen as non-HIV lymphoma patients • Patients received HAART treatment • Most patients received antibiotic and G-CSF prophylaxis • Patients in our clinical trial had lower stage of lymphoma and different regions of involvement than AIDS related lymphoma patients 17 AIDS related lymphomas Mesti Tanja,MD; Gregoric Brigita.MD; Horvat Matej, MD Mentor: doc.dr.Jezersek Barbara, MD, PhD Objective • Discuss the most important issues in AIDS related lymphomas - what we, as oncologists, should be aware of Incidence of AIDS - related and AIDS - Non related cancers 11-9-1i>artciiis mclmicii; 251 cancels diuuuosctf ot C1>J Ifal Olir, ■ rufrtt*! i . rMnh.311 lu'J 4* ^(ti'lläd^kiti ^ ! vmj^icnnj 01 QdJ Krlpll'i ' -«J •1*11.1 41 1« Cnm mm ' 1 xdnoma J No« AIDS drf mine * aitn 142 S7 4(1 N .13« HTcm:h0("u1inpn;«% r JI n and I RT* 4» it Skin fltlBfcDE (Rituximab with CDE); R-CHOP (Rituximab with jH|k.doxorublci 'irfff prednisone (CHOP)); R-DA-EPOCH (Rituximab with dose adjusted (DA)EPOCH) Sparano et 72 >pj.»fiiH At, ft.i ■ H but iH nHiiiinr.il (Ydcpliinphiiiildr. rtBt3ii1i*iii nU nopain» in P«ri#n" wJrn HlV inwtinl molt Hwlfkhrt lyfflfhbtM; mi E«ttrll fnrrPriti»TOnrnlr^üriiii|r I nil |t J Clin Of* KW; 3i HIJMSM^IHI« T rt »I; HltfWr»fhdratIri.linintnf«c»i«»itliiniiiiiiiHji|i[|uirtVJuiiliui«F Klu««»|yn In «ml eUipnM« In IIIV tiKcltted nwvHadffUu i,nip)|ti0ii: (JtHf d '»Will rr -.rw I piu.t i vuIl Se^-J MOVM&UKUlM f. i*pts* LO ri Mh BtiMnuk dan «wltmi» In ■ •►-danwrniplwui Wl tra< «*f rrtCfP wirfi a. *iMk*rt MnMwli In piO*n1* xTh WiV illmMl«J 111*1 Hpiltfwi »twpliiaii»- AIIH maiiKiunrwi rtyuisitliim tiiti 0]H, Ib^lflW. J06,IV=1 JM*; rl Al; ftllirfnm3rrt|t1niilimjtnf Irefujinnil HqcpihitimlMrtpy £i"AII »lll.ii ► inlrtiHttilif with ir '»i|ii nilriTy fiilloii rd hy Muunub in ttfy uwxiuuil 4|Hi|iliaiiui Aldi HillfliMn^ -Cum«■ luwrvTi l«l 41 ] 200 cells/ml • Primary prophylaxis of FN (20% risk) with hGFs Conclusion • Central nervous system prophylaxis should only be done in subjects with the highest risk for developing neurologic disease, such as in patients with Burkitt's lymphoma, those with stage IV, and those with lymphomas of the ORL area • In HIV patients with refractory or relapsed lymphomas, if the clinical situation is good enough and it is decided to proceed with salvage therapy, special consideration should be given to autologous hematopoietic cell transplantation • In HIV-infected individuals, there is an increased incidence -1-1-u-1_c_:_I_I_I 28 MALIGNANT PLEURAL MESOTHELIOMA (MPM) Mojca Unk Domen Ribnikar Jana Pahole Goličnik Branko Zakotni k Question 1 The correct statement is: MPM is 1. a frequent tumor (incidence > 20/100000) 2. affects mostly older than 60 years 3. good prognosis 4. most patients are treated with surgery 5. mainly detected in early stages 1 Etiology and epidemiology • Rare tumor, incidence about 1 - 2/100000 • Males • Mesothelial surfaces of coelomic cavities (pleura, peritoneum, pericardium, tunica vaginalis) • Poor survival (1 year) • Azbestos (occupational exposure) • Latency 40 years (15-67) Azbestos fibres • Primary occupational) and secondary exposure • Diseases: azbestosis, MPM, lung,... • Dose effect relatonship but there is no treshold of cummulative exposure below which there is no risk • All asbestos fibers are cancerogenic • Chrysotile - white azbestos - 99% products - 2-4x more cancerogenic than other typs of fibers • Crocidolite 2 Slovenia • Oscilating incidence in recent years (between 24 and 33 /100000) • 29 new patients in year 2007 (26m,3f) • 28% of patients from the Primorska region Rak v Sloveniji 2007. Ljubljana: Onkološki inštitut Ljubljana, Epidemiologija in register raka, Register raka Republike Slovenije, 2010. Clinical presentation • Symptoms, shortness of breath, pain, cough, fatigue, weight loss, sweating, fever, palpable masses of the chest, paraneoplastic syndromes • Occupational exposure to asbestos • signs of pleural effusion 3 Diagnosis * Chest x-ray- unilateral pleural effusion or thickening * CTof the chest ring like tumour along the pleural cavity, diffuse or nodular pleural thickening * Thoracocentesis for cytology conformation (diagnostic error) * Pleural biopsy (thoracoscope- video asssisted thoracoscopy-VATS, open surgery) for histology conformation (4 histological subtyps- epitheloid 60%, sarcomatoid, mixed, desmoplastic) * Serum mesothelin relatedpeptid (SMRP) and osteopontin Question 2 The correct statement is: Serum mesothelin related peptid is 1. A very sensitive biomarker 2. A specific biomarker 3. Useful in screening 4 Staging (IMIG classification) international mesothelioma interest group Stage I la TlaNO lb TlbNO Stage II T2N0 Stage III AnyT3, any N1 or any N2 Stage IV Any T4, any N3 or any Ml Rusch et al. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Wesothelioma Interest Sroup. Chest 1995;108:1122-8. Travis et al. WHO classification of tumours. Tumours of the lung, pleura, thymus and heart. Lyon, France:! ARC;2004 9 Treatment: surgery extrapleural pneumonectomy (EPP)- radical, but R1 or debulking pleurectomy/decortication- R2 - Stage I-III: adequate cardiac- pulmonary function and technical possibilities • Stage I: surgery or follow up until disease progression • Stage II-III: technically resectable are treated with trimodality regiment (OP+RT+ChT), unresectable ChT only - Stage IV and sarcomatoid subtype: ChT only Palliative pleurodesis or PleuRx® and parietal pleuretomy 5 Question 3 Survival of patients following completed trimodality treatment is equal for patients with NO-1 and N2 disease. 1. YES 2. NO Survival according to mediastinal nodal status (N2 disease) and completion of the entire trimodality regimen. ' NO-1 disease, trimodality completed NO-1 diesease, trimodality not completed J_ N2 disease, trimodality completed N2 disease, trimodality not completed I I —! — 24 36 48 Time (months) ! 60 —r 72 de Perrot M et al. JCO 2009;27:1413-1418 12 6 Treatment- radiotherapy ■ Adjuvant radiotherapy to whole hemithorax after EPP for local disease control (80% local reccurence rate after EPP only and 13/o after RT following EPPX50-60 6y) • significant improvement in overall survival after EPP+RT (33,8 months vs. lU months: p = 0.04) in early stages (I-II) but not in stages III-IV Rusch et al. A phase H trial of surgical resecfion and adjuirant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thoroe Cardiovose Surg. 2001 Oct;I2Z{4)'788-95. • Prophylactic drain site radiotherapy (21 Gy) ??? O'Rourke et al. A randomised controlled trial of intervention site radiotherapy in malignant pleural mespthelioma. Radiother Oncol 2007:84:18-22. • No improvement after adjuvant radiotherapy following debulking pleurectomy (R2), more toxicity Baldini. Radiation therapy options for malignant pleural mesothelioma. Seminar Thorac Cardiovascular Surg. 2009; 21:159-163. • Palliative radiotherapy for pain relief (RR 60%, duration of response 23 months) 13 Treatment- chemotherapy • As neoadjuvant or ad iuvant therapy (platinum based doublets) • Unresectable patients stage II in III, sarcomatoid subtype and stage IV • Platinum analogues, folate antimetabolites (pemetreksed, ralitreksed), gemcitabin, vinorelbine and doksorubicin 7 Question 4 * The wrong statement is: 1. Combination cis/pem is more effective than monotherapy with cisplatinum. 2. Platinum based doublets are comparable in terms of efficiency. 3. Response rates to chemotherapy are higher than 45 /o. 4. Patients without dispnoe do not need drainage of pleural effusion before application of pemetrexed. Dickgreber et al. Pemetrexed safety and pharmacokinetics in patients with third-space fluid. Clin Cancer Res. 2010 May 15;16(10):2872-80 Treatment- chemotherapy 1st line • Combination pemetreksed/cisplatinum in Is line improves overall survival; -12.1 m vs. 9.3 m (p=0.02) compared to single agent cisplatinum - RR 41 % vs. 16.7% compared to single agent cisplatinum Vogelzang et a|. Phase III study of pemetrexed in combination with cisplatin versus cisplotm alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003.: 21:2636-2644. 8 Kaplan-Meier estimates of overall survival time for all patients (Pts) (A) and for fully supplemented patients (fl). Overall survival wos significantly longer for the pe metre xed/dsp latin-treated patients {Pem/Cis) in the group of oil potient; (P OZO) and approathed significance for the group of fully supplemented patients (P 051) MS, median survival; CIs. cisplatin alone. Vogelzang N J et al. JCO 2003;21:2636-2644 17 Treatment- chemotherapy 1st line • Combination pemetreksed/carboplatin: - Ceresoli: median survival 12.7 months and RR 18.6% - Castaqneto: median survival 14 months and RR 25% Ceresoli et al. Phase II study of pemetrexed plus carboplatin In malignant pleural mesothelioma. J Clin Oncol. 2006:24:1443-1448. Castaqneto et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma Ann Oncol. 2008:19:370-373. 18 Treatment- chemotherapy 1st line • Combination gem/eis: - van Haarst: median survival 9.6 months and RR 16% - Nowak: median survival 11.2 months and RR 33%) van Haarst et al. Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma, ßr J Canter. 2002:86:343-345. Nowak et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer. 2002;87:491-496. Question 5 Cisplatinum and carboplatinum are comparably effective. 1. YES 2. NO Chemotherapy cisplatinum or carboplatinum Comparison of cis/pem and carbo/pem in 1704 patients conf irmed similar activity (DFS and 1-year survival); combination carbo/pem is a better choice for patients with poorer performance status and comorbidity. Santor a et al Pemetrexed plus cisplotin or pemetrexed plus carboplatin for chemorioive patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thoroc Oncol. 2008;3:756-763. 21 Santoro et al. J Thorac Oncol 2006. 22 11 Treatment- targeted therapies Different drugs have been or are being evaluated (alone or in combination with chemotherapy) —► targeting: - EGFR: gef itinib, erlotinib, cetuximab - PDGFR - VEGF and VEGFR: bevacizumab, sorafenib, vatalanib, pazopanib, sunitinib, talidomid - histone deacetylase (HDAC): vorinostat - proteosome: bortezomib vanMeerbeeek et al Malignant pleural mesothelioma: The standard of core end challenges for future management. crit Rev Oneol/Hematol (2010).doi:10.1016/j.critrevone. 2010.04.004 Question 6 There is no benefit with 2nd line chemotherapy. 1. YES 2. NO 24 12 Treatment- radiotherapy 2nd line Phase III study compared peme+reksed single agent in 2nd line chemotherapy to best supportive care in pemetreksed naive patients: • significantly better RR (18 vs. 1.7%) • siqnificantly longer time to progression (3.7 vs 1.5 month; p=0.015) • no improvement in overall survival (8.4 vs. 9.7 months; p=0.74). Jassem et al. Phase III trial of pemBtrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. J Clin Oncol. 2008:26:5139-40. S 1 oo 0.75 O SO 0.2S 1\ - P«rrt*tr*M«d plu* B6C BSC Loo-rank P - 7434 Overall Survival (months) i .oo O 75 O.BO 1Î-Ï5 IV Tn»r«pv - P«m8ti«x«d plu< BSC Proaresslon-Frea Survival (months) - P«m»tr*x«d plua BSC BSC Uog-ranh P- 0002 Time to Progressive Disease (months) Jassem J et al. JCO 2008;26:1698-1704 26 13 Treatment- radiotherapy 2nd line Gemcitabine and vinorelbine show some efficacy in the 1st line chemotherapy an option for a 2nd line: • 63 patients treated with weekly vinorelbin: RR 16%, median survival 9.6 months Stebbing et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer, 2009:63:94-7. ■ 30 patient treated with vinorelbin-gemcitabin (day l.,8;Q3): disease control in 43% (10% PR and 33% stable disease), median survival 10.9 months Zucaii et al. Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. Cancer;112:1555-1561. Evaluation • Clinical examination • CT of the thorax after 2 to 3 cycles of chemotherapy (modified RECIST criteria*) Byrne et ol. Modified RECIST criteria for assessement of response in malignant pleural mesothelioma. Ann Oncol 2004:15;257-260. 26 14 Conclusions • Only a small proportion of patients might benefit from aggressive interventions with radical or curative intent • Effective, albeit palliative chemotherapy, increases life expectancy and helps to relieve symptoms • Relieving symptoms is the cornerstone in the management of patients with MPM at all stages of disease • Enroll the patient in clinical (prospective) study • Primary prevention and targeted treatments are the future in management of MPM Modified RECIST criteria Growth pattern of MPM (on CT of the thorax sferica! changes for two- dimensional measurements are ussually not seen) Combination of one- and two- dimensional measurements: - pleural plaque at the thoracic or mediastinal wall is measured in two places, at least 1 cm interval, three cuts or the CT chest examination, the sum of the six measurements is defined as one-dimensional measurements of pleural changes - two-dimensional lesion are measured using conventional RECIST criteria - pleural effusion is not measurable lesion - regression in lesions by 30% in 4 weeks: partial response - increase in lesions by 20% in 4 weeks: progres Conclusion: The modified RECIST criteria coincide with the survival (15.1 m to B.9 m, p s 0,03) and pulmonary function, but require further research to integrate them into regular clinical practice Byrne et al. Modified RECIST criteria for assessement of response in malignant pleural mesothelioma. Ann Oncol 2004'.15;257-260. Malignant pleural mesothelioma Clinical case report Domen Ribnikar, MD Jana Pahole Goličnik.MD Mojca Unk, MD Mojca Juvan, MD Mentor: prof dr. Branko Zakotnik, MD 6 DIO, 12 ,13 11 20010 N.B.,$, 1973 September 2006: - 2 months dyspnea on exertion, epigastric blunt pain ^ family history: no malignant disease ^ no (family) exposure to asbestos, ex smoker Physical examination: . PS (WHO) 1, subfebrile ^ auscultatory dullness on the left, up to 6th rib 6 DIO, 12 ,13 2 20010 22 Diagnostic procedures blood count: WBC 11,0 G/l. platelets 411 G/l. normal Hb, CRP 54 U, normal renal and liver function tests, no electrolite disturbances chest X-ray: pleural effusion up to 6th rib diagnostic pleural paracentesis: exudate, no evidence of malignant cells ii DIU. i: 13 li 2üUiü Diagnostic procedures blind needle biopsy of the parietal pleura: non specific chronical pleuritis with hyperplastic mesothelium VATS • histology: mesothelioma, epitheloid type CTof the thorax (4.9.2006): 6 D.IG 1-5.13 11 2Q010 q 2 3 I reaiment Multidisciplinary tumor board opinion: chemotherapy with gemcitabine and cisplatinum, then operation Planned: 4-6 cycles of gemcitabine (250mg/m2 in 6h infusion, day 1 and 8) and cisplatinum (80mg/m2, day 1) Q3W - Recieved: cisplatinum 3x, gemcitabine 10x - Toxicity: transient hepatotoxic effect of chemotherapy (AST, ALT elevation 4 x IULN) alopecia G2 mielosupression (neutropenia) 6 DIO 12 13 ii 20010 S Treatment evaluation January 2007: Clinically - absence of symptoms CT (17.1.2007): Partial response (almost complete regression of the tumour mass) Multidisciplinary tumor board opinion: technically inoperable - follow up 6 pjo il* u. r) abo.te 4 hollow-up July 2007: - constant thoracic pain on the left (asymptomatic with NSAIDs) - CT (September 2007): left sided pleural effusion, visceral + parietal pleura thickening progression 0 DIO i2 13 11 20010 9 26 October 2006 19. September 2007 6 DIO. 12., 13 11 20010 10 Treatment decision: 1. radiotherapy 2. second-line chemotherapy 3 best supportive care CT 19.9.2007 CT 22.2.2008 6 Follow-up the patient did not decide for treatment immediately —> follow up and supportive care ^ CT (February 2008): spontaneous remission - May 2008: pleuropneumonia with pericardial effusion -»antibiotics - December 2009: Horner's syndrome, pain in her left shoulder 6 DIO. 12 .13 11 20010 13 Second line chemotherapy? - 1. reinduction gemcitabine-cisplatinum ^ 2. pemetrexed-single agent ^ 3. pemetrexed-cisplatinum ^ 4. vinorelbine ^ 5. gemcitabine ^ 6. None of the above 7 Second line treatment January 2010: - 5 cycles pemetrexed + cisplatinum, 6th cycle pemetrexed only - side effects of cisplatinum (hearing loss and paresthesias of the hands) - cummulative dose of cisplatinum: 1070 mg 6 DIO 12 13 11 20010 15 Treatment evaluation after 2nd line ChT - clinically: no pain, no use of NSAIDs, persisting Horner's sy and auscultatory dullness ^ radiologically: 6 DIO 12 13 11 20010 16 9 Chest X-ray 12.10.2009 15.3.2010 ^ f! 1f w arvj t i 6 DIO 1^.13 11 20010 18 Follow up September 2010: - progressive pain, Horner's sy - raising platelet count, Hb levels stable - Ultrasound of the abdomen: minimal ascites, celiac lymph nodes susp. enlarged Thrombocytosis 1) toxic effect of gemcitabine 2) paraneoplastic 3) reactive - due to anemia 6 DIO 12 13 11 20010 20 10 Next step? ^ 1. best supportive care ^ 2. radiotherapy ^ 3. 3rd line chemotherapy ^ 4. targeted therapy 6 DIO, 12 ,13 11 20010 22 Conclusions Benefit of 1st line chemotherapy Unpredictable course of disease - spontaneous regression, infections Benefit of 2nd line chemotherapy The aim: to keep the quality of life (throughout disease course part time job, physically active) dig ;:: ^ n ::cc-I'J> TIME SAVINGS ASSOCIATED WITH ONCE-MONTHLY C.E.R.A.: A TIME AND MOTION STUDY CONDUCTED <»> IN DIALYSIS CENTERS IN ITALY, FRANCE AND POLAND W Klatko,i G Villa,2 JC Glachant,3 E De Cock4 1Nephrology Department, Specjalistyczny Szpital Wojewodzki, Ciechandw, Poland; 2Fondazione Salvatore Maugeri, Pa via, Italy; 3Service Néphrologie - Hémodialyse, Bourg en Bresse, France;4United Biosource Corporation TH-P0471 INTRODUCTION • Anemia is a common complication of chronic kidney disease (CKD) contributing to morbidity, mortality, and reduced quality of life in these patients.' • Erythropoiesis-stimulating agents (ESAs) have been a key development in the treatment of anemia in patients with end-stage renal disease (ESRD) on hemodialysis ESAs such as epoetin alfa, epoetin beta, and darbepoetin alfa have relatively short half-lives and require frequent administration, ranging from three times a week up to once every 2 weeks to maintain patients'hemoglobin (Hb) levels within the recommended target range1 • The continuous erythropoietin receptor activator (CE.RA") has been proven to smoothly correct anemia and maintain Hb levels within the desired target range when administered once monthly (Q4W) in patients with CKD both on or not on dialysis1'** • Anemia management in CKD is time consuming both for healthcare professionals and patients. A major challenge for hemodialysis centers is to improve efficiency while maintaining high standards of quality and care for patients. OBJECTIVES To quantify and compare healthcare personnel time for frequent routine anemia management-related tasks in hemodialysis centers for maintenance therapy with both shorter-acting ESAs and CLHAQ4W. To model time savings for a 100% u ptake of C E.RA. Q4W in centers across three European countries SAMPLE • This study was conducted in nine dialysis centers across three European countries: three centers each in Italy, France, and Poland. METHODS_ • This was a multi-country, multicenter, prospective, observational study using time and motion methodology to describe processes and document the time taken by healthcare staff to perform frequent ESA administration-related activities. • The study was non-interventional as patients were treated according to individual center practice. • No patient demographics were collected and all data were blinded to preserve the anonymity of individuals participating in the study. Anemia management activities • The processes associated with current anemia management were identified Through interviews with center healthcare staff. - Observed tasks were frequent and observable activities associated with ESA treatment for which time could be clearly measured and was not intertwined with hem odia lysis-related activities - Observed tasks included preparation, distribution, and injection of ESAs, as well as record keeping. • For selected anemia management tasks separate samples were collected for patients receiving traditional ESAs orC E.RA Target sample sizes of 40 observations for activities per patient {eg injection) and 20 observations for activities per group of patients (eg preparation) were collected. • Tasks were observed by trained designated observers using a stopwatch and time was recorded onto case report forms. • A weighted number of ESA administrations per patient per year were calculated in each center based on the distribution of ESA products used and injection frequency by ESA product (obtained from interviews with healthcare staff). • Time data were analyzed using SAS software assuming a gamma distribution and statistics were calculated for each task sample. Modeling the Impact of once-monthly C.ER.A. • Average time per ESA-treated patient and the frequency distribution of injections at each center were used to estimate the total time savings that could be achieved with a 100% uptake of C.E R.A Q4W. • The main study end point, time per patient per ESA session, was used to calculate the annual time per patient percenter. RESULTS______ Characteristics of hemodialysis centers The number of patients with ESRD receiving ESA treatment at the time of interviews ranged from 56-90 in Italian, 39-87 in French, and 60-136 in Polish centers (Table 1). • The proportion of CE.RA. uptake across hemodialysis centers in three European countries at time of Interviews ranged from 24-48% in Italian, 26-49% in French,and 22-34% in Polish centers (Table 1) • The number of ESA injections per country per week categorized by ESA type and route of administration are shown in Figure 1. • The average number of ESA injections per patient per year for traditional ESA products was 103 in Italian, 89 rn French, and 93 in Polish centers • The average number of C E RA injections per patient per year was 12 across Italy and France, and 13 in Poland. Figure 1. Number and type of ESA injections per center per week Observed time per patient per year • Estimated observed time per patient per year across three European countries ranged from 91 to 380 min for ESAs and from 12 to 68 min for C E.RA. (Figure 2). Figure 2. FrrCrWl»^ ■ vdurtlftn lp> O :r year by center (min) Figure3. Estimated time savings with 100% uptake ofC-E.R-A.Q4W percenter Table 1 Ch.ir.Kterhtics of ESA .»dm niylMtio pe rcenler per cour try M_ t 7 ■ «TOrafl* 1 2 » Avtraqa 1 2 1 Total no. ptj r«c*Mng ESAs* 56 62 90 69 59 39 87 62 60 85 136 94 CEAÀ ubu**. N.' » O 2* M « M ÏS n M to 3» A wag« no. ESA administra Hons/pt/ywr (excluding pts receiving ŒRAJ* 118 es 103 103 66 125 76 89 68 124 88 93 Ho- ÍSA Kfe*ri4tra±ltWH t trti{(ni p(.'y# if bp jwl«»U«g loC£AJL04W 10« 7* «I t\ SI 11» 6* 17 W 111 » «I titra»i wvd t»ii«rj'pVy«nr, irun £SAi 101 231 « IS« 91 IÎ7 wa 1?« t£,BA 12 Jl £0 39 M X, 2* 2S u 21 n 39 OfcubtMi «¡mw Mvinçj 1« rtwrwd Haiti at 1OOV C-EJm. upiak« 1% W •a P* 7S. m 74 7f K iff u ** S s X 1 " .o_ IL. m s*« h ■ i ;s1 _. éu ¿1 ï 1300 250 - S. 200 Time savingr perpatien t convening to once-monthly CF.R.A • Average reductions in time when converting a patientfrom traditional ESAs to CE RA Q4W were similar across all countries. Average annual time savings of 87% in Italian, 81% in French, and 85% in Polish centers were found (Figure 2) Modeling the Impact of once-monthly C.E.R.A. at the center level • The reductions in observed task frequencies following conversion of a 100% uptake of C.E.R A Q4W produced estimated annual time savings of 87-88% (84-217 hours) in Italian, 74-86% (70-109 hours) in French, and 82-88% {221-477 hours) in Polish centers (Figure 3) CONCLUSIONS • Data from hemodialysis centers across three European countries showed that a 100% uptake of C E.RA Q4W maintenance therapy could offer substantial annual time savings on frequent anemia management tasks. • The per country results for time savings ranged from 87-88% In Italian, 74-86% In French, and 82-88% (n Polish centers. • Administration of 12 Injections of CERA per patient per year would allow scarce healthcare resources to be reallocated to other Important CKD therapy needs and improve overall patient care. • These results are In line with findings from other countries where this observational study was conducted, showing estimated annual time savings following a 100% uptake of CE.RA Q4W of 69-84% across three centers In Spain and of 79-91% across four centers In Germany. • These results confirm data from previous time and motion studies carried out In centers across Germany, the USA, and the UK which showed that an ESA administered Q4W would offer annual time savings of 79-84%.7,a ACKNOWLEDGMENTS The authors take full responsibility forthe scope, direction and content of the poster und have appiwed the submitted poster. They would like to thank Tanya Chaudry at Complete HeilthVizion for her »uotance in the prrpara tion of this poster. Editorial ■uijlance w»5 funded by f. Hoflminn L»-HDche Ltd "C-ERA is marketed under the trade name MIRCERA* (methoary polyethylene glycol-epoetin beo) wtikh is a registered trademark trf F. Hoffmann-La Roche Ltd REFERENCES 1 Ghth« F et a] Hp|lf lOOg, tumor necrosis, fibrous brands, vascular Invasion, number of mitoses per high-power field, p53 mutations Consistent with malignancy Virilism, Cushlng's virilism, no hormone production Nuclear pleomorphism, aneuploidy Suggestive of malignancy Elevated urinary 17-ketosteroids Capsular invasion, inhibin, 21-hydroxylase deficiency Unreliable Hypercortlsolism, hyperaldosteronism Tumor giant cells, cytoplasmic size variation, ratio between compact and clear cells ad ran il gland 2-)t™ ACC-Clinical presentation: adrenal Steroid hormone excess in 60% cases: rapidly progresing Pushing syndrome Androgen secreting Estradiol secreting in males: gynecomastia High DHEA-S suggests ACC Aldosteron secreting (rare) 4 ACO Staging Staging systems for jJn-iututlitjl carcinoma (ACQ proposed by the Union Internationale Gontre Cancer (UIOC) 2004 and European Network (or the Study "f Adrenal Turnout! (ENSAT) 2008."*° _ »ate UVOWI*) 30« I TT, NU, Mil TI.WP.MO II TiNU MO T2.ra.Md It n.lNI.MO n-;,Ni,Mo T3, KD. ht> 7>< NO-l MO IV tu na- i.Mi n.NI,M0 u no-i. mo T1, tumour £3 cm; 72, tumour >3cm;T3. tumour Infiltration In surrounding tissue: T4. tumour Invasion In adjacent organs (ENSAT: also venous tumour thrombus In vena cava/renal vein); NO, no positive lymph nodes; N1, positive lymph nodefs); MO, no distant metastases; M1, presence ofdlstantmetastasls, ACO Treatment flow chart Stage Mil Si age IV com pi ote nurgic* rwecion | gucceaaful | | not suceaeaful | — ■ adjuvant ihorapy wiin minta™ (äxceptons wo Idjtlj • cafisida tumour t»:i Inscllallw follow-up ovary 3 months Imaging and tumov markers L tumoix-freo I condor surqary C'no —[ complete resection"] not poealUe or Incomplete resection mitotan» only or combinad with of EDP f_mz I foUow-up every 2 montha tumour regression 1 progressiva stable disease dlseaB« 1 1 con oaor surgery • continue Iherepy ctarnottwrepy 5 ACC\ Prognosis * 5-year survival rate: - Stage X: 60% - Stage XX: 58% - Stage III: 24% - Stage IV: 0% Allolio E and Fassnaht M, Adrenocortical carinoma, Clinical update, J Clin Endocrinol Metab 2006, 91: 2027-2037 Pheocromocytoma • Epidemiology: 2-8 per million per year, «10% of them malignant - Few cases in last decade (no case in year 2007 in Slovenia) - Similar incidence in women and men - Peak incidence between 30-50 • 30% patiens with genetic background • 5-year survival rate for malignant pheochromocytoma is 40 - 50% 6 ôene+ic syndromes with pheochromocytoma risk Syndrome Type of mutation Tumors MEN 2A and 2B t&o* innnmed » MilasdftMi dominant tralL 50% now rnirtnllo.nsj A RET prolo-Oncogene 7A: inQdulliarv myroW cancer + plteoc hromo cytoma (iO*iO%, benign, bilateral, acJronaUn sncrotingl * piiralhyrotri hypifrpin^« m m«Ju|l»yy trtyfoid cancar» (itiftachromocytcunn (00%, banlgn, bflntorml, flilrurinllr» «err ting} 4 rjnriQiiotitj-urommoais Von Hippel - Lindau disease (60% inriorM a* autwwmjil dornlrianr tro»i, nirW TrtufBllans) A VHl tumor suppressor gene iiifiDHnsjiatiia.iioma'i + iMGiurn?tloais -+ win» coll aiicMomn * cafe ku fail spots * piirrcroailccyirtt * phrochroitioi.ytuma (1040%, bflnJgru bilateral, ricif.idrcnalm ■aerating) PGL 1,3 and 4 (Fwtiiwh purtiQanfllitirna nyndrnmu») A SDHB, C and D (genes for different sub units of succinate dehydrogenase) phflOChrontocytorMa ♦ Gxtra-adrwnal paraganglioma* (>507. mnligrnnt. dopamine or noradiiirnilln or ndtsnaJIn oocrijiJng) Neurofibromatosis type 1 (formerly vwi RecMfn(jfwtU«>n dlaonso -60* autosomal dorn In a rrt trait) A gene for neurofibroma (negative regulator of RAS oncogene) Neuralibomas * .schwannomas * fujurolibrasaroomas * caio nu tart spots + optic gliomas + astrocytomas-» phttochromocytonm (0,1 -5.7*. banian, adrenalin tmcrollng] Carney triad (autosomal dominant syndrome) extra-adrenal paraganglioma + GIST + pulmonary chondroma Carney - Stratakls dyad (flui.asornaä dominant syndroms) extra-adrenal paraganglioma + GIST Pheocromocytoma-Pathology ■ 90% in the adrenal medulla, 10 % extraadrenal - paragangliomas * Ectopical presence of chromaffin cells is the strongest sign of malignancy • pathologic distinction between benign and malignant is not entirely clear: ■ Commonly larger and weigh more ' Less nuclear pIsomorphism, more mitoses ■ AAIB-1 pssitMty aneuploidy, high S-phase fraction ' Gene expression profiling 7 Pheocromocytoma - Clinical manifestations and Diagnosis • Clinical manifestations: - Pressure (elevated blood pressure),Pain (headache), Perspiration, Palpitations, Pallor ■ Biochemical investigations: 24-hour urine collection for free catecholamines and metanephrines, plasma metanephrines ■ Imaging: CT, MRI, 123I-MIBG scanning, octreoscan, PET Adrenal gland tumors: Adrenocortical carcinoma (case report 1) Tanja Ovčariček, Ksenija Strojnik, Rok Oevjak Mentor: Simona BorŠtnar JANUARY 2000 * History: 29-years old women presented with signs of hypersecretion of Cortisol and androgens (Cushing syndroma, hirsuitism, thinning of the skin with bruising, virilization with deepening of the voice and amenorrhea, psyhological disturbances) adrenal gland c^Ai (jt-f nwdul (Id Cortisol aldosterone èndro$*nt J tt-j st/mnjfino Physical examination: acne, male hair pattern,multiple bruises of the skin, otherwise b.p. Lab. findings: complete blood count, renal and liver tests:normal, K: 3.4 mmol/l | MORPHOLOGIC EVALUATION • Chest X-ray: normal • US/CT abd.: 8 cm heterogeneous tumor in the right suprarenal gland with irregular margins, poorly circumscribed, with some calcifications, displacing v.cava inf., pancreatic head and duodenum, but without local invasion or lymph node involvement or other metastases: ACC susp • CT thorax: no signs of metastases w -Lung and liver predominant metastatic sites of r J" ACC, abdominal and thoracic scans integral of the staging ACC JUL 9 3L Hormonal worn-up and imaging in patients with suspected or proven AUU recommendation of the ACC working group of the European Network for the Study of Adrenal Tumors (ENSAT), May 2005 Hormonal work-up: Glucocorticoid excess Dexamethasone suppression test (1 mg, 2300 h) Excretion of free urinary Cortisol (24 h urine) Basal Cortisol (serum) Basal ACTH (plasma) Sexual steroids and steroid precursors DH EA-S (serum) 17-OH-progesterone (serum) Androstendione (serum) Testosterone (serum) 17-estradiol (serum, only in men and postmenopausal women) Mineralocorticoid excess Potassium (serum) Aldosterone to renin ratio (only in patients with arterial hypertension and/or hypokalemia) Exclusion of a pheochromocytoma (1 of 2 tests) Catecholamine excretion (24 h urine) Meta- and normetanephrines (plasma) Imaging CT or MRI of abdomen and thorax Bone scintigraphy (when suspecting skeletal metastases) Cholastarol OH (»r0| » f fiywroiy**** — ^ •oH/eortl«o*i*ron« J | 11* O*oxyeofi)*ol Carllcoaloiono I I Cortl»o( 4- Cortlaol prthw Androgen | AldoBl*ron* pathway HORMONAL WORK-UP 1 .Assessement of glucocorticoid excess: * dexametason suppresion test (2 mg): no Cortisol suppresion * basal Cortisol le vel (serum): 1465 nmol/l * basal ACTH level (plasma): normal 5.2pmol/l 2. Assessment of sexual steroids and steroid precursors: * DHEA -5."t 24.0 fimol/l * 17-OHprogesteron: 132.7nmol/l Autonomous secretion of A _/ -J. /• . a. 4 A C ^ !/I iW * Androstend/on: \14.5 nrngUi^m from odreml tumor * Testosteron: | 58.7pmol/l 3. No mineralocorticoide excess 4. Exclusion of pheocromocitoma 10 WHAT KIND OF PRIMARY LOCOREGIONAL TREATMENT WOULD YOU RECOMMEND? • 1. Laparoscopic adrenalectomy • 2. Open surgery with adrenalectomy • 3. Adrenalectomy with radiotherapy of the tumor bed 7 u PRIMARY TREATMENT 28.1.2000: right adrenalectomy Histology: (Weiss classification): 8x6x4 cm large tumor, the cancer cells with marked nuclear polymorphism, atipya, high mitotic rate, atypical mitoses, diffuse architecture with capsular and angiolymphatic invasion and extensive necrosis Hormonally active ACC :pT3, NO, MO, (st III), RO resection 11 Postsurgical hormonal work-up: indicated radical resection 1. Assessement of glucocorticoid excess: * dexametason supp. test: no suppression ■ — 'T * Basal Cortisol level (serum):]465nmol/l - * Basal ACTH level (plasma) normal:4.6 pmol/l suppression of Cortisol level to 15rmol/l jßas.cortisol level 41.69nmol/l (norm.) Basal ACTH; 5.8 pmol/I Testosteron: ]58,7prnol/l I basal DHEA5: 0.1 pmol/l 2. Assessment of sexual steroids and steroid precursors: * ÙHEAS:-\22,5i.imol/l * 17-OHprogesteron: 132,7 nmol/i * Androstendion: f 14.5nmol/l * 17-OHP: 0.24 nmol/l Jbasol androstendiorii 0.1 nmol/l 1 basal testosteroff 0.2 pmol/l K ADJUVANT THERAPY? The risk of recurrence after R0 resection is 60% Due to the rarity of ACC, there ore no published randomized prospective trials of adjuvant therapy, majority retrospective reports examined the use of adjuvant mitotane, an oral adrenocorticolytic agent The largest retrospective study (controlled) of 177 patients with resected ACC (stage I-III) with 2 cohort (Italy, Germany) In Italian cohort 47/102 pts received adjuvant mitotane(median treatment duration 29 months), German norte out of 75 pts Radiaton Th of tumor bed recommended for ftl or Rx resection 3S> is» i : : *mDFS (42 months vs 10, p<0.001,42 vs 25, p=0.005) *mOS (110 months vs 52 , p=0.001,110 vs 67, p=0.10) _Terzolo M, et al. N Engl J Med 2007 12 * . ADJUVANT MITOTANE (recommendations) ■ The optimal dose and duration of adjuvant treatment with mitotane have not been standardised, but blood levels of mitotane should be monitored and kept at about 14-20 mg/ml ■ The daily dosage needed to achieve and maintain blood levels greater than 14 mg/l is variable * Treatment usually initiated with 1.5 g/d, rapidly increasing dose depending on tollerability to 5-6 g/cf * Measurement of plasma mitotane levels 14 d after initiation of treatment * Due to adrenolityc effects of mitotane, replacement doses of corticosteroids (hydrocortisone or prednisolone) should be prescribed in order to prevent adrenal insufficiency * Mitotane has narrow therapeutic window, more than 80% of the pts experience at least one undesirable side effect_ TREATMENT(cont J * Adjuvant mitotane (Jan 2000) 1.5 g daily with gtucocorticoide replacement with hydrocortisone (15 g daily) * Rapidly improving symptoms, gain of menstruation, male hair pattern almost disappeared * No serious mitotane adverse effects * After 7 months patient decided to stop with mitotane therapy * CT abdomen+thorax:normal, hormonal levels normal 13 FOLLOW-UP (recommendation) • Follow-up with CT scans of the abdomen and thorax and hormonal work-up is recommended every 3-6 months FOLLOW UP: OCTOBER 2001 (10 months after initiation of treatment) • History, clinical status, lab. findings: normal • Hormonal tests: Tcortisol, DHEAS, 17-OHP, testosteron and androstendion, |ACTH • CT and MRI of the abdomen adrenal bed recurrence • CT thorax: 2 metastatic lung nodes (4 mm) in left lower lung lobe 14 m TREATMENT OF THE l.st. I RECURRENCE (recommendations) * Surgery should be performed if complete surgical removal of local recurrence is feasible and the interval to a previous complete resection is >4 months, In these pts adjuvant therapy is mandatory * If complete resection of metastatic sites is feasible, it should be done (even if 2 steps are needed) followed by adjuvant mitotane therapy * If surgery is not feasible, pts should be treated like pts with metastatic disease (mitotane+/-cytotoxic therapy) ^ WHICH TREATMEN IS THE MOST #r. APPROPRIATE IN THIS SETTING? # (1.recurrence: 2 metastases in left lung, adrenal bed recurrence) • 1. systemic therapy (mitotane) • 2. systemic therapy (mitotane +/- other cytotoxic regimen) • 3. surgery of local recurrence and metastatic lesions • 4. surgery of local recurrence and metastatic lesions and adjuvant mitotane therapy 15 TREATMENT OF 1. st RECURRENCE * 18.10.2001: resection of metastase in riqht adrenal bed * 7.11.2001: resection of metastases in left lower lung lobe * After resection decrease in Cortisol androgen, 17-OH and normalisation of ACTH level * 3.12.2001: mitotcne ressumed adjuvantly (10 g 1 month, 5 g 5 months, 3 g 3 months, followed by 1 q daily)+ hydrocortisone replacement therapy (20+10 mg) * Regular 3 monthly follow-up JUNE 2003 (1 year, 7 months after initiation of treatment of l.st recurrence) * Symptoms free, CT scan abdomen and thorax negative, hormonal work-up normal • Mitotane therapy stopped 16 JUNE 2005 Asymptomatic, regular follow-up: CTscan thorax: Small (lcm) lesion in the right lower lung lobe US abdomen, bone scan: without metastatic lesions WHAT KIND OF TREATMENT WOULD YOU RECOMMEND? • (2.nd recurrence after 2 years disease free interval,single metastasis in the lung, prior adjuvant mitotane th 7 mths, lyear+7mths ) • 1. mitotane • 2. mitotane in combination with chemotherapy • 3, resection of metastasis • 4. resection of metastasis and adjuvant mitotane • 5. resection of metastasis and chemotherapy 7 17 TREATMENT OF 2.nd RECURRENCE • 30.6.2005: resection of iung metastasis • CT scan of the thorax 4 weeks after the surgery: no radiological evidence of the disease • 15.7.2005 reinstitution of mitotan therapy (2 g, titrated to 5 g daily), hydrocortisone replacement (30+20 mg) REASONS FOR "ADJUVANT" MITOTAN THERAPY • Retrospective case-controlled study demonstrated survival benefif of mitotane in the adjuvant setting (Berutti et al J Clin Oncol 2005, Terzolo M et al N Engl J Med 2007) • Patient was disease free after metastatectomy-expected potential benefit from "adjuvant" therapy • The role of postoperative cht with streptozocin after metastatectomy is less evident and the toxicity profile may outweigh any potential benefit • Patient benefited from previous mitotane treatments by possible lengthening of previous recurrences with postoperative use in the past (after initial resection 2000, after metastatectomy in 2001) -V 18 FOLLOW-UP AFTER 3 MONTHS • Hormonal assessement: increased levels of androgens • CT thorax: pleural metastases in the right lung-radical with no suspicious changes in the pleura of the left pulmonary lobe and no pathological masses in lung parenchima-Only right pleuropneumectomy feasible • No other metastatic lesions METASTATIC UNRESECTABLE DISEASE • in metastatic setting mitotane is the backbone of the therapy -studies with different mitotane-cytotoxic Th combinations, no randomized trials *2 imporatnt phase II trials; International consensus conference of the management of adrenal cancer (2003): Recommended first-line cytojKlxle drug regimens; Etoposide, doxorubicin and cisptatin (EAPJplus mitotane (EAP/M) (adapted from Serruti et, Endocr Re/at Cancer 2005) every 21-28 days: day 1 40 mg/m2 t> day 2 100 mg/m2 E day 3 * 4 100 mg/m2 E * 40 mg/m2 P plus oral mitotane aiming at a blood level between 14 and 20 mg/L Stnejjtozotocln (Sz) plus mitotane (Sz/M) (Khan et at. Ann of Oncology induction; day 1-5; 1 g Sz/d afterwards 2 g/d Sz every 21 days plus oral mitotane aiming at a blood levet between 14 and 20 mg/L »ongoing first randomised, phlll trial in ACC (FIRM-ACT) «consider enrollment in a clinical trial! 19 METASTATIC UNRESECTABLE DISEASE(cont) • Several new treatment options were also investigated • Targeted therapies are of particular interest (gefitinib, erlotinib+gemcitabin, bevacizumab+capecitabin), no response was seen • Occasional tumor responses have been reported for the antiangiogenic coumpound thalidomide (Chacon R et al. Journal of Clinical Oncology 2005) TREATMENT(metastatic disease) (16.11.2005-5.1.2006) • Mitotan (5g/dan) + chemotherapy regimen EAP: doxorubicin (40 mg/m2 Dl) + etoposide (100 mg/m2 D 2-4) + cisplatin (30 mg/m2, D 2-4)/4 week • Evaluation after 2 cycles: CT thorax: progression of pleural metastases in the right lung, no signs of other metastatic lesions • Surgical procedure recomended 20 SECOND OPINION Results of XHC staining of the tumor: positive for expression of PDGFR alpha and beta, EGFft, VEGFR and COX-2 * phasel clinical trial: DTIC/dacarbazin 250 mg/m2 D 1-3, capecitabin 1000 mg/m2 b 1-14, imatinib 400 mg/daily D 121, 3 week cycles in attempt to reduce tumor mass followed by surgery TREATMENT (DTIC+capccitabin+imatinib) (18.1.2CX)6-8.3.2006) • After 1. cycle grade III neutropenia, otherwise no serious adverse af f ects • Evaluations after 3 cycles: CT thorax: progression of pleural metastases, without evidence of other metastatic sites • 12.4.2006: pleuropneumonectomy and RT of right thorax (60 Gy) 21 FOLLOW -UP (5 months later) • US abd: progression in the abdomen with a bulky metastatic masses in the abdomen (retroperitoneum, peritoneum, omentum) • Trial with thalidomide 200 mg/daily and mitotane (4g/daily) (Chacon R et al. Journal of Clinical Oncology 2005) • Control US: progression in the abdomen and new lesions in the liver (37x 30 mm in VII segment, 33 mm v II segment), citologically confirmed • 24.11.2006: Surgery with excision of bulky masses in the abdomen and RFA of liver metastases TREATMENT (cont) • After 1 month: CT thorax and abdomen: progress in the left lung, mediastinum, thoracic wall, abdominal progression • Therapy with thalidomide and mitotane stopped • 6.2.2007: exploratory laparotomy with adhesiolisis, metastatectomy in the liver, mesenterium, pelvis, colon • After surgery: acute respiratory distress with citologically negative pleural effusion with mediastinal displacement • Patient was put on supportive therapy 22 fu FUTURE PERSPECTIVES Currently active clinical trials: AGENTS __ RATIONALE EAP-M vs Sz-M establishment of a first line cytotoxic drug regimen (phase III) mitotane vs observation adjuvant mitotane after RO resection (phase III) sunitinib multiple TKI (phase II) sorafenib and metronomic paclitaxel multiple TKI in combination i with metronomic cht (phase II) mitotane vs mitotane+IMC-A12 IGF-R1 antibody in addition to mitotane in first line systemic treatment (randomized phase III) Tumors or adrenal gland: Metastatic pheochromoc^toma Case report 2 Ksenija Strojnik, Rok Devjak, Tanja Ovčanček Mentor; Simona Borstnar 23 Initial diagnosis (actober 1992): 32-year-old female with incidental tumor of adrenal gland: * Family diseases: no malignant or benign tumors: - Past medical history: mumps and acute pancreatitis (at the age of 11), acute myocarditiiTat the age of 29), no personal history of malignant or benign tumors; * History and physical examination: ocassiona! left back pain, no abnormal physical findings * ¡Diagnostics: CTabdomen: 8x5 cm inhomogeneous tumor in left adrenal gland with small cysts and calcinations, without local invasion into adjacent organs or tissue, no enlarged lymph nodes Hormonal testing - 3 samples of metanephrines, catecholamines and VMA in 24h urine: normal - plasma free metanephrines: not done - plasma aldosteran and renin: normal - suppression test with 2 thg of dexamethasone; no denivelation of Cortisol Treatment: - Surgical treatment: open left adrenalectomy - Histopathological report: 8x5cm pheochromocytoma, small-cell, with high mitotical activity and vascular invasion, RO resection - Staging with CT abdomen and chest x-ray: no distant metastases 24 7 • I Adjuvant treatment: Which of the following would you recommend? 1. Adjuvant chemotherapy 2. Adjuvant targeted therapy 3. Adjuvant radiotherapy 4. No adjuvant therapy, follow-up for 5 years 5. No adjuvant therapy, follow-up for lifetime Recommendations on primary treatment and surveillance in pheochromocytoma: PRIMARY TREATMENT* SURVEILLANCE' 3-12 mo poctrsHCtlon; • h&p, blood prwuira, and mirk«' RNMtab!«| Resid (laparostopic pic'smsd when stfs add feasible) long term: »HiP, blow) pressure, and martm;1 ► YoanMevwyiiiio > Imaging Ms as clMy IndlctM www.nccn.orp. NCCN Clmkoi Proctk* SvfMhmr In Otcohgy 25 7 0 . Genetic testing: Would you recommend genetic testing to this patient? 1. Yes 2. No Genetic syndromes with pheochromocytoma risk: Syndrome Type of mutation Tumors MEN 2A and 20 tsöx inherited aa autawmal donvre»r|t trait» ÜOX new rnifftmän«) ¿RET pro to-oncogene 2A, mtdülbiY thyrafäcenctr • phtochromocytomo {20-50%, benign, bilateral, adrsnolln secreting) * parathyroid hyperplasia 2B. medullary thyroid cancer • plicochromocytoffu) (50%, benign, bilateral, adrenalin secreting} > ganglioneurompto t|f Van Hippel - Lindau disease {B0% inhenrwd as autosomal tfomWnt Irait, 20% nc* mutation«) A VHL tumor suppressor gene ^tmcwglübbftfjqwi »ongiamatoeie * rerri I cell corclfiamo • cofo au fait spats • fXjiiQ'efliiccyits + pheoehrflmeeytomo (1.0-30%, benign, b¡totere 1. iwradntMalln accreting) P6L 1,3 and 4 (familmf parage* flM tyndrom«) A 5DHB* C and D (genes for indifferent subunits of succinate dehydrogenase) phuochromocytorw * cxtni-udrcnal paraganglioma! {>50% malignant, dopamine or noradrendin or adrenalin secreting) Neurofibromatosis type 1 {formerly von ftecMtoghausen diicoie ■ 50% autosomal dominant trait) A gene for neurof ibromin (negative regulator of RA5 oncogene) Neurof Ibamas + schwannomas ♦ neurofibrosarcomas + cafe au lait spots + optk glioma a * astrocytomas + pheochromocytoma (0,1 -5,7%, benign, adrenalin secreting)... Carney triad (autosomal dominant syndrome) extra-adrenal paraganglioma + GIST + pulmonary chondroma Carney - Stratakis dyad (autosomal dominant syndrome) extra-adrenal paraganglioma + GIST 26 All should be reffered to a genetic counselor! Genetic testing is recommended in patients: • less than 40 years old • bilateral or multifocal tumors • sympathetic or malignant extra-adrenal paragangliomas • personal or family history of clinical features suggestive of a hereditary pheochromocytoma-paraganglioma syndrome w>MilS£[Lei31. NCCN Clinical Practice Guidelines - vH.2010 gov. NC3 Pheoch',ornocytftmo and Paraganglioma Treatment. Follow-up november 1996 (4 years after operation): • On follow-up ultrasound: 4 cm hepatic lesion (fine-needle biopsy: blood) • CT chest: multiple round lesions 0,5 - 1,5 cm (transthoracic fine-needle biopsy: metastases of pheochromocytoma) • History and physical examination: asymptomatic, no abnormal physical findings • Hormonal testing: metanephrines, catecholamines and VMA in 24h urine - normal 27 Management of metastatic pheochromocytoma: Which treatment would you recommend? 1. Surgery 2. Chemotherapy 3. Clinical triai 4. l31I-MIBG radiation therapy 5. none Recommendations on treatment of metastatic pheochromocytoma: Locally I unreMctabla PRIMARY TREATMENT* I CytQTwJirtilvv [RÏJ rt action, If poulbte I \i RT » MjHu-WiNkWi» h *lph*inrHi*ri!,TP.Iiw tbrti-bloctodi | SURVEILLANCE» i continu«» Bi^fl-blocksd* £ »lph* fn*1hyliyr«lno AyuMfiLle (•tt, d*c«rb«zJn», cyetoplwnpfiiiftliW, vinerteitfw) 1 ai r Mapfl it cnmp«MioftM* MM on cilni**! irai' (r#quli*» pimk M100 »«ait wlUi i^iUrmoy) Evtl) 9- « mo ■ Hi P. blood prttMura, irwl nwkiri1 • Imaging studtw n dlnkalty IndloMad www.nccr.ofy NCCN CT/hko/ Practfem SukWkM In Oncology 28 Treatment success with CVD (cyclophosphamide, vincristine, dacarbazine) for metastatic pheochromocytoma : TABLE 1, CVD chemotherapy for malignant PCC (selected reports) Mitatra j*r (rtf.) No. of patients Biodnmkal rapóme (*) Complete Parti»! Tumor mpoM»(%) Complete Partial Stable dieeaie (») Pngrailoii(t) 1988(62) 14 21 67 14 43 36 T 1996 (56) 2 0 60 60 0 60 0 1998(44) 3 NE NE 0 0 33 67 1999(86)" 4' 0 0 0 60 0 60 2001 mr 3 33 0 0 33 67 0 2003(26) 4 ND ND 26 26 25d Î5 % of mluable otea 20 46 14 32 36 18 Scholtiet td. Maiigrxntpheochomocytoma therapy. JOm EndocrMMetab. apri!2007,92 W1217-1225 52. Averboch et al. Matignwtt pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine and dacarbazwie, Ann Intern Med 1988.109; 267-273. 55. Ahshkv •taifk* camttof M^AMr(lAMf^WKiffWil treat** with cyclophosphamide, vrtcristine aid dactrbazine in a combmed chemotherapy. EndocrJ1996 43; 279-284. 44. Toda eta/. Three caxs of maiiytant trv¡ft*d «n Iff rfxtepJiotphxn-iJrí vincristine twtd daca-bazine combination chemotherapy aid a-methyt-p-tyrosine to control hypercathecholaninemia. Harm Res 1998. 49- 295-297. 86. Sisson et al. Treatment of maii^yast pheochromocytoma with 131-1 metaodobenzylguanidine aid chemotherapy. Am J Clin Oncol1999- 22: 264-370. 87. Hartley eta!. Matagemait o f malignant pheochromocytoma: a re trospectitm review of the use of 131-1MIBG twtd chemotherapy m the West M>dhndt CHa OncaiiOO! ¡3 361-366 26. Edstrom et at. The management of benign and malignant pheochromocytoma aid abdominal paragaig/ioma Etr J Surg Onco! 2003: 29- 278-283. Treatment success with 131-I MIBG radiation therapy for metastatic pheochromocytoma: TABLE 2. MIBG radiotherapy for mrîgnint PCC (selected reportai Biocbeml roponae tarrel|IODK(%) Publication year (nf.) No. of patients _ StaUediswwW Prtgnwon (*) Cmpltte Partial Complet« Partit] 1997 (88)° i? 2001 (W 9 2003(96)« 12* % of mluablí cases' 18 82 4 26 67 18 48" tf 6 18 66 21 1? 17 0 88 88 33 0 20 0 0 67 33 38 SO 19 18 46 18 13 32 4 25 66 16 Schölts et ist Maligmtpheochomocytoma theropy. J Clin EndocrM Metab. april 2007.92 (4): 1217-1225 Bß. Loh etat. The treatment of maliyumt pheochromocytoma with iodine-131 mstaiedobensytguanidme (131-IMIBSJ: a comprehensne reviem of 116 reported patients. J Endocrhol Inveet 1997.20.■ 648-658. 89. Tronconeetal.HMiermvik:** rkmrvpf of ^SA-hrtrrecyteeM otd/mgo^fttM Q J Nucf Med1999.43:344-355. ei iartnf r tf Trustent lV miri&mt phw/vmacftom* w-H tjl'tmwtovMentytymMTS anl " il* Cm-'IPFP l! 264-370 87. Haßley et al. Mavtgment of maUpant pheachromocytama: a rétrospective review of the use of 131-1 MISS ml chemotherapy in the West Midhnds. Clin Oneoi 2001.13:361-366. 96. Rose et al. High dose 13I-I metaiodobeniytguatidine therqiy for 12 patients mth mati^mt pheochromocytoma Ctsicer2003.98:239-248. 29 1-iine treatment of metastatic disease (january - may 1997): ■ 123-I MIB6 scintigraphy: negative • She was treated with 6 cycles of CVD (cyclophosphamide, vincristine and dacarbazine) I stable disease in the lungs and liver September 1998 (1 year and 4 months after chemotherapy): * Severe pain in upper abdomen * CT scan: progression of lung and liver metastases 30 2-line treatment of metastatic disease (october 1998 - January 1999): - m-In pentetreotide scintigraphy: neg. * 3 cycles of etoposide and cisplatin progression of disease in lung 1 External beam irradiation of the whole lung (january 1999) Stable disease February 2000 (1 year and 1 month after RT of lung): * Medical history and physical examination; headache and left arm weakness • CT scan: 1,5 cm metastasis in CNS Surgery of brain metastasis Radiotherapy of the whole brain 31 October 2000 (1 year and 9 month after RT of lung): • Medical history and physical examination; dyspnea, cough, hemoptysis; painful induration in the left upper arm and under nail on the left thumb ' CT scan: progression in the lungs and liver • Fine needle biopsy: metastases in soft tissue Radiotherapy of painful soft tissue lesions Bronchoscope electrocauterisation of lung metastases 3-line treatment of metastatic disease (october 2000 - july 2001): Thalidomide: stable disease for 9 months I progression I symptomatic treatment died after 2 months (5 years after diagnosis of metastatic disease) Novel agents and clinical trials in pheochromocy toma : Theoretical bockround ürugs Results and ongoing clinical trials PI3Mkt/mT0R pathway everolimus Cose-reports of monotherapy with dissepointrng results; ongoing phase II: everolimus + erlotinib PD6F-R, VESFund E&F-ft overexpressed imotinlb su ni ti nib fast a matan ib bevacizumab pertuzumab Cose-reports of monotherapy with dissopointing results Cose -reports with Cft and PR; ongoing ph II trial monotherapy Positive in preclinical trials; ongoing ph II monotherapy Positive in preclinical trials; ongoing ph. II with ^ capecitabine and ocreotide MR Ongoing ph.II pertuzumab + erlotinib HSP90 overexpressed geldanamycine Positive preclinical trials; ph II trials in the near future HKWy-WH wxiitvt* - ¿felted/. Tmit.