Razvan Popescu Tumor Center Aarau Switzerland
Pancreatic Ductal AdenocarcinomaRazvan PopescuTumor Center AarauSwitzerland
Median Survival of Patients With Pancreatic Cancer Localized/ Resectable15 - 24 months10% Locally Advanced6 - 15 months30% Metastatic/ Advanced3 - 12 months60%Importance of Supportive and Palliative Care
Pancreatic cancer symptom burden Asthenia85%Weight lossAnorexiaAbdominal / epigastric painDark urineJaundiceNauseaBack painDiarrheaVomitingSteatorrheaAbdominal fullnessThrombophlebitis2-3%
Recent guidelines call for early palliative careas a new standardPotentially Curable Pancreatic Cancer: AmericanSociety of Clinical Oncology Clinical PracticeGuideline 2016:“Patients should have full assessment ofsymptoms, psychological status, and socialsupports and should receive palliative care early”www.asco.org/guidelines/PCPC
Supportive and Palliative Care Start supportive and palliative care as soon asdiagnosis is suspected – pancreatic cancer is anEMERGENCY Assess symptoms and their speed of development Consider pain, weight loss, exocrine pancreaticinsufficiency, jaundice*, delayed gastric emptying*,VTE, depression, etc.* Biliary obstruction: endoscopic stent placement* Duodenal obstruction: endoscopic metal stent placement
Many patients assume they can be curedwith palliative measures 1193 patients participating in the Cancer Care Outcomes Researchand Surveillance (CanCORS) study receiving chemotherapy forstage IV lung or colorectal cancers 69% lung and 81% colorectal cancer patients did not understand thattheir treatment was not at all likely to cure their cancer. Inaccurate beliefs were higher among patients who rated theircommunication with physicians very favorably ! Educational level, functional status, and the patient's role in decisionmaking were not associated with such inaccurate beliefs aboutchemotherapy– Weeks JC, et al. Patients' expectations about effects of chemotherapy foradvanced cancer. N Engl J Med. 2012 Oct 25;367(17):1616-25.
Recent Randomized Trials document Impact ofEARLY Palliative Care Benefits of OUTPATIENT concurrent palliative care:– Avoided admissions and readmissions, increase referral tohospice,– Better communication and satisfaction– Equal or lowered costs to the health system– Equal or better symptom management– Equal or improved quality of life– Equal or LONGER survival– Not a single trial showed harm, added cost, or burden
Most Palliative Care consults in Medicare beneficiaries with Pancreatic cancer are placed close to deathPresented By Mohamed Beg at 2018 ASCO Annual Meeting
Locally advanced inoperable / metastaticPancreatic Cancer
Predicting Prognosis in advanced PDACThe MSKCC Prognostic Score (MPS) A modification of the Glasgow Prognostic Score(CRP 10 and Albumin 3.5 g/dl) Neutrophil / Lymphocyte Ratio (NLR) 4 and Albumin 4g/dl) get each 1 pointAndrew Cheung Yang, Abstract 4105, ASCO 2017
Gemcitabine Established as TreatmentStandard for PDAC over 20 Years Ago First-line gemcitabine vsbolus 5-FU in advancedpancreatic cancerGemcitabine5-FU80OS (%)– Median OS: 5.7 vs 4.4 mos(P .0025); 1-yr OS: 18%vs 2%– Clinical benefit (pain KPS weight): 23.8% vs 4.8%(P .0022)100604020002468 10 12 14 16 18 20MosBurris HA, et al. J Clin Oncol. 1997;15:2403-2413
FOLFIRINOX TrialTrial SchemaPatient Characteristics
FOLFIRINOX Trial - Toxicity
OS 11.1 vs. 6.8 monthsHR 0.55, p 0.001No PD atFOLFIRINOXGem6 months52.8%17.2%12 months12.1%3.5%18 months3.3%0 %
Time until definitive deterioration of QoLFOLFIRINOXGemcitabine
Design of PRODIGE 35 PANOPTIMOX studyPresented By Laetitia Dahan at 2018 ASCO Annual Meeting
PRIMARY ENDPOINT (mITT): br / 6 months Progression Free Survival ratePresented By Laetitia Dahan at 2018 ASCO Annual Meeting
PROGRESSION FREE SURVIVAL (PFS)Presented By Laetitia Dahan at 2018 ASCO Annual Meeting
OVERALL SURVIVAL (OS)Presented By Laetitia Dahan at 2018 ASCO Annual Meeting
TOLERANCE: br / Most common grade 3-4 adverse eventsPresented By Laetitia Dahan at 2018 ASCO Annual Meeting
TOLERANCE: br / Neurotoxicity grade 3-4Presented By Laetitia Dahan at 2018 ASCO Annual Meeting
MPACT TrialMedian OS8.5 vs. 6.7 monthsMedian PFS5.5 vs. 3.7 monthsSurvivalResponse Rate23% vs. 7%
Sequential nab-pacli followed by gem24 hours later might be superior PDAC mouse model suggested that nabP potentiatesGEM activity by reducing cytidine deaminase levels andscheduling may be important 146 patients randomized to concurrent vs. sequentialnabP and GemSequentialConcomitant6 m PFS47%33%Median PFS5.84 monthsHR 0.66, CI .46-.95Median OS10.1 months7.9 monthsHR .88, CI 0.61-1.29 More side effects (hematological, fatigue, QoLdeterioration) in SEQ groupPhilippa Corrie, Abs 4100 ASCO 2017
Comparative Effectiveness of nab-Paclitaxel PlusGemcitabine vs FOLFIRINOX in Metastatic PancreaticCancer: A Nationwide Chart Review in the United StatesSunnie Kim et al, ASCO GI Cancers Symposium 2018
UpToDate 2018
Second Line Therapy
Meta-analysis on 2nd line Therapy for PDAC 5 Studies with 895 patients receivingmonofluoropyrimidine(FP) chemo orcombinations of FP and Irinotecan or Oxaliplatin HR FP Iri vs. FP 0.64 (0.47-0.87, p 0.005) forPFS and 0.7 (0.55-0.89, p 0.004) for OS HR FP Ox modest improvement for PFS andnone for OSSunbol et al, Cancer, 2017; 123: 4680-4686
NAPOLI-1: Nanoliposomal Irinotecan With 5-FU/LV AfterPrevious Gemcitabine-Based TreatmentStudy design: Phase 3, open-label RCT; mPDAC progress on Gem-basedtreatmentRandomization: nal-IRI (MM-398) (n 151) 5-FU LV (n 119) or nal-IRI 5-FU LV (n 117) Primary endpoint: OSSecondary endpoints:PFS, TTF, ORR, andsafetyAs yet unpublished datasuggest QoL maintainedunder Nanoliposomal Iri 5FU/LVNanoliposomal irinotecan: Enhanced tumor penetration andretention - EPR. Wang-Gillam A et al;. Lancet. 2016;387:545–557.
Optimal therapeutic sequence ?First-lineFOLFIRINOXSecond-lineGemcitabineGem Nab-P?GemNal-IRI 5-FUFOLFIRIOx FP?FOLFIRINOX?Gem Nab-PNal-IRI 5-FU?FOLFIRI?Ox FP?FOLFIRINOX?Quality of life is paramount in this setting – we need data!
Novel Approaches to PDAC Systemic Treatment
Hyaluronan: Major Component of theExtracellular Matrix PEGPH20: recombinanthuman hyaluronidase Hyaluronan degradation can– Normalize tumor interstitialpressure– Improve drug delivery
Phase II HALO-109-202: Addition ofPEGPH20 to Gem/Nab-Pac in MetastaticPancreatic CancerPts with stage IV pancreaticcancer, no prior treatment formetastatic disease, KPS 70%(planned N 279)Gemcitabine 1000 mg/m2 Nab-Paclitaxel 125 mg/m21 x/wk for 3/4 wks/cyclePEGPH20 3 µg/kg IV2x/wk in cycle 1 then weekly Gemcitabine 1000 mg/m2 Nab-Paclitaxel 125 mg/m21 x/wk for 3/4 wks/cycle Primary endpoint: PFS Secondary endpoints: ORR, OS, safety, PKTreat untilprogression,intolerable toxicity,death, or choice todiscontinue
Phase II HALO-109-202: PreliminaryResults Outcome by PopulationGem Nab-P PEGPH20Gem Nab-PP ValueHRTotal Median PFS, mos ORR, % (n/N)5.741 (30/74)5.234 (21/61).11.480.69HA-high Median PFS, mos ORR, % (n/N)9.252 (12/23)4.324 (5/21).05.040.39HA-low Median PFS, mos ORR, % (n/N)5.337 (14/38)5.638 (9/24).74.960.89Higher rate of thromboembolic events on PEGPH20-containing arm during first stage of enrollment(42% vs 25%); mitigated during second stage with addition of prophylactic enoxaparin[1]Phase III HALO-109-301 study of gem/nab-P PEGPH20 limited to HA-high pts currentlyenrolling[2]
Immune Checkpoint Inhibitors in PDAC– 2 of 4 dMMR/MSI-highpts on pembrolizumabhad objectiveresponsesTarget Lesion MeasurementsChange From BaselineSLD (%) Minimal to no activityin advanced PDAC 1% of pancreaticcancers associatedwith defectivemismatch repair(dMMR/MSI-high) IGastricAmpullarySmall bowelPancreaticCholangio10050P050100PPP
BRCA- or PALB2-mutation carriers Objective responses in early trials:– Rucaparib: 3/19 (16%)– Olaparib: 5/23 pts (22%)– Veliparib: 0/16 pts
Metastatic Pancreatic Cancer: ASCOClinical Practice Guideline UpdateSohal, et al.www.asco.org/gastrointestinal-cancer-guidelines American Society of Clinical Oncology 2018. All rights reserved.
Non-metastatic Pancreatic Cancer
Pancreatic Cancer Resection Categories Resectable Borderline resectable– A distinct category– Neoadjuvant therapy increases likelihood of R0 resection Unresectable (eg, locally advanced or metastatic)Ryan, David et al, New England Journal of Medicine. 371(11):1039-1049, 2014Cancer of the pancreas: ESMO Clinical Practice Guidelines, Ducreux M et al, 2015https://doi.org/10.1093/annonc/mdv295
Resectability in Pancreatic AdenocarcinomaPancreatic Adenocarcinoma.Ryan, David; Hong, Theodore; Bardeesy, NabeelNew England Journal of Medicine. 371(11):1039-1049, 2014.DOI: 10.1056/NEJMra1404198
Whipple Procedure(Pancreatoduodenectomy)en bloc removal of: Distal stomachDuodenumHead of pancreasDistal bile ductGallbladderProximal jejunum
53 resectable PDAC trials on clinicaltrials.gov
CONKO-001Gemcitabine vs. No ChemotherapyR0 13.1 vs 7.3 monthsR1 15.8 vs 5.5 monthsJAMA. 2007;297: 267-277
ESPAC – 4 DataASCO 2016
PRODIGE 24/CCTG PA.6, an Unicancer GI trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resectedpancreatic ductal adenocarcinomas.Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Slide 3Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Six-month treatment completionPresented By Thierry Conroy at 2018 ASCO Annual Meeting
Slide 7Presented By Colin Weekes at 2018 ASCO Annual Meeting
Slide 9Presented By Colin Weekes at 2018 ASCO Annual Meeting
Upfront Resectable Pancreatic CancerPrimary Surgery versus Neoadjuvant Chemo Database of 15,237 patients, stage I or II resectedpancreatic head Adenocarcinoma 2,005 patients receiving Neoadjuvant Chemo matchedwith 6,015 patients with primary surgery Chemo first group had improved survival compared withSurgery first group:– median survival: 26 months versus 21 month, P 0.01; HR 0.72 Surgery first patients vs. Chemo first patients:– higher pathologic T stage (pT3 and T4: 86% v 73%; P .01)– higher positive lymph nodes (73% v 48%; P .01)– higher positive resection margin (24% v 17%; P .01)Mokdad AA et al. J Clin Oncol 2016, Sept
Many ongoing trials looking at best strategyESPAC-5F: randomised patients to 4 approaches
Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC) : br / A randomized, controlled, multicenterphase III trial of the br / Dutch Pancreatic Cancer GroupPresented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
Preoperative Radiochemotherapy Versus Immediate Surgery For (Borderline) Resectable Pancreatic Cancer: br / (PREOPANC)Presented By Colin Weekes at 2018 ASCO Annual Meeting
Resection RatePresented By Colin Weekes at 2018 ASCO Annual Meeting
Disease-Free SurvivalPresented By Colin Weekes at 2018 ASCO Annual Meeting
Overall Survival AnalysesPresented By Colin Weekes at 2018 ASCO Annual Meeting
Borderline Resectable DiseasePotential benefits of primary chemotherapy Better diffusion of chemotherapy in wellvascularized tissues (before surgery andradiotherapy) Better tolerance and feasibility in patients beforesurgery (50% of adjuvant postoperativetreatment not done or uncompleted) Decrease of the delay to the first treatment Downstaging effect Exclusion of patients with rapidly progressivetumours
Slide 15Presented By Douglas Evans at 2018 ASCO Annual Meeting
S
Upfront Resectable Pancreatic Cancer Primary Surgery versus Neoadjuvant Chemo Database of 15,237 patients, stage I or II resected pancreatic head Adenocarcinoma 2,005 patients receiving Neoadjuvant Chemo matched with 6,015 patients with primary surgery Chemo first group
single tumor. Tumor; mass; tumor mass; lesion; neoplasm o The terms tumor, mass, tumor mass, lesion, and neoplasm are . not. used in a standard manner in clinical diagnoses, scans, or consults. Disregard. the terms unless there is a . physician's statement . that the term is malignant/cancer o These terms are used . ONLY to determine .
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is associated with poor clinical prognosis, which is mainly caused by tumor recurrence and metastasis. Circulating tumor cells (CTCs) are tumor cells shed into the bloodstream and regarded as the “seeds” of tumor recurrent or metastatic lesions.
Keller and Pantel, 2019; Pantel et al., 2019). Liquid biopsy may include tumor-derived nucleic acid such as circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), circulating tumor microRNA (ctmiRNA), RNA or DNA from exosomes, and circulating tumor cells (CTC) collected from peripheral blood, which can be obtained .
e thermo/chemo-therapy is proven to be eec-tive in cancer treatments. However, the ecient deliv-ery and penetration of therapeutic agents into a solid tumor remain a thorny problem [2]. Previous studies 1, showed that the blocking of angiogenesis can slow down the tumor growth, but it may paradoxically increase the tumor metastasis [3].
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A Mathematical Model of Biomass Combustion Physical and Chemical Processes Florin Popescu, Razvan Mahu, Ion V. Ion and Eugen Rusu * . mathematical model is particularly challenging; therefore, the present study proposes a versatile . been much utilized for simulating coal-powered combustion systems, but less published work is to be found .
a. Cell (dark pink) acquires a mutation for repeated cell division. b. New mutations arise, and one cell (brown) has the ability to start a tumor. tumor c. Cancer in situ. The tumor is at its place of origin. One cell (purple) mutates further. invasive tumor lymphatic vessel blood vessel 3 mutations d. Cells have gained the ability to invade .
Anatomi jalan lahir penting untuk keberhasilan kelahiran . Jalan Lahir Bagian tulang terdiri atas tulang- tulang panggul. - os coxae - os sacrum - os coccygis Bagian lunak (Diafragma pelvis )terdiri atas otot- otot , jaringan, dan ligament. - Pars muskulus levator ani - Pars membranasea - Regio perineum Tulang panggul terdiri atas a. os. Coxae (inominata) - os. Ilium - os. Ischium - os. Pubis .
