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  • Given this context, we randomized stage II and stage III patients into 2 arms. We compared 8 cycles of Xelox with observation. Most recently, the Korean phase III CLASSIC study reported a significant benefit in DFS from adjuvant combination chemotherapy. Following D2 resection, patients with stage II-IIIb gastric cancer were randomly assigned to eight cycles of adjuvant capecitabine and oxaliplatin (CAPOX) or to observation alone. This positive study shows that a 6-month course of CAPOX after D2 gastrectomy improves 3 year DFS compared with surgery only (74% vs. 59%; p < 0.0001). Chemotherapy reduced the relative risk of disease recurrence, new disease occurrence, or death compared with surgery alone. The OS data are not yet mature; however, the data suggest an improvement in OS with capecitabine and oxaliplatin compared with surgery only (83% vs. 78%; p = 0.0493).10 An analysis after a median follow-up of 5 years is planned to conclusively establish the OS benefit of capecitabine and oxaliplatin in this setting.

Vakalis - gastric ca radiotherapy Vakalis - gastric ca radiotherapy Presentation Transcript

  • Αθηηλνζεξαπεία ζηνλ εληνπηζκέλν θαξθίλν ζηνκάρνπθαη ρεηξνπξγηθή εθηνκή:Πξηλ, κεηά ή θαζόινπ; ΒΑΚΑΛΗΣ ΞΕΝΟΦΩΝΑκτινοθεραπεστής ΟγκολόγοςΙΑΤΡΙΚΟ ΚΕΝΤΡΟ ΑΘΗΝΩΝEUROMEDICA-ΑΘΗΝΑΙΟΝ Α
  • Καινγεξίδε Μ-Α, MD, PhD. Επηκειήηξηα Β’ Αθηηλνζεξαπεπηηθήο Ογθνινγίαο. Παλεπηζηεκηαθό ΓΝ ΛάξηζαοΕΠΙΠΣΩ΢Η ΓΑ΢ΣΡΙΚΟΤ ΚΑΡΚΙΝΟΤ• Ο θαξθίλνο ηνπ ζηνκάρνπ απνηειεί ην 9.9% ηωλ δηαγλώζεωλ θαξθίλνπ.• Η ζπρλόηεηά ηνπ παξνπζηάδεη ζηαζεξή κείωζε ζηηο Δπηηθέο θνηλωλίεοηηο ηειεπηαίεο δεθαεηίεο.• ΗΠΑ: 22.280 λέεο πεξηπηώζεηο ην έηνο, 11.430 ζάλαηνη.
  • 5-year overall survival: 15%-54%Parkin DM, et al. CA Cancer J Clin. 2005;55:74
  • • (1) patients with apparent locoregional carcinoma(stages I to III or M0)(a) those who are medically fit and whose canceris resectable,(b) those who are medically fit but whose cancer isunresectable, and(c) those who are inoperable (medically unfit).• (2) those with obvious metastatic carcinoma (stage IVor M1).ΑΔΡΗ ΣΑΞΙΝΟΜΗ΢Η
  • Καινγεξίδε Μ-Α, MD, PhD. Επηκειήηξηα Β’ Αθηηλνζεξαπεπηηθήο Ογθνινγίαο. Παλεπηζηεκηαθό ΓΝ ΛάξηζαοΡηδηθή Μεηεγρεηξεηηθή Αθηηλνζεξαπεία. Γηαηί?• Η ρεηξνπξγηθή εμαίξεζε είλαη ε θπξηόηεξεζεξαπεπηηθή πξνζέγγηζε ζε εμαηξέζηκν θαξθίλνηνπ ζηνκάρνπ.• 60% ηωλ αζζελώλ κε δηήζεζε ηνπ κπηθνύηνηρώκαηνο ή (+) ιεκθαδέλεο παξνπζηάδνπληνπηθή ππνηξνπή.• ΢ην 20% ε ηνπηθή ππνηξνπή ζηελ θνίηε ηνπόγθνπ, ηνπο ιεκθαδέλεο, ην θνιόβωκα ή ηελαλαζηόκωζε απνηειεί θαη ηε κόλε ζέζεππνηξνπήο.Seligmann Adalbert,Billroth operating (Vienna)
  • We need to help our surgeons!
  • Adjuvant RT
  • Καξθίλνο ηνπ ζηνκάρνπ΢πκπιεξσκαηηθή Αθηηλνζεξαπεία• British Stomach Cancer Group (1994):– N = 436, ΢ηάδην II – III [N = 63 (14%) κε ππνιεηπόκελε λόζν]– Όινη νη αζζελείο ππεβιήζεζαλ ζε γαζηξεθηνκή .– 3 ζθέιε: γαζηξεθηνκή vs +ΑΚΘ vs +ΥΜΘ.– ΑΚΘ: 4500/25 ± 500cGy boost (Ζεύγνο πξνζζην-νπίζζησλ πεδίσλ)– ΧΜΘ: MAF x 8 .• Σνπηθή ππνηξνπή (12 κήλεο): 26% vs 9% vs 15%Σν εύξνο ηεο δηαθνξάο δελ επαλαιακβάλεηαη ζηνπο60 κήλεο• 5-εηή επηβίσζε: 20% v 12% v 19% (NS).Hallissey MT et al. The second British Stomach Cancer Group trial ofadjuvant radiotherapy Or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet 1994;343:1309-12.
  • Αθηηλνζεξαπεία (σο κνλνζεξαπεία)• Πεξηνξηζκέλεο κειέηεο• Χσξίο επίπησζε ζηελ επηβίσζε, κείσζεηνπηθώλ ππνηξνπώλΔΕΝ ΥΡΗ΢ΙΜΟΠΟΙΕΙΣΑΙ ΜΟΝΗ ΣΗ΢ ΢ΣΗ ΚΑΘΗΜΕΡΙΝΗ ΠΡΑΚΣΙΚΗ
  • Adjuvant chemotherapy
  • Ο ξόινο ηεο επηθνπξηθήορεκεηνζεξαπείαοSun et al, Br J Surg 2009
  • YES! Finally adjuvantchemotherapy in gastric cancerseems to work!
  • ΘΑΠΩΝΘΚΗ ΜΕΛΕΣΗ
  • Surgically (D2)resected Stage II,IIIA, or IIIB GC,6 weeks prior torandomizationNo priorchemotherapy orradiotherapyn=1035Capecitabine: 1,000mg/m2 bid, d1–14, q3wOxaliplatin: 130mg/m2, d1, q3wRANDOMIZATION1:1†n=520n=515• Primary endpoint: 3-year DFS‡• Secondary endpoints: overall survival and safety profile†Stratified by stage and country with age, sex, and nodal status as covariates‡GASTRIC project: 3-year DFS and 5-year overall survival are strongly associated,Burzykowski et al. ASCO 2009ΚΟΡΕΑΣΙΚΗ ΜΕΛΕΣΗCLASSIC8 cycles of XELOX (6 months)Observation: No adjuvant therapy
  • Primary endpoint (3-year DFS)ITT population; DFS = disease-free survivalMedian follow-up 34.4 months (range 16–51)1.00.00.20.40.60.83-year DFS74%60%HR=0.56 (95% CI 0.44–0.72)P<0.0001Time (months)Observation, n=515XELOX, n=520520 410 333 246 166 74 30 10443515 352 286 209 147 58 22 6414XELOXObservationNo. left0 6 12 18 24 30 36 42 48
  • Stomach Cancer AdjuvantMulti-institutional Trial(Samit) trial.2x2 factorial randomized phase III trial to investigateweekly paclitaxel (PTX) followed by oralfluoropyrimidines (FPs) versus FPs alone as adjuvantchemotherapy in patients (pts) with gastric cancer.
  • Adjuvant Chemo-RT
  • RANDOMObservation5FU/LV Radiation5FU/LV5FU/LVX245Gy/25d281 pts275 ptsΜετεγχειρθτικι ΑκτινοκεραπείαIntergroup 0116 Trial (INT 0116)/SWOG 9008• 556 αςθενείσ• χειρουργηθζν (R0)αδενοCa ςτομάχουήγαςτροοιςοςφαγικήσςυμβολήσ.• IB-IV (M0)5FU/LV Median OS: χειρουργείο=27 μινεσ, +ΧΜΘ-ΑΚΘ=36 μινεσ, follow-up=5 ζτθ Hazard Ratio for death=1.35, P=0.005 Hazard Ratio for relapse=1.52, P<0.001 ΢υμπζραςμα: Εφαρμογι ΧΜΘ-ΑΚΘ ςε αςκενείσ υψθλοφ κινδφνου για υποτροπι με αδενοκαρκίνωμαςτομάχου ι γαςτροοιςοφαγικισ ςυμβολισ που υποβλικθκαν ςε ριηικι χειρουργικι εξαίρεςθ.1 month 1 monthMacdonald, NEJM 2001
  • Μετεγχειρθτικι ΑκτινοκεραπείαIntergroup 0116 Trial (INT 0116)Median Overall Survival: (↑ 9 months) surgery only group = 27 months chemo-RT group = 36 months P=0.005Median Duration of Relapse-free Survival: surgery only group=19 months chemo-RT group=30 months P<0.001Macdonald, NEJM 2001
  • Macdonald JS et Al – New Eng J Med -2001RESULTS41% 50%3 yr OS:41%
  • Μεηεγρεηξεηηθά΢ύγρξνλε ρεκεην-αθηηλνζεξαπείαGastric Surgical Adjuvant Trial(Macdonald et al 2001):ζεκαληηθή βειηίσζε ηνπηθνύ ειέγρνπ & επηβίσζεο
  • ΙΝΣ 0116 Μικρζσ-μεγάλεσ παρεκλίςεισ ςτο 35% των πλάνωνΑΚΘ. Αριθμόσ αςθενών που δεν ολοκλήρωςαν την ΑΚΘλόγω τοξικότητασ: 36%. Αιματολογική τοξικότητα ≥grade 3: 54%. Σοξικότητα ΓΕ΢ ≥grade 3: 33%.Survival benefitΑΚΘ για καρκίνο ςτομάχουΠροκλιςεισ ςτθ χοριγθςθ ακτινοκεραπείασ
  • Adjuvant treatment in gastric cancer:The reality!CONTROLSURGERYADJUVANT TREATMENTR- Delayed surgical recovery- Poor food intake- Dumping syndrome etc.- Poor performance status- Treatment refusal(~50%?)BUT:frequent poor patient tolerancewith- Retreatment delays- Dose reductions- Early termination=> Adjuvant for fit patients only!
  • ESTRO: Evidence-basedIΝΣ 0116: Έθηαζε ηεο ιεκθαδελεθηνκήοD210%D136%D054%
  • Εξωηήκαηα πνπ ηέζεθαλ κεηά ηελINT 0116• Αλαπιεξώλεη ε ρεκεην-αθηηλνζεξαπεία ην θαθό ρεηξνπξγείν;• Είλαη ε D0/D1 εθηνκή + ρεκεην-αθηηλνζεξαπεία πην αζθαιήο θαηαπνηειεζκαηηθή ζηξαηεγηθή από πην εθηεηακέλν ρεηξνπξγείν;• Πξέπεη νη αζζελείο πνπ ππνβιήζεθαλ ζε D2 εθηνκή λα ιάβνπλρεκεην-αθηηλνζεξαπεία ;• Θα κπνξνύζε ε ρξήζε πην εμεδεηεκέλσλ κεζόδσλ ρεκεην-αθηηλνζεξαπείαο λα βειηηώζεη ην απνηέιεζκα;
  • Japanese vs Intergroup 0116 study
  • SWOG 9008/INT 0116Macdonald, ASCO 2004Up-date: Subset analyses - OS in D2 resection
  • Dutch Observational study
  • Dutch Observational study
  • Dutch Observational study
  • Adjuvant chemovsAdjuvant chemo + ( chemo-RT)
  • HeCOG, Greece (2002-2005)adjuvant Taxol/Carbo chemotherapy with or withoutradiation therapyConclusion: Addition of RT to chemo did notimprove outcomesAdjuvant chemo vs Adjuvant chemo-RTARTIST
  • Lee J et al. JCO 2012;30:268-273The ARTIST trial: adjuvant XP ± RxAll patientsN+ patients458 patients60% stage IB –IIDFS significant in N+patients5% improvement in 3 yearDFS, HR 0.69
  • Guidelines
  • Guidelines
  • Guidelines
  • Guidelines
  • Guidelines
  • Guidelines
  • NEOADJUVANT THERAPY
  • Ajani JA et Al – JCO - 2005R0 vs R+pCRWhy preoperative treatments ?treated 40 patients 5-FU, paclitaxel and cisplatin, radiotherapy Followed by surgery(pCR) of 20%, R0 resection rate of 78%, and median survival beyond 36 months
  • PREOPERATIVE RT
  • Preoperative Radiotherapy(1998)40 Gy + surgery vs surgery alone (n=370)5 yr OS20 % vs. 30 %p<0.01Zhang et al (IJROBP, 1998)Further Randomised Trials are required
  • Πξνεγρεηξεηηθή αθηηλνζεξαπεία-πιενλεθηήκαηα• ΢ηόρνο: ε κείωζε ηνπ κεγέζνπο ηνπ όγθνπ, ε αύμεζε ηεο εμαηξεζηκόηεηάο ηνπ θαη ηνππνζνζηνύ ηεο R0 εμαίξεζεο.• Η ΑΚΘ κπνξεί λα κεηώζεη ηελ ηνπηθή ππνηξνπή θαη πεξηνρηθέο κεηαζηάζεηο. Η απνζηείξωζε ηωλ θαξθηληθώλ θπηηάξωλ κπνξεί λα κεηώζεη ηηο πεξηηνλαϊθέοεκθπηεύζεηο από ηε δηαζπνξά θαξθηληθώλ θπηηάξωλ θαηά ηνπο ρεηξνπξγηθνύορεηξηζκνύο. ΄Ιζωο ε ίδηα δόζε αθηηλνβνιίαο είλαη πην απνηειεζκαηηθή όηαλ ρνξεγείηαη πξνεγρεηξεηηθάπαξά κεηεγρεηξεηηθά, αθνύ ε αηκάηωζε θαη ε νμπγόλωζε ελόο όγθνπ είλαη πην πινύζηαπξηλ δηαηαξαρζεί από ηε ρεηξνπξγηθή παξέκβαζε.
  • Πξνεγρεηξεηηθή αθηηλνζεξαπεία-πιενλεθηήκαηα• Ο ζρεδηαζκόο ηνπ όγθνπ ζηόρνπ πξνεγρεηξεηηθά είλαη πην εύθνινο θαη ν θίλδπλνογεωγξαθηθήο απώιεηαο κηθξόηεξνο, αθνύ ν όγθνο θαη νη δηεζεκέλνη ιεκθαδέλεο είλαηνξαηνί ζηελ αμνληθή ζρεδηαζκνύ. Είλαη θαιύηεξα αλεθηή. Μπνξεί λα ρνξεγεζεί ζε ηνπηθά πξνρωξεκέλν κε εμαηξέζηκν θαξθίλν ηνπ ζηνκάρνπ ήζε αζζελείο πνπ δε κπνξνύλ λα ππνβιεζνύλ ζε ρεηξνπξγείν ιόγω ζπλππάξρνπζαολνζεξόηεηαο.
  • ΠΡΟΕΓΧΕΙΡΗΣΙΚΗ και ΠΕΡΙΕΓΧΕΙΡΗΣΙΚΗ ΧΗΜΕΙΟΘΕΡΑΠΕΙΑ
  • Neoadjuvant Treatmentsimprove SV in 4 Random TrialsFNCLCC/FFCD (1995-2003)EORTC 40954MRC MAGIC Trial (1994-2002)Dutch FAMTX
  • Peri-operative chemotherapy...Two positive randomized trialsFNLCC-FFCD 9703MAGIC TRIALR RSurgery SurgeryCF x 2-3SurgeryCF x 3-4224 pt503 ptECF x 3SurgeryECF x 3Boige, Asco 2007Cunningham, NEJM 2006• Adk of thestomach orlower third of theoesophagus• Stage II or grater• Suitable forcurative resection
  • ...Two positive randomized trialsMAGIC TRIAL FNLCC-FFCD 9703Primary endpoint: Overall Survival5-y OS: 24% vs 38%5-y OS: 23% vs 36%Peri-operative chemotherapy
  • ...Two positive randomized trialsMAGIC TRIAL FNLCC-FFCD 97035-y DFS: 21% vs 34%Secondary endpoints: Progression Free Survival5-y DFS: 19% vs 33%Peri-operative chemotherapy
  • ...Two positive randomized trialsMAGIC TRIAL FNLCC-FFCD 9703Secondary endpoints:Curative ResectionsSafety:No difference in postoperative mortality and morbidity444169(70%*)S + CT* Of resections with know outcome5RX70R+p=.03166(79%*)R0S1(1%)2 (2%)4 (4%)95 (87%)S + CT1(1%)RX12 (11%)R26 (5%)R1p=0.0481 (74%)R0SPeri-operative chemotherapy
  • ...Two positive randomized trialsCT + SN=113SurgeryN=109 (96%)Preop CTN=98 (87%)Postop CTN=54 (50%)SN=111SurgeryN=110 (99%)SurgeryN=240 (95%)SN=253CT + SN=250Preop CTN=215 (86%)SurgeryN=219 (88%)Postop CTN=104 (42%)TRIALPROFILESMAGIC TRIAL FNLCC-FFCD 9703Peri-operative chemotherapy
  • Magic TrialConclusionsPerioperative chemotherapy in resectablecarcinoma of the stomach and distal esophagusresults in:• Tumor downsizing and downstaging ?• Increased PFS• Increased OSPeri-operative Chemo is now standard of care in Europe
  • Πεξηεγρεηξεηηθή ρεκεηνζεξαπείαΠιενλεθηήκαηα• Μεγαιύηεξα πνζνζηάR0 εθηνκώλ• Πξώηκε εμάιεηςε ηεοκηθξν-κεηαζηαηηθήολόζνπ• Έγθαηξε αμηνιόγεζε ηεορεκεην-επαηζζεζίαο ηνπόγθνπ• Καιύηεξε αλνρή ησλαζζελώλ ζε ζρέζε κε ηεκεηεγρεηξεηηθή Χ/ΘΜεηνλεθηήκαηα• Κίλδπλνο επηδείλσζεο ηεολόζνπ θαηά ηε δηάξθεηαηεο ζεξαπείαο• Πηζαλή θαζπζηέξεζε ηεορεηξνπξγηθήο εμαίξεζεοηνπ όγθνπ ιόγσηνμηθόηεηαο• Θεσξεηηθά απμεκέλεπεξη-εγρεηξεηηθήλνζεξόηεηα
  • Is neoadjuvant chemotherapythe best? Should we addradiation to the preoperativetreatment for locally advancedgastric cancer?
  • Neoadjuvant Chemo-RTOnly phase II trials
  • Πξνεγρεηξεηηθή αθηηλνζεξαπεία Retrospective 61 patients cT3-4/N0 and/or N+ Follow-up 38.7 monthsChemo group (Ch)21 ptsChemo-RT group (ChRT)40pts4-6 weeks Surgery andD2lymphadenectomyA. paclitaxel, cisplatin, 5-FUB. docitaxel, oxali[platin, capecitabine2-6 cycles of chemo, median 3 cyclesTaxane-based chemoSurgery andD2lymphadenectomy4-6 weeks0-7 cycles of chemo, median 2 cyclesTaxane-based chemoA. paclitaxel, cisplatin, 5-FUB. docitaxel, oxali[platin, capecitabineC.cisplatin, 5F-URT, 45Gy, 5weeks+Int J Radiat Oncol Biol Phys. 2011 Jul 1;80(3):698-704.
  • Πξνεγρεηξεηηθή αθηηλνζεξαπείαBecker’s Criteria for Pathologic ResponseMajorpathologicresponseGr 1a Complete tumor regressionGr 1b <10% of vital tumor tissuein relation to themacroscopicallyidentifiable tumor bedMinorpathologicresponseGr 2 10-50% residual tumor pertumor bedGr 3 >50%residual tumor pertumor bedChemo ChemoRT PvaluetotalpCR(pathologiccomplete response)-- 19% <0.001Major response 33% 64% 0.032 53%Tumordownstaging57% 86% 0.024 75%Nodaldownstaging43% 47% NS 45.6%The only patient-, tumor-, and treatment related factor associated with pathologic responsewas the use of preoperative chemo-RT. 3year DFS for pts who achieved major pathologic response: 63% 3year DFS for pts with poorer grade of pathologic response: 34%
  • RTOG 99-04Two phase II studies fromthe M. D. Anderson CancerCenterpCR in 26%, R0 resection in 77% MS 23 months, 1yr OS 72%
  • ΢ΤΜΠΕΡΑ΢ΜΑΣΑ
  • Multidisciplinary approach for thecure of localised gastric cancerConclusions• Adjuvant treatment is efficient but cumbersome and badlytolerated after gastrectomy• The role of XRT in (neo)adjuvant TTT of gastric cancer isstill unclear• Peri-operative or neoadjuvant chemotherapy are bettertolerated and leave less patients behind• We needed huge meta-analyses to be convinced ofadjuvant therapy while only few studies were sufficient forthe peri-operative strategy!
  • Chemo + radiation: more = better!
  • Postoperative ChemoRTGeographic Practice VariationsPerioperative Chemo
  • More = better??
  • Postoperative S-1Geographic Practice VariationsCapoxPostoperative ChemoRT
  • Be patientCRITICS and other trials are coming up!ΕΤΥΑΡΙ΢ΣΏ ΓΙΑ ΣΗ ΠΡΟ΢ΟΥΗ ΢Α΢