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RECTAL CA - VAKALIS . X

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RECTAL CA - VAKALIS . X

  1. 1. Rectal Cancer Surgery is the mainstay of treatment of RC After surgical resection, local failure is common Local recurrence after conventional surgery: 15%-65% (average of 28%)
  2. 2. ΣΟΠΙΚΕ΢ ΤΠΟΣΡΟΠΕ΢ ΜΕΣΑ ΑΠΟ ΕΓΥΕΙΡΗ΢Η ζηάδην T1 T2 T3 T4 N+ 5 έηε , ρωξίο άιιε ζεξαπεία 10% 15-35% 20-45% >50% 40-65% McCall J, et al. Int J Colorectal Dis 1995 10. 126-132 Bokey EL, et al. BJS 1999; 86:1164. Shirouzu et al., Am J. Surg 1993; 165:233
  3. 3. ΜΕΣΕΓΥΕΙΡΗΣΙΚΗ ΘΕΡΑΠΕΙΑ ΟΡΘΟΤ Number of pts. GITSG NCCTG 202 204 NSABP-R01 555 Surgery alone LF (%) 24 25 S (%) Radiotherapy LF (%) S (%) Chemotherapy LF (%) S (%) Chemoradioth. LF (%) S (%) 43 20 52 27 21 11 59 43 16 41 21 53 8 58 25 47 14
  4. 4. ΜΕΙΩ΢Η ΣΩΝ ΣΟΠΙΚΩΝ ΤΠΟΣΡΟΠΩΝ: 1980s–2000s 35 Local failure (%) 30 Norway GITSG-2 Dutch-TME NSABP-R01 INT-0114 Ulsan GITSG-1 NSABP-R02 CAO/ARO/AIO Mayo-NCCTG INT-PVI 25 20 15 10 5 0 sx only sx  RT sx  CTRT TME + RT/CTRT
  5. 5. Ca ξοθξύ ΠΟΛΤΠΑΡΑΓΟΝΣΙΚΗ ΘΕΡΑΠΕΙΑ ΕΓΥ +(ΥΜΘ + ΑΚΘ)   Σοπικές σποτροπές: Από 40% σε <10% ΢σνολική επιβίωση: Από 50% σε 75% Σα τελεσταία 40 τρόνια
  6. 6. ΜΕΣΕΓΥΕΙΡΗΣΙΚΗ ΘΕΡΑΠΕΙΑ ΟΡΘΟΤ National Cancer Institute Consensus Conference 1990 T3-4 και/ή N1-2 θεραπεία εκλογής για μεηεγτειρηηική θεραπεία είναι ο ζσνδιαζμός ΧημειοΑκηινοθεραπείας. JAMA 1990;264:1444-50.
  7. 7. Chemoradiation for Locally Advanced Rectal Cancer O'Connell MJ, Martensen JA, Wieand HS et al. 660 patients TNM stage II or III rectal cancer Randomized to: Continuous infusion 5-FU (225 mg/m2/d) 5-week during the radiotherapy (45 Gy + 5.4 Gy boost) vs  Bolus 5-FU (500 mg/m2/d) days 1-3 weeks 1 and 4 during the radiotherapy  N Engl J Med 1994;331:502–507
  8. 8. Optimal combination of chemo- radiotherapy? δύν θύθινη 5-FU αθνινπζνύκελνη από ζπλερή έγρπζε 5-FU θαη 50.4 Gy ΑΘ πνπ κε ηελ ζεηξά ηνπο αθνινπζνύληαη απν δύν επηπξόζζεηνπο θύθινπο 5-FU If radiochemotherapy is used postoperatively, protacted infusion of 5-FU is superior to bolus 5-FU during radiotherapy O`Connell. NEJM 1994;331:331 No DFS, OS or locoregional failure (LRF) difference Intergroup 0144 (SWOG-9304 )
  9. 9. ΜΕΣΕΓΥΕΙΡΗΣΙΚΗ CRT ΕΠΙΠΛΟΚΕ΢     ΢νβαξή δηάξνηα Υξόληα βιάβε ηνπ εληέξνπ (25%) Απμεκέλε θηλεηηθόηεηα ηνπ εληέξνπ (7/εκ) Αθξάηεηα θνπξάλωλ
  10. 10. ΜΕΣΕΓΥΕΙΡΗΣΙΚΗ CRT Απμάλεη ηνλ ηνπηθό έιεγρν Aπμάλεη ηελ επηβίωζε Αξθεηέο παξελέξγεηεο Δελ κεηώλεη ηηο θνινζηνκίεο
  11. 11. NEOADJUVANT ΘΕΡΑΠΕΙΑ πξνζπάζεηα ε λόζνο λα θαηαζηεί ρεηξνπξγήζηκε θαη λ απνθεπρζεί θνινζηνκία
  12. 12. ΚΤΡΙΕ΢ ΜΟΡΦΕ΢ NEOADJUVANT ΘΕΡΑΠΕΙΑ΢  Short course Radiotherapy (SCRT) 5 Gray (Gy) daily over 5 days without chemo followed by surgery within 1 week     Long course preoperative chemoradiotherapy (LCRCT) 1,8 Gray (Gy) per fraction-day, five days a week over 5-6 weeks to a total dose of 50,4 Gy with concurrent 5-Fu based chemo followed by surgery 6-8 weeks later
  13. 13. Short-Term Pre-Op Radiotherapy vs Surgery Alone Local Recurrence Swedish Rectal Cancer Trial 1987-1990 - NEJM 1997 1,168 pts - (T1-3) disease Short Course RT + Surgery vs Surgery Alone LR p<.001 11% 27% (5-yr FU) 58% OS 48% p<.001 (5-yr) LR p<.001 Dutch CRC Group Trial 1996-2000 - NEJM 2001 1,861 pts - (T1-3) disease Short Course RT + TME Surgery vs TME Surgery Alone N Engl J Med 1997; 336: 980-7. OS pvalue 2.4% 8.2% (2-yr) 82% OS 82% NS (2-yr) Kapiteijn, E., et al., N Engl J Med, Vol. 345, No. 9
  14. 14. Pre-operative high-dose short-term radiotherapy The Dutch Trial Pre-operative radiotherapy had no impact on survival . E Kapitaijn et al. N Engl J Med 2001; 345:638-646 Pre-operative radiotherapy did not allow to achieve down-staging of the tumoral lesion. This treatment cannot be used to facilitate either sphincter preservation or secondary resection of initially unresectable tumors. CAM Marijen et al. J Clin Oncol 2001; 19: 1976-1984
  15. 15. SCRT - ΑΚΡΑΣΕΙΑ
  16. 16. Τπεοέςει η εισαγωγική ακτιμξθεοαπεία τηπ επικξροικήπ ςημειξ- ακτιμξθεοαπείαπ; Phase III MRC trial, 4 countries, 1350 patients with operable rectal cancer.  Standard  Pre-op Arm: RT 25Gy/5  Experimental Arm:  No Pre-op XRT  Post-op chemo RT 45Gy/25 only if + CRM Lancet 2009
  17. 17. Medical Research Council Trial (MRC) CR07-2006 Results: local relapse (4.7% vs 11.1%) 3-year disease-free survival (79.5% vs 74.9%) in favor of the preoperative RT arm. J Clin Oncol 24(18S):148s, ASCO 2006
  18. 18. Τπεοέςει η εισαγωγική ςημειξακτιμξθεοαπεία τηπ εισαγωγικήπ ακτιμξθεοαπείαπ; ΑΚΘ έλαληη ΑΚΘ + ΥΜΘ Υεηξ. Υεηξ. . ΢το ερώτημα αστό προσπάθησαν να απαντήσοσν 2 μελέτες:  EORTC-22921, Bosset et al. N Eng J Med 2006  FFCD-9203, Gerard et al. J Clin Oncol 2006
  19. 19. Short vs Long RT course
  20. 20. EORTC study
  21. 21. Chemo RT vs. Radiotherapy Local control in T3/T4 rectal cancer Trials Pre-op CRT Pre-op RT EORTC 22921 8.7% 17.1% FFCD 9203 8% 16.5%
  22. 22. Chemo RT vs. Radiotherapy Survival in T3/T4 rectal cancer Trials Pre-op CRT Pre-op RT EORTC 22921 65% 65% FFCD 9203 67% 66%
  23. 23. Randomized Phase III Trial of Preoperative Conventional Fractionation Radiation vs Chemoradiation for T3-T4 Resectable Rectal Cancer FFCD-9203, Gerard et al. J Clin Oncol 2006 ARM No.PTS cT3 uN+ pCR 5y DFS 5y OS 5y LR PREOP RT 363 89% 68% 3% 56% 66% 16.5% PREOP CRT 370 89% 67% 11% p<.05 59% p: n.s 67% p: n.s 8% p=0.0016 733 pts PREOPERATIVE CHEMORADIATION INDUCES SIGNIFICANTLY BETTER LOCAL CONTROL THAN PREOPERATIVE RADIATION ALONE , WITHOUT ANY EFFECT ON OVERALL SURVIVAL
  24. 24. Short vs Long RT course 5 x 5 Gy 28 x 1.8 Gy • Δελ αιιάδεη ην ζηάδην • Καιή αλνρή ζην ρεηξνπξγείν • Υακειό θόζηνο • Πεξηζζόηεξε κείωζε όγθνπ,pCR • Εμαηξεηηθή ζπκκόξθωζε • Ληγόηεξε ρξόληα ηνμηθόηεηα (;) • Αλακέλεηαη > 66 % κείωζε Σ.Τ. • Αλακέλεηαη > 80 % κείωζε Σ.Τ. Η Berlin Cancer Society ζηηο κέξεο καο ζρεδίαζε κηα κειέηε γηα λα ζπγθξίλεη ηελ κηθξήο δηάξθεηαο ΑΘ κόλν κε ηελ καθξάο δηάξθεηαο ΑΘ ζπλδηαζκέλε κε Υεκεηνζεξαπεία
  25. 25. Η ςημειξακτιμξθεοαπεία είμαι καλύτεοη σαμ εισαγωγική ή σαμ επικξροική; ΑΚΘ + ΥΜΘ Υεηξ. Υεηξ. έλαληη ΑΚΘ + ΥΜΘ ΢το ερώτημα αστό προσπάθησαν να απαντήσοσν 3 μελέτες: • NSABP R-03 – Low Accrual • INT-0147 – Low Accrual • German Trial – CAO/ARO/AIO-94 Results presented ASTRO – Oct. 2003
  26. 26. Rectal Cancer ASTRO ‘03 The German pre-op vs. post-op trial T3Nx Rectal R A N D O M I Z A T I O N 50.4 Gy CI 5-FU Surgery Surgery 50.4 Gy CI 5-FU 5-FU x 4 5-FU x 4
  27. 27. Randomized Phase III Trial of Preoperative vs Postoperative Conventional Fractionation Chemoradiation for Resectable Rectal Cancer THE GERMAN RECTAL CANCER STUDY GROUP, 2004 ARM No. PTS DFS at 5 y OS at 5 y DM at 5 y LR at 5 y PREOP CRT 405 68% 76% 36% 6% POSTOP CRT 394 65% 74% P=n.s P=n.s 38% P=n.s 13% P=0.006 823 pts PREOPERATIVE CHEMORADIATION INDUCES SIGNIFICANTLY BETTER LOCAL CONTROL THAN POSTOPERATIVE CHEMORADIATION, WITHOUT ANY EFFECT ON OVERALL SURVIVAL
  28. 28. CAO/ARO/AIO-94 Trial: Results pCR (%) Acute GI Late G 3/4 GI Toxicity G 3/4 (%) Toxicity (%) Sph Preserv Rate (%) Preop Tx (405 Pts) 8* 12 * 13* 39* Postop Tx (392 Pts) 0 18 27 19
  29. 29. Η ςημειξακτιμξθεοαπεία είμαι καλύτεοη σαμ εισαγωγική ή σαμ επικξροική; • Η εηζαγωγηθή ρεκεηναθηηλνζεξαπεία ππεξέρεη ηεο επηθνπξηθήο ρεκεηναθηηλνζεξαπείαο ωο πξνο • ηελ κείωζε ηωλ ηνπηθώλ ππνηξνπώλ θαη • ηελ κεηωκέλε ηνμηθόηεηα. • Δελ ππήξμε δηαθνξά ζηελ επηβίωζε. Since 2004, the standard of care for patients with cT3-4 and/or N+ rectal cancer
  30. 30. ΜΕΙΟΝΕΚΣΗΜΑΣΑ ΠΡΟΕΓΥΕΙΡΗΣΙΚΗ΢ ΘΕΡΑΠΕΙΑ΢  Τπεξζεξαπεία ζε αξρηθά ζηάδηα  Τπνζεξαπεία ζε κε αληρλεύζηκε κεηαζηαηηθή λόζν  ΢ηεξίδεηαη ζε θιηληθή ζηαδηνπνίεζε θαη όρη παζνινγναλαηνκηθή  Απώιεηα ηεο αξρηθήο παζνινγναλαηνκηθήο θαηάζηαζεο ηεο λόζνπ
  31. 31. • 188 αζζελείο 5-Fu/RT + S MSKCC • cT3N0 • 22 % είρε N+ ζην ρεηξνπξγείν • T3N0 → Δικαιολογημένη η θεραπεία
  32. 32. Capecitabine vs 5-FU Hofheinz R et al. Proc ASCO 2011;Abstract 3504. phase III MARGIT trial Capecitabine (Cape) versus 5-Fluorouracil (5-FU)–Based (Neo)Adjuvant Chemoradiotherapy (CRT) for Locally Advanced Rectal Cancer (LARC): Long-Term Results of a Randomized, Phase III Trial
  33. 33. Study Design Arm A Chemoradiotherapy 50.4 Gy + Cape 1,650 mg/m² days 1 – 38 plus 5 cycles of Cape 2,500 mg/m² d 1 – 14, rep. d 22 S I: 2 x Cape  CRT  3 x Cape S II: CRT  TME surgery (4 – 6 weeks after CRT)  Cape x 5 Arm B Chemoradiotherapy 50.4 Gy + 5-FU 225 mg/m² c.i. daily [S I] or 5-FU 1,000 mg/m² c.i. d 1 – 5 and 29 – 33 [S II] plus 4 cycles of bolus 5-FU 500mg/m² d 1 – 5, rep. d 29 S I: 2 x 5-FU  CRT  2 x 5-FU S II: CRT  TME surgery (4 – 6 weeks after CRT)  5-FU x 4
  34. 34. RESULTS Cape 5 Yr DFS 5FU p-value 67.8% 54.1% P=0.035 P<0.001 (non-inferiority) 5 Yr OS 75.7% 66.6% Distant Mets (%) 18.9% 27.7% P=0.0367 Local Recurrence (%) 6.1% 7.2% p = 0.7795
  35. 35. TOXICITY Capecitabine 5-FU n = 197 p-value n = 195 Total1 1/2 3/4 Total 1/2 3/4 Hemoglobin 62 58 – 52 49 2 0.32 Leukocytes 50 47 3 68 50 16 0.047 Platelets 23 23 – 32 29 1 0.19 GGT 5 5 – 7 6 – 0.57 Bilirubin 8 6 1 2 1 1 0.10 1 CTC-grade 2 is missing in some pts. p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.
  36. 36. TOXICITY Capecitabine 5-FU n = 197 p-value n = 195 Total 1/2 3/4 Total 1/2 3/4 Nausea 36 33 2 32 30 – 0.69 Vomiting 14 11 1 9 8 1 0.39 Diarrhea 104 83 17 85 76 4 0.07 Mucositis 12 11 1 17 15 2 0.34 Stomatitis 8 8 – 12 11 – 0.37 Abdominal pain 23 19 1 14 11 – 0.17 Proctitis 31 26 1 10 9 1 < 0.001 1 2 CTC-grade is missing in some pts. p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.
  37. 37. TOXICITY Capecitabine 5-FU n = 197 n = 195 p-value Total 1/2 3/4 Total 1/2 3/4 Fatigue 55 50 – 29 27 2 0.002 Anorexia 13 13 – 6 5 1 0.16 Alopecia 4 4 – 11 10 – 0.07 Hand-foot skin reaction 62 56 4 3 3 – < 0.001 Radiation dermatitis 29 22 2 35 32 1 0.41 Thrombosis / Embolism 10 2 7 11 5 2 0.83 1 CTC-grade 2 is missing in some pts. p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.
  38. 38. Author’s Conclusions Both treatment regimens were well tolerated. Cape patients had more all grade HFS, proctitis, diarrhea and fatigue, while alopecia and leukopenia were more frequently observed with 5-FU. In the neo-adjuvant stratum Cape led by trend to improved downstaging and a numerical higher rate of pCR. Cape was non-inferior to 5-FU regarding 5-year survival. Exploratory test for superiority was borderline significant. 3-year DFS was significantly better with Cape. HFS indicated superior 3-year DFS and 5-year OS. Capecitabine may replace 5-FU in the perioperative treatment of locally advanced rectal cancer.
  39. 39. Μετά τημ εισαγωγική ςημειξακτιμξθεοαπεία και τξ ςειοξρογείξ, ςοειάζεται και επικξροική ςημειξθεοαπεία; ΥΜΘ + ΑΚΘ ΥΕΙΡ. έλαληη ΥΜΘ + ΑΚΘ ΥΕΙΡ. ΥΜΘ • Τπάξρνπλ αλαδξνκηθέο κειέηεο πνπ ππνδεηθλύνπλ όθεινο. • Δελ ππάξρνπλ πξννπηηθέο ηπραηνπνηεκέλεο κειέηεο. • Οη πεξηζζόηεξνη νγθνιόγνη, όκωο, ηελ ππνζηεξίδνπλ, εηδηθά γηα ηνπο αζζελείο κε ζεηηθνύο ιεκθαδέλεο.
  40. 40. Postop chemo είμαι ρπεοθεοαπεία? De Gramont et al – ASCO 2007
  41. 41. ADJUVANT THERAPY
  42. 42. NEOADJUVANT THERAPY
  43. 43. NEOADJUVANT THERAPY
  44. 44. chemoradiation in rectal cancer recommended regimen
  45. 45. Adjuvant chemotherapy
  46. 46. Summary of Randomized Trials Are rectal tumors downstaged (pCR) with neoadjuvant CRT? FFCD 9203 Trial: YES (11.4% CRT v. 3.6% RT; p<0.0001) Polish Trial: YES (16.1% CRT v. 0.7% RT; p<0.001) EORTC 22921 Trial: YES (13.7% CRT v. 5.3%; p<0.001) German Trial: YES (8% Preop CRT v. 0% Postop CRT) All Studies Show ↑pCR with CRT Does neoadjuvant CRT ↑ rate of sphincter-sparing surgeries? FFCD 9203 Trial: NO Polish Trial: NO EORTC 22921 Trial: NO German Trial: NO (Preop vs Postop CRT) No. But, in German Trial those Determined to need AR prior To randomization had ↑ rates of Sphincter-preservation with CRT Preoperatively.
  47. 47. Impact of pComplete Response Kalady et al. Ann Surg 2009;250: 582–589 50 50
  48. 48. Newer drugs in chemo-radiation of rectal cancer • Capecitabine (―Oral 5-FU‖) – Thymidylate synthetase inhibition • Irinotecan – Topoisomerase I inhibition • Oxaliplatin – Inter/intra-strand DNA crosslinks • Anti-EGFR: Cetuximab(Erbitux), Gefitinib(Iressa), Erlotinib(Tarceva) • Anti-VEGF: Bevacizumab(Avastin)
  49. 49. Newer drugs in chemo-radiation of rectal cancer ACCORD 12 45 Gy + 5-FU 50 Gy + capécitabine + oxaliplatin STAR-01 50,4 Gy + 5-FU 50,4 Gy + 5-FU + oxaliplatin NSABP R-04 50,4 Gy + 5-FU or capécitabine 50,4 Gy + 5-FU or capécitabine + oxali CAO/ARO/AIO 05 50,4 Gy + 5-FU 50,4 Gy + 5-FU + oxaliplatin
  50. 50. CONCLUSIONS • Addition of oxaliplatin did not improve outcomes and added significant toxicity • Longer follow up will be needed to assess localregional tumor relapse, DFS and OS Roh MS et al. Proc ASCO 2011;Abstract 3503.
  51. 51. Outcomes of Stage II/III Rectal Cancer  Low Locoregional relapse rates: 6-8% However, 50-70% with LRR also have Distant Relapse  Poor Disease Free Survival Rates: 5-Year DFS in modern trials: 56-74%  DISTANT RELAPSE is the major issue
  52. 52. Current Questions in Rectal Cancer: HOW CAN WE REDUCE DISTANT RELPASE?  Give systemic therapy BEFORE radiation?    Better systemic therapy WITH radiation?    Will this increase % patients treated and dose intensity? Get the chemotherapy in earlier STAR, ACCORD , R04 negative so far Many phase II trials, pending Give oxaliplatin Post-Operatively – PETTAC pending, many already do this
  53. 53. INDUCTION CHEMOTHERAPY EXPERT-C Patients with MRI defined poor-risk rectal cancer D1 D1 D22 D22 …x4 …x4 T M E R D1 D22 D1 D22 …x4 Phase II n=164 Oxa: 130 mg/m2/d …x4 Cape: 1650 mg/m2/d RT:45 Gy+ 9Gy boost Cape: 2000 mg/m2/d Cetuximab: 400 mg/m2 D1 than 250 mg/m2 weekly Oxa: 130 mg/m2/d Cape: 2000 mg/m2/d
  54. 54. Neoadjuvant chemo followed by chemoradiation
  55. 55. Απόθξαμε εληέξνπ Αθξάηεηα Μαιαθά θόπξαλα – αέξηα ΢εμνπαιηθή δπζιεηηνπξγία Παξελέξγεηεο νπξνπνηεηηθνύ Δεπηεξνγελείο θαξθίλνη Μείωζε QoL
  56. 56. Reducing Toxicity from CRT
  57. 57. Toxicity Chemoradiotherapy is more toxic than radiotherapy alone To reduce toxicity:  Preoperative rather than post op  Radiation volume  Radiation techniques
  58. 58. 3-D Conformal RT ΢πλνιηθή δόζε 50.4 Gy ζε 28 ζπλεδξίεο • 45 Gy ζηελ πύειν ζε 25 ζπλεδξίεο πξελήο - 3 πεδία • 5.4 boost ζηνλ όγθν/κεζννξζό ζε 3 ζπλεδξίεο πιάγηα πεδία ή 3 πεδία • θεθαιέο κεξηαίωλ, ιεπηό έληεξν ≤ 45 Gy
  59. 59. T4 Rectal Cancer: 4 Fields M. Mohiuddin 2006
  60. 60. 3DCRT vs IMRT 5040 cGy 5040 cGy
  61. 61. Σςέζη δόζηπ – ξνείαπ ηξνικόηηηαπ λεπηξύ εμηέοξρ V15 (cm3) # Pts < 150 G0-2 G3 20 100% 0% 150-299 20 70% 30% ≥ 300 20 30% 70%
  62. 62. ΟΥΙ ΑΚΘ Neoadjuvant FOLFOX with Bevacizumab but without Pelvic Radiation for Locally Advanced Rectal Cancer Schrag D et al. Proc ASCO 2010;Abstract 3511.
  63. 63. Investigator comment on the results of a study of neoadjuvant FOLFOX/bevacizumab without radiation therapy for locally advanced rectal cancer The standard treatment approach for most patients with locally advanced rectal cancer is neoadjuvant chemoradiation therapy. Most acknowledge that radiation therapy is probably the more toxic component of this treatment, particularly the long-term side effects. I have patients who have radiation proctitis, which is nasty and leads to pain, constant diarrhea and sphincter dysfunction. It would be a paradigm shift if we could utilize highly active systemic therapy without radiation therapy. Memorial Sloan-Kettering Cancer Center had two interesting pilot studies — one with FOLFOX with bevacizumab and one with FOLFOX alone — and in their series, they had an approximately 30 percent pathologic complete response rate for patients with mid- or higherrectum adenocarcinomas without radiation therapy, which is as good as it gets when you talk about These data suggest that appropriately selected patients with locally advanced rectal cancer may forego pelvic XRT without adversely affecting R0 resection and pathologic CR rates. Based on these preliminary results, a cooperative group study is planned to examine neoadjuvant FOLFOX without XRT in patients with locally advanced rectal cancer. Schrag D et al. Proc ASCO 2010;Abstract 3511.
  64. 64. Σξπική εναίοεση(LE) αμτί TEM Trial GRECCAR 2 (phase III)
  65. 65. Tailoring Therapy ?
  66. 66. Multidisiplinary Therapeutic Alliance
  67. 67. Εσταριστώ για την προσοτή σας

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