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Pancreatic Cancer

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Pancreatic Cancer. Dr Matt Katz

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Pancreatic Cancer

  1. 1. Multimodality management of pancreatic cancer Matthew HG Katz, MD Department of Surgical Oncology UT MD Anderson Cancer Center AUBHO 2015 Bangkok, Thailand August 29, 2015
  2. 2. • Absence of extrapancreatic disease • Tissue plane between tumor and SMA/CA • Patent SMV-PV confluence 2 3 1 Criteria yield high rates of microscopically complete (R0) resection T V A Resectable pancreatic cancer
  3. 3. Trial Year n Treatment arm Control arm Median OS (mos) (treatment v. control) p GITSG 1985 43 5-FU-based chemoradiation followed by maintenance 5-FU Observation 21.0 v. 10.9 0.03 EORTC 1999 114 5-FU-based chemoradiation Observation 17.1 v. 12.6 NS CONKO 2008 368 Gemcitabine Observation 22.8 v. 20.2 0.005 Postoperative (adjuvant) therapy helps
  4. 4. Median age: 61 Median PS: 80 Postop CA 19-9: < 2.5 ULN Time to randomize: 3 wks 3-year DFS: 24% Oettle, JAMA 2007 …but is not the answer
  5. 5. Problem with surgery first: Ignores known biology of the tumor and physiology of the host
  6. 6. TUMOR BIOLOGY 25% of patients ≥ 5yrs n = 328 resected patients Median OS = 20.4 months Katz, Annals Surg Onc 2008 25% of patients ≤ 12 months
  7. 7. Metastasis occurs early and often Problem 1
  8. 8. Occult Microscopic Disease Van den Broeck, E J Surg Onc 2009 Rapid recurrence common following “radical” resection
  9. 9. Glant, Surgery 2011 Frequency of unanticipated metastases identified
  10. 10. Rhim Cell 2012 We’re behind the 8 ball Preop chemotherapy is a more rational approach Hematogenous spread and liver seeding precede tumor formation
  11. 11. The CT scanner is not a microscope Problem 2
  12. 12. Series (Year) N Margin Status % Median OS (Mos.) p Johns Hopkins (2006) 1175 R1/R2 42 14 < 0.0001 R0 58 20 University of Leeds - UK (2006) 26 R1 85 11 0.01 R0 15 37 ESPAC -1 (2001) 541 R1 19 11 0.006 R0 81 17 University of Naples - Italy (2000) 75 R1/R2 20 9 0.001 R0 80 26 Rush-Presbyterian- St. Luke's (1999) 75 R1 29 8 0.01 R0 71 17 MGH (1993) 72 R1/R2 51 12 0.05 R0 49 20 Influence of margin status on survival At least macroscopically complete resection is critical to OS
  13. 13. Katz JOGS 2010 Occult extension even in resectable cases
  14. 14. SMA distance (mm) by pathology SMAdistance(mm)byradiology 0 2 4 6 8 0102030 Distance between cancer and margin is routinely overestimated by CT Concordance Coefficient 0.07 (95% CI: 0.02 – 0.13) OverestimatedUnderestimated Katz JOGS 2010
  15. 15. Yamada, Pancreas 2013 Worse with increasing TVI n OS (mo) Resectable 137 24 PV 91 15 CHA 21 14 SMA 30 13 Cohort- Preoperative Imaging Any radiographic interface between tumor and vessel None (n = 137) PV (n = 91) CHA (n = 21) SMA (n = 30) P R0 rate 77% 70% 48% 37% 0.0001
  16. 16. Problem 3 Postoperative therapy is not guaranteed
  17. 17. Merkow, Ann Surg 2013 2047 patients in NSQIP-NCDB, pancreatectomy 2006-2009 Adverse events prevent postoperative tx
  18. 18. • United States – SEER-Medicare 1992-2002 – 1383 resected patients >65 years – Only 49% received adjuvant therapy – Pts ≥ 75 half as likely to receive (OR 0.43, HR 0.34-0.54) • Australia – Data from 12 hospitals 1990-2011 – 439 resected patients – Only 47% received adjuvant therapy – Pts ≥ 70 less likely to receive (30% v. 52%, p < 0.0001) Davila, Pancreas 2009 Nagrial, BJC 2014 Elders do not receive adjuvant therapy
  19. 19. 66 y/o Vein + splenorenal shunt 73 y/o Vein + hepatic artery 66 y/o Vein + celiac trunk AEs occur after big operations
  20. 20. Surgery first sequencing is an INappropriate strategy for BLR PDAC • Surgery does not address known systemic disease • Surgery is suboptimal local therapy • Niether postop chemo nor cXRT do much… • …and only 50% receive it
  21. 21. CTXS OR Neoadjuvant therapy for PDAC Three primary components Varadhachary, Ann Surg Onc 2006 Katz, JACS 2008 Abrams, Ann Surg Onc 2009 XRTS S R NR • CTX: Cytotoxic effect on systemic cancer cells • XRT: Sterilization of surgical margins and local cytotoxicity • Time: Selection of tumor biology and patient physiology for surgery
  22. 22. Guarantees administration of non-operative therapy to all patients who undergo pancreatectomy Advantage 1
  23. 23. NA: no severe AEs NA: severe AEs SF: no severe AEs SF: severe AEs NA: not resected SF: no adjuvant Ameliorates long-term adverse effects of severe postoperative complications
  24. 24. High risk populations patients ≥ 70 who presented with res/BL PDAC 179 (76%) treated curatively 26 (15%) resected 153 (85%) CTX +/- CXRT 79 (52%) Unresected 74 (48%) Resected 11 (42%) CTX +/- CXRT Cooper, JACS 2014 All patients who underwent surgery received essential nonoperative therapy
  25. 25. Selection for meaningful operations Advantage 2
  26. 26. Evans, JCO 2008 Katz, JACS 2008 Neoadjuvant therapy selects for surgery Resectable Borderline Resectable
  27. 27. Tzeng, Ann Surg Onc 2012 “Failure” of preoperative therapy Most fail due to progression of pre-existing micrometastases
  28. 28. Early local and systemic cytotoxic effects Advantage 3
  29. 29. Wang, Cancer 2012 IV Pathologic response is associated with survival For some patients: therapy is active! – may improve with better regimens
  30. 30. SMA margin SMA margin R1/R2 10 – 85% and 80% die with LR Good surgery is not good enough! Iacobuzio-Donahue, JCO 2009
  31. 31. SMA Margin Distance N (n = 194) Preop CXRT (n = 147) Initial Surgery (n = 47) p* Positive 8 3 (2) 5 (11) 0.01 ≤1mm 40 28 (19) 12 (26) >1mm < 1cm 72 53 (36) 19 (40) ≥1cm 66 57 (39) 9 (19) SMA margin distance measured histopathologically following pancreaticoduodenectomy * Not recorded in 8 patients Preop CXRT increases SMA margin clearance Katz, JOGS 2011
  32. 32. 0 12 24 36 48 60 72 84 96 0 20 40 60 80 100 CXRT, > 1mm Initial Surgery, > 1mm CXRT, <= 1mm Initial Surgery, <= 1mm Months Percentsurvival DFSTime to LR Greer, JACS 2008; Katz, JOGS 2011 Preop CXRT prolongs TTR Cytotoxic activity at the margin translates to a survival advantage (not OS)
  33. 33. “Downstaging” to resectability Advantage 4
  34. 34. Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages Sonja Gillen1 , Tibor Schuster2 , Christian Meyer zum Bu¨schenfelde3 , Helmut Friess1 , Jo¨ rg Kleeff 1 , 4 * 1 Department of Surgery, Technische Universita¨t Mu¨nchen, Munich, Germany, 2 Institute of Medical Statistics and Epidemiology, Technische Universita¨t Mu¨nchen, Munich, Germany, 3 Department of Hematology and Oncology, Technische Universita¨t Mu¨nchen, Munich, Germany, 4 Center of Cancer Systems Biology, Department of Medicine, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts, United States of America Abst ract Background: Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease and microscopic incomplete resections are common. The objective of the present analysis was to systematically review studies concerning the effects of neoadjuvant therapy on tumor response, toxicity, resection, and survival percentages in pancreatic cancer. Methods and Findings: Trials were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1966 to December 2009 as well as through reference lists of articles and proceedings of major meetings. Retrospective and prospective studies analyzing neoadjuvant radiochemotherapy, radiotherapy, or chemother- apy of pancreatic cancer patients, followed by re-staging, and surgical exploration/resection were included. Two reviewers independently extracted data and assessed study quality. Pooled relative risks and 95% confidence intervals were calculated using random-effects models. Primary outcome measures were proportions of tumor response categories and percentages of exploration and resection. A total of 111 studies (n = 4,394) including 56 phase I–II trials were analyzed. A median of 31 (interquartile range [IQR] 19–46) patients per study were included. Studies were subdivided into surveys considering initially resectable tumors (group 1) and initially non-resectable (borderline resectable/unresectable) tumors (group 2). Neoadjuvant chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to 63 Gy. Averaged complete/partial response probabilities were 3.6% (95% CI 2%–5.5%)/30.6% (95% CI 20.7%–41.4%) and 4.8% (95% CI 3.5%–6.4%)/30.2% (95% CI 24.5%–36.3%) for groups 1 and 2, respectively; whereas progressive disease fraction was estimated to 20.9% (95% CI 16.9%–25.3%) and 20.8% (95% CI 14.5%–27.8%). In group 1, resectability was 35% with unresectable cancers had partial or complete response 33% of patients underwent resection “One-third of initially staged non-resectable tumor patients would be expected to have resectable tumors following neoadjuvant therapy”
  35. 35. RECIST of 122 patients restaged following neoadjuvant therapy RECIST Example N (%) Resected n (%) Stable Disease 84 (69) 70 (83) Partial Response 15 (12) 15 (100) Progressive Disease (Local) 2 (2) 0 (0) 21 (17%) progressive disease due to metastases, 0 resected v v +6% v v -38% v +22% Katz, Cancer 2012
  36. 36. Change in stage of 122 patients restaged following neoadjuvant therapy 21 (17%) upstaged due to metastases, 0 resected Stage Change Example N (%) Resected n (%) No change 98 (80) 82 (84) Downstaged 1 (1) 1 (100) Upstaged (Local) 2 (2) 2 (100) H A A V V C C Katz, Cancer 2012
  37. 37. T AV Successful downstaging Or inaccurate interpretation of pretreatment stage? • 73 yo woman, mass in HOP • Attempted resection but mass “surgically unresectable” • Biliary-enteric bypass performed • FOLFIRINOX • 5-FU based CXRT • Referred: R0 resection Pretreatment scan Poor staging leads to overestimation of the effects of preoperative therapy
  38. 38. • 68 year old man with mass in HOP • Clinician: “it’s borderline… let’s see what happens with some ‘preoperative therapy’” • FOLFIRINOX • 5-FU-based CXRT • Remained unresectable • (+/- “exploration with attempt at resection”) “But I was told it would shrink!” Rational treatment relies on precise staging T A V Pretreatment scan Should this patient have received chemoradiation? – LAP-07
  39. 39. Treatment phase Break ~ 6 wks CTX Staging CT Restaging Treatment Program Restaging CXRT OR Clinical Assessment • Assessment of “tumor biology” • Assessment of patient physiologic state • Local control concerns • Likelihood of surgery • Psychosocial concerns and logistics • Modulate agents based upon PS, etc.
  40. 40. •How can treatment sequencing best be individualized? •What treatment modalities should be used and when? •How long is “long enough” (and “too long”)? •How can response to preoperative therapy be measured? •When is postoperative therapy also indicated? Unanswered Questions
  41. 41. • Advantages: – Gaurantees receipt of nonoperative therapy – Selects patients for effective operations – Allows for early cytotoxic effects • Treatment decisions: on the basis of an analysis of anatomy, biology and host physiology • Treatment sequence must be optimized and individualized • Neoadjuvant therapy is an appropriate treatment strategy for patients with anatomically resectable and borderline resectable disease Conclusions
  42. 42. Thank you Matthew Katz mhgkatz@mdanderson.org

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