Download Neoadjuvant therapy in pancreatic adenocarcinoma

Neoadjuvant Treatment for
Pancreatic Adenocarcinoma
CH MAN
Department of Surgery
Caritas Medical Centre
Background
 Aggressive malignancy
 Overall median survival: 5-6 months
 5-year survival rate: approx. 5%
 Risk factors:




Smoking
Heavy alcohol consumption
Chronic pancreatitis
Family history
Background (cont’d)
15%
55%
local disease
30%
loco-regional
disease
metastatic
disease
History of
Pancreatic AdenoCa Treatment
 The only chance of cure: SURGICAL RESECTION
 Outcome not satisfactory
 Median survival: 15-19 months
 5-year survival after resection: less than 20%
 Recurrence in 30-50% of patients after presumed
curative resection
J Gastrointest Surg. 2001 Mar-Apr;5(2):121-30.
Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas.
Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, Pinover WH, LeVoyer TE, Sasson AR, Eisenberg BL.
History of
Pancreatic AdenoCa Treatment
(cont’d)
 In 1985, Gastrointestinal Tumor Study Group reported:
 Median survival of patients after resection prolonged
for almost twofold by adjuvant chemoradiation
 2-year survival:
 42% in adjuvant chemoradiation group VS
15% in control group
Arch Surg. 1985 Aug;120(8):899-903.
Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection.
Kalser MH, Ellenberg SS.
History of
Pancreatic AdenoCa Treatment
(cont’d)
 RCT in 2008
 Treatment with gemcitabine for 6 months after
complete resection
 Significantly increases
 5 years disease-free survival: 16%
 Median overall survival: 22.8 months
J Clin Oncol26: 2008
Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotheraoy with gemcitabine versus
observation in patients with resected pancreatic cancer.
Neuhaus P, Riess H, etal.
Questions
 How to enhance the chance of resection?
 How to further improve the survival after resection
besides adjuvant therapy?
Therapies
 Neoadjuvant Chemotherapy and Radiotherapy
 Is there a role?
 Who will benefit?
 What is the optimal regimen?
Pancreatic AdenoCa
 Resectable
 Absence of extrapancreatic disease
 Clear tissue plane around celiac axis, hepatic artery
and SMA
 A patent SMV-PV confluence
Pancreatic AdenoCa
 Borderline resectable
 Absence of extrapancreatic disease
 Tumor involvement or occlusion of SMV/PV confluence
amenable to resection and reconstruction
 Short segment of abutment/encasement of hepatic artery
 Tumor abutment of the SMA < 180 degrees of the
circumference of the vessel
Pancreatic AdenoCa
 Unresectable
 Distant metastases
 Lymph nodes metastases beyond the field of
resection
 Aortic invasion
 Greater than 180 degrees SMA encasement
 Unreconstructible SMV/portal occlusion
Potential Benefit of Neoadjuvant
Therapy in Resectable Disease
 The administration is not affected by the surgical
morbidities
 20% of patients did not receive the assigned adjuvant therapy
 Occult metastases is allowed to manifest
 exclude patient from resection
 avoid the surgical morbidity
 Improve the chance of negative resection margin
Ann Surg 1999; 230:776–82.
Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase
III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group.
Klinkenbijl JH, Jeekel J, Sahmoud T, et al.
Neoadjuvant Therapy in
Resectable Disease
 Involved resection margins are a
poor prognostic factor
Neoadjuvant Therapy in
Resectable Disease
 Negative impact on survival with an increasing number
of positive margins
J Gastrointest Surg. 2001 Mar-Apr;5(2):121-30.
Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas.
Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, Pinover WH, LeVoyer TE, Sasson AR, Eisenberg BL.
Neoadjuvant Therapy in
Resectable Disease
 Neoadjuvant therapy can improve the chance of R0
resection and decrease the number of multiple positive
margins
J Gastrointest Surg. 2001 Mar-Apr;5(2):121-30.
Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the
pancreas.
Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, Pinover WH, LeVoyer TE, Sasson AR, Eisenberg BL.
Neoadjuvant Therapy in
Resectable Disease
 The overall median survival from the time of tissue
diagnosis was 21 months
 At median 14 weeks of follow-up, 31% of patients showed
no evidence of disease
 Survival duration is improved by the combination of
neoadjuvant therapy and surgery
Neoadjuvant Therapy in
Resectable Disease
 Phase II trial for preoperative gemcitabine-based
chemoradiation and surgical treatment
Neoadjuvant Therapy in
Resectable Disease
 Median survival was
34 months for patients
who underwent
neoadjuvant therapy
and surgery
Neoadjuvant Therapy in
Resectable Disease
 However, 15% of the patients developed into
unresectable disease because of disease progression
J Clin Oncol. 2008 Jul 20;26(21):3496-502. doi: 10.1200/JCO.2007.15.8634.
Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head.
Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, Vauthey JN, Wang H, Cleary KR, Staerkel GA,
Charnsangavej C, Lano EA, Ho L, Lenzi R, Abbruzzese JL, Wolff RA.
Potential Disadvantages of
Neoadjuvant Therapy
 Requirement
for
biliary
decompression
before
chemotherapy
 Potential complications from biliary stents
 Requirement
for
tissue
diagnosis
before
chemotherapy
 Procedure related Cx including seeding of tumor cells
 Percutaneous FNA causing 16.3% peritoneal seeding
 Side effects from chemotherapy
Gastrointest Endosc. 2003 Nov;58(5):690-5.
Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs.
percutaneous FNA.
Micames C, Jowell PS, White R, Paulson E, Nelson R, Morse M, Hurwitz H, Pappas T, Tyler D, McGrath K.
Conclusion of Neoadjuvant Therapy on
Resectable Pancreatic Cancer
 The adoption is still controversial
 Improvement of survival but risk of disease progression
at the same time
 No global consensus is reached at the moment
 National Comprehensive Cancer Network (NCCN):
 Does not recommend
 Except on clinical trial
Potential benefit of
neoadjuvant therapy in
borderline resectable disease
 The administration is not affected by the surgical
morbidities
 20% of patients did not receive the assigned adjuvant
therapy
 Occult metastases are allowed to manifest
 exclude patient from resection
 avoid the surgical morbidity
 Improve the chance of negative resection margin
 Increase the chance of resection
Ann Surg 1999; 230:776–82.
Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial
of the EORTC Gastrointestinal Tract Cancer Cooperative Group.
Klinkenbijl JH, Jeekel J, Sahmoud T, et al.
Neoadjuvant therapy in
borderline resectable disease
 Several trials have revealed that neoadjuvant treatment
is effective in borderline resectable case
Neoadjuvant therapy in
borderline resectable disease
 Recent retrospective study on borderline resectable
disease
 61.7% negative margin of resection with neoadjuvant
chemoradiation
 38.3% negative margin of resection without neoadjuvant
chemoradiation
J Clin Oncol 30, 2012 (suppl 4; abstr 304)
Margin status and neoadjuvant chemoradiation in patients with borderline resectable pancreatic cancer
Pavlos Papavasiliou, Jonathan R Piposar, Rodrigo Arrangoiz, Kathryn T Chen, Fang Zhu, Yun Shin Chun, John Parker Hoffman
Neoadjuvant therapy in
borderline resectable disease
 Respective review on patients with pancreatic cancer resection
 Patients
with borderline
neoadjuvant therapy
resectable
 46% underwent surgical resection
 67% had margin-negative (R0) resection
cancer
received
Neoadjuvant therapy in
borderline resectable disease
 Median survival: 23.3 months
 Similar to resectable
disease
HPB (Oxford). 2010 Feb;12(1):73-9. doi: 10.1111/j.1477-2574.2009.00136.x.
Neoadjuvant therapy may lead to successful surgical resection and improved survival in patients with borderline resectable
pancreatic cancer.
McClaine RJ, Lowy AM, Sussman JJ, Schmulewitz N, Grisell DL, Ahmad SA.
Neoadjuvant therapy in
borderline resectable disease
 No randomized phase III trials for comparison
 Although there is no high level evidence supporting its
use
 Neoadjuvant therapy is still an option
 Improve treatment outcome
Neoadjuvant Regimen
 There is no standard regimen at the moment
 In early days
 Radiotherapy
 Progress to switch to chemoradiation
 EBRT + 5-FU
 Recently
 Gemcitabine-based chemoradiation
Conclusion
 Pancreatic cancer is an aggressive malignancy with
minority of the patients suitable for surgical resection
 Adjuvant therapy can improve the outcome of the
illness
 The role of neoadjuvant therapy is still under further
exploration
Conclusion
 Resectable case
 Suggest proceeding to surgery ASAP
 Except in clinical trial
 Borderline resectable case
 Neoadjuvant therapy is an option
Reference
 J Gastrointest Surg. 2001 Mar-Apr;5(2):121-30.








Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas.
Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, Pinover WH, LeVoyer TE, Sasson AR, Eisenberg BL.
Arch Surg. 1985 Aug;120(8):899-903.
Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection.
Kalser MH, Ellenberg SS.
J Clin Oncol26: 2008
Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotheraoy with gemcitabine versus
observation in patients with resected pancreatic cancer.
Neuhaus P, Riess H, etal.
Ann Surg 1999; 230:776–82.
Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase
III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group.
Klinkenbijl JH, Jeekel J, Sahmoud T, et al.
Ann Surg Oncol. 2001 Mar;8(2):123-32.
Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration.
Breslin TM, Hess KR, Harbison DB, Jean ME, Cleary KR, Dackiw AP, Wolff RA, Abbruzzese JL, Janjan NA, Crane CH, Vauthey JN,
Lee JE, Pisters PW, Evans DB.
J Clin Oncol. 2008 Jul 20;26(21):3496-502. doi: 10.1200/JCO.2007.15.8634.
Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head.
Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, Vauthey JN, Wang H, Cleary KR, Staerkel GA,
Charnsangavej C, Lano EA, Ho L, Lenzi R, Abbruzzese JL, Wolff RA.
Gastrointest Endosc. 2003 Nov;58(5):690-5.
Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs.
percutaneous FNA.
Micames C, Jowell PS, White R, Paulson E, Nelson R, Morse M, Hurwitz H, Pappas T, Tyler D, McGrath K.
J Clin Oncol 30, 2012 (suppl 4; abstr 304)
Margin status and neoadjuvant chemoradiation in patients with borderline resectable pancreatic cancer
Pavlos Papavasiliou, Jonathan R Piposar, Rodrigo Arrangoiz, Kathryn T Chen, Fang Zhu, Yun Shin Chun, John Parker Hoffman
HPB (Oxford). 2010 Feb;12(1):73-9. doi: 10.1111/j.1477-2574.2009.00136.x.
Neoadjuvant therapy may lead to successful surgical resection and improved survival in patients with borderline resectable
pancreatic cancer.
McClaine RJ, Lowy AM, Sussman JJ, Schmulewitz N, Grisell DL, Ahmad SA.
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