NEOADJUVANT THERAPY IN POTENTIALLY RESECTABLE PANCREATIC CANCER

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NEOADJUVANT THERAPY IN POTENTIALLY RESECTABLE
PANCREATIC CANCER

• Hematology Oncology Grand Rounds 3/20/09

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Financial Disclosure

• No financial interests to disclose, unfortunately

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Overview

• Background pancreatic cancer
• Defining resectibility in pancreatic cancer
• Neoadjuvant therapy
• 5-FU based
• Gemcitabine-based
• Targeted agents
• Summary and conclusions
• References

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Pancreatic Cancer

• American Cancer Society estimates that in 2008,
  approximately 37,680 new cases of pancreatic
  cancer will be diagnosed, and approximately
  34,290 will die of the disease
• Only 10-20 of patients at the time of diagnosis
  are eligible for curative resection, and even the
  majority of those who were resected for cure die
  from their disease
• 5 year survival rate for this cancer is an
  abysmal 4
• In some patients, the issue of surgical
  resectability, which offers the only chance for
  cure, is unclear secondary to tumor
  characteristics
• National Comprehensive Cancer Network Clinical
  Practice Guidelines in Oncology describes one set
  of criteria for borderline resectable tumors

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Pancreatic Cancer NCCN Criteria for Defining
Resectability Status

• Resectable
• Head/Body/Tail
• No distant mets
• Clear fat plane around celiac artery and SMA
• Borderline resectable
• Head/Body
• Severe unilateral or bilateral SMV/portal
  impingement
• Less than 180 degrees tumor abutment on SMA
• Abutment or encasement of hepatic artery, if
  reconstructible
• SMV occlusion, if of a short segment, and
  reconstructible
• Tail
• SMA or celiac encasement less than 180 degrees

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Pancreatic Cancer NCCN Criteria for Defining
Resectability Status

• Unresectable
• Head
• Distant metastases
• Greater than 180 degrees SMA encasement, any
  celiac abutment
• Unreconstructible SMV/portal occlusion
• Aortic invasion or encasement
• Body
• Distant metastases
• SMA or celiac encasement greater than 180 degrees
• Unreconstructible SMV/portal occlusion
• Aortic invasion
• Tail
• Distant metastases
• SMA or celiac encasement greater than 180 degrees
• Nodal status
• Mets to lymph nodes beyond the field of resection

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Pancreatic Cancer

• For patients with resectable disease, standard of
  care is surgical resection
• Resection terminology
• R0 no margins involvement
• R1 microscopic involvement
• R2 macroscopic residual disease
• Although surgery offers a low cure rate, it is
  also the only chance for cure
• Following a potentially curative PD, disease
  recurs in 8090 of patients, suggesting that
  surgical resection by itself
• Median survival ranges from 13-20 months
• Most common site of first recurrence is distant
  from the pancreas, often liver
• Loco-regional failure is also common

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Chemotherapy And Radiotherapy in Resectable
Disease

• Is there a role?
• Who benefits, if any?
• What is the optimal regimen is there one?
• When to give it?
• Neoadjuvant versus adjuvant
• Currently, for patients with resectable disease,
  resection is the standard of care. Neoadjuvant
  therapy is NOT standard of care in resectable
  disease
• What are the complications of treatment?

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Adjuvant Therapy - Briefly

• 1st trial of adjuvant therapy conducted by GITSG
  (70s to 80s)
• 49 patients with resected pancreatic cancer
  (negative margins) randomized to split course XRT
  (2 courses of 20 Gy separated by 2 weeks)
  together with 5-FU (500 mg/m2) IV bolus on the
  first 3 days of XRT and then weekly after XRT,
  for 2 years vs no adjuvant treatment
• Median survival 18 months vs 11 months, and 2
  year survival 43 vs 18 in chemo-XRT arm and no
  adjuvant treatment
• EORTC conducted a similar study (except 5-FU was
  administered as a continuous infusion, and was
  not continued beyond chemo-XRT) showed no
  significant improvement in median survival in
  patients with carcinoma of the pancreatic head.
• Concluded that the addition of chemoradiation to
  surgery did not produce an overall benefit in
  resected pancreatic cancer

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Adjuvant Therapy - Briefly

• ESPAC-1 study analyzed 289 patients
  controversial design, many criticisms
• 2x2 factorial design surgery only (69), 5-FU
  based chemoradiation (75), chemotherapy with 5-FU
  and leucovorin (73), and both chemoradiation and
  chemotherapy (73)
• Major conclusions were 5 year OS comparisons
  between patients who received chemotherapy vs
  those that did not(21 vs 8), and those who
  receieved radiotherapy and those that did not (10
  vs 20)
• Authors concluded that adjuvant chemotherapy had
  a beneficial effect in resected pancreatic cancer
  whereas chemoradiation had a deleterious effect
• RTOG 97-04
• Chemotherapy with either 5-FU or gemcitabine for
  3 weeks prior to 5-FU based chemoradiation and 12
  weeks after chemoradiation
• Enrolled 451 patients, 388 with pancreatic head
  tumors

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Adjuvant Therapy - Briefly

• RTOG 97-04 Cont
• Median survival of 20.5 months vs 16.9 months and
  3 year survival of 31 vs 22 (Gemcitabine vs
  5-FU, respectively)
• Grade 4 hematologic toxicity is 1 in 5-FU, and
  14 in Gemzar
• Authors concluded that addition of gemcitabine to
  adjuvant 5-FU based chemoradiation was associated
  with a survival benefit, though not statistically
  significant
• CONKO-001
• Phase III prospective, open, multicenter,
  controlled trial randomizing patients after
  complete resection (R0 or R1) to gemcitabine x 6
  months or observation
• Median DFS of 13.4 months vs 6.9 months, and
  median OS 22.8 months vs 20.2 months, for
  gemcitabine vs observation
• Pattern of recurrence did not differ between the
  two arms local recurrence was a component of
  failure in 34 and 41 of patients in gemcitabine
  vs observation groups respectively

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Neoadjuvant Therapy

• Currently, for resected pancreatic cancer (no
  evidence of recurrence or metastatic disease),
  NCCN guidelines recommend that enrolment in a
  clinical trial is preferred
• Investigation into neoadjuvant therapy is
  motivated by low rate of resectability and poor
  long-term outcomes following pancreaticoduodenecto
  my - Can we improve outcomes?
• Potentially give full-dose chemotherapy and
  radiotherapy
• Post-operatively, about 20-30 of patients unable
  to complete adjuvant treatment
• Potentially avoid delays to systemic and local
  treatments
• Patient observation and selection
• Restaging of patients upon completion of
  neoadjuvant treatment to identify patients with
  aggressive disease
• Downstaging to convert to resectability in
  borderline cases
• Interest in neoadjuvant therapy for
  locally-advanced disease motivated by poor
  outcome of these patients, and the potential for
  resection to improve survival
• Modalities
• Chemotherapy
• Radiotherapy
• Chemoradiation

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The Early Days

• Radiotherapy only (Ishikawa et al)
• Compared 23 patients with resectable disease
  receiving pre-op XRT to 31 patient with surgery
  only
• XRT group had similar survival to surgery only
  group and higher rate of metastatic recurrence
• In locally advanced disease, radiotherapy only
  has been compared to chemoradiotherapy
• Mayo Clinic
• EBRT (35-40 Gy/3-4 weeks) vs EBRT (35-40 Gy/3-4
  weeks)5FU
• Median survival 6.3 vs 10.4 months
• 1 year survival 6 vs 22
• GITSG
• EBRT (60 Gy/10 weeks) vs EBRT(40 Gy/10 weeks)
  5FU vs EBRT (60 Gy/10 weeks) 5FU
• Median survival 5.3 vs 8.4 vs 11.4 months
• 1 year survival 10 vs 35 vs 46

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Neoadjuvant Chemoradiation

• ECOG Study (Hoffman et al)
• EBRT (59.4 Gy/ five 1.8 Gy fractions/week) vs
  EBRT 5FU (1000 mg/m2 per day on days 2 through
  5 and 29 through 32) and mitomycin (10mg/m2 on
  day2)
• 53 enrolled patients with localized, resectable
  disease
• Only 24 patients underwent resection, rest had
  progressive disease, met disease, or significant
  toxicities (43 with grades 3-5 liver toxicity)
• Of resected patients, median survival was 15.7
  months
• Of resected patients - positive peritoneal
  cytology (n 3), close surgical margins (n
  13), involved nodes (n 4), and the need for
  resection of the superior mesenteric vein (n 4)

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Neoadjuvant Chemoradiation

• MD Andersons early experiences with neoadjuvant
  chemoradiation (Evans et al)
• 28 patients
• Continuous infusional 5-fluorouracil (5-FU 300
  mg/m2/day) in combination with standard
  fractionation external beam radiation therapy
  (EBRT 50.4 Gy 180 cGy/fraction for 28 fractions
  over 5.5 weeks)
• 1/3 of patients hospitalized for severe GI side
  effects
• Restaging radiographic evaluation 45 weeks after
  completing preoperative therapy
• Evidence of metastatic disease in 25 of patients
• Another 15 had intraoperative evidence of
  metastatic disease at laparotomy
• Overall resectability rate of 61 (17 patients)
• Median survival for the patients who underwent PD
  with curative intent was 18 months

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Neoadjuvant Chemoradiation

• Rapid-fractionation pre-op chemoradiation with
  5-FUand intra-op XRT (Pisters et al MD
  Anderson)
• 35 patients
• 2 week course of 5-FU (300 mg/m2 daily) and
  radiation 30Gy and 3 Gy daily and 5 days a week
• 3 patients with grade 3 nausea/vomiting
• 27 patients taken to surgery
• 20 patients had pancreaticoduodenectomy with
  EB-IORT
• 7 with unresectable disease because of clinically
  occult liver mets (5), peritoneal implants (1),
  or locally advanced (1)
• 3 year survival was 23
• Median survival of 25 months in resected patients

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Neoadjuvant Chemoradiation

• Pre-op Paclitaxel and concurrent rapid
  fractionation radiation (Pisters et al MD
  Anderson)
• 35 patients enrolled in study
• 30 Gy EBRT and concomitant weekly paclitaxel (60
  mg/m2) days 1, 8, and 15. Restaging 4-6 weeks
  after completion
• 16 (46) with Grade 3 toxicities (7 with N/V, 3
  with neutropenia, 3 with anorexia, 1 each with
  fatigue, allergic reaction and diarrhea)
• 10 patients did not undergo surgery 7
  metastatic disease, 1 locally advanced involving
  SMA, and 2 with unrelated medical complications
• 25 patients underwent surgery - EB-IORT in 13
  patients
• No histologic CR
• 3 year survival of 28 in these patients

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Gemcitabine

• Nucleoside analogue, metabolized intracellularly
  to diphosphate and triphosphate metabolites,
  which are active
• Cytotoxic effects thought to be secondary to two
  mechanisms
• Gemcitabine diphosphate inhibits ribonucleotide
  reductase, which catalyzes reactions that
  generate deoxynucleoside triphosphate for DNA
  synthesis
• Gemcitabine triphosphate is a fraudulent base
• Cell-phase specific (S-phase killing, and
  blocking transition through G1-S interphase)
• For advanced pancreatic cancer, gemcitabine is
  first line treatment and is superior to 5-FU in
  terms of clinical benefit, median survival, and
  12 month survival rate

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Gemcitabine-Based Neoadjuvant Chemoradiation

• Full dose gemcitabine with radiation (Talamonti
  et al)
• Multi-institutional phase II
• 20 patients with potentially resectable
  pancreatic cancer
• 3 cycles of full dose gemcitabine (1000 mg/m2)
  and radiation during 2nd cycle (36 Gy in daily
  2.4 Gy fractions)
• 95 of patients completed therapy without
  interruption, one experienced grade 3 GI toxicity
• 20 patients taken to surgery and 17 resected
• Pathologic analysis with clear margins in 16 of
  17 (94) and uninvolved lymph nodes in 11 of 17
• Complication rate of 24 - 3 major (one with
  bleeding at anastomosis, one requiring
  re-exploration for delayed gastric emptying and
  revision of anastomosis, one with liver abscess)
• Median follow-up of 18 months - 7 patients with
  no recurrence, 3 alive with distant metastases, 7
  have died

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Gemcitabine-Based Neoadjuvant Chemoradiation

• Reduced dose gemcitabine with radiation (Evans et
  al)
• 86 patients with potentially-resectable
  pancreatic head / uncinate process adenocarcinoma
• 7 weekly IV infusions of gemcitabine (400 mg/m2)
  and radiation (30 Gy in 10 fractions over 2
  weeks)
• Restaging 4 -6 weeks after completion of
  chemo-XRT
• 73 patients taken to surgery
• 64 resected, extrapancreatic disease found in 9
• Post-operatively, major complications in six
  patients (9)
• Median survival was 34 months for resected
  patients and 7 months for the 22 unresected
  patients
• 5 year survival was 36 for resected patients and
  0 for unresected

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Gemcitabine-Based Neoadjuvant Chemoradiation

• Gemcitabine Cisplatin followed by gemcitabine
  based chemoradiation Varadhachary et al (more
  from MD Anderson)
• 90 patients
• Gemcitabine (750 mg/m2) and cisplatin (30 mg/m2)
  every 2 weeks for four doses, followed by
  chemoradiation with 4 weekly infusions of
  gemcitabine (400 mg/m2) combined with XRT (30Gy
  in 10 fractions over 2 weeks)
• Restaging 4-6 weeks after XRT
• 79 (88) completed chemo-chemoradiation
• 62 taken to surgery and 52 underwent resection
• Median overall survival for patients who
  completed chemo-chemoradiation was 18.7 months
• Median survival of 31 months for the 52 resected
  patients
• Median survival of 10.5 months for the 27
  unresected
• Did not improve survival beyond Gem-XRT alone

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Neoadjuvant Chemotherapy Without Radiation

• Gemcitabine and cisplatin (Heinrich et al)
• Prospective phase II study
• 28 patients enrolled
• Four biweekly cycles of gemcitabine at 1,000
  mg/m2, and cisplatin 50 mg/m2 with restaging
  prior to OR
• Most side effects were mainly GI and hematologic,
  mostly mild
• 26 patients with resectable on restaging, and R0
  resection rate of 80
• Histologic tumor response and cytopathic effects
  in 54 and 83 of patients respectively
• Disease free and overall survival of 9.2 months
  and 26.5 months

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Neoadjuvant Therapy With Targeted Agents

• Gemcitabine bevacizumab XRT by Varadhachary
  et al
• Enrolled 11 patients
• Gemcitabine (400 mg/m2) weekly x 6 doses
  bevacizumab (10 mg/kg) q 2 weeks x 3 doses XRT
  50.4 Gy at 1.8Gy per fraction
• Restaging 4-6 weeks after radiation
• At restaging, 1 patient with metastatic disease,
  1 died from cardiac arrest before restaging, and
  9 went on to successful (R0) resection
• However, post op complications in 5/9 patients
  which were major, including wound dehiscence (3)
  requiring repeat OR, large ventral hernia related
  to fascial dehiscence (1) and biliary anastomotic
  leak (1)
• Authors conclude that the combined use of
  bevacizumab with radiation or gemcitabine (or
  both) might have contributed to poor wound healing

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On-Going Trials

• Gemcitabine oxaliplatin XRT (Hopkins)
• Induction chemo with gemcitabine docetaxel,
  followed by neoadjuvant chemoradiotherapy with
  Xeloda/oxaliplatin IMRT, post op adjuvant chemo
  with gemcitabine oxaliplatin (Hutch)
• Gemcitabine oxaliplatin neoadjuvant, followed
  by surgery and adjuvant gemcitabine (MSK)
• Gemcitabine docetaxel Xeloda stereotactic
  body radiation (Moffitt)
• Xeloda proton beam radiation (Dana Farber)
• Gemcitabine oxaliplatin erlotinib in
  borderline resectable (Cincinnati)

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Summary

• Bottom line - Many studies, no clear answer
• Only chance for curative treatment of pancreatic
  cancer remains complete resection of disease
• Cure rates with surgery alone are low
• Adjuvant and neoadjuvant therapy strategies have
  been investigated, but the optimal regimen has
  yet to be determined
• In setting of resectable disease, no direct
  randomized controlled trial comparing neoadjuvant
  to adjuvant treatment in setting of resection
• Surgery-related toxicities remain a consideration

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The End
"Penso che una vita per la musica sia una vita
spesa bene ed è a questo che mi sono
dedicato." English translation "I think a life
for music is a well-spent one, and that's what I
have dedicated mine to.
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References

• Picozzi VJ, Pisters PWT, Vickers SM and Strasberg
  SM Strength of the evidence adjuvant therapy
  for resected pancreatic cancer. J Gastrointest
  Surg. 2008 12657-61
• Regine WF, Winter KA, Abrams RA et al.
  Fluorouracil vs gemcitabine chemotherapy before
  and after fluorouracil-based chemoradiation
  following resection of pancreatic adenocarcinoma
  a randomized controlled trial. JAMA. 2008 Mar
  299(9)1019-26
• Neuhaus P, Riess H, Post S et al. CONKO-001
  Final results of the randomized, prospective,
  multicenter phase III trial of adjuvant
  chemotherapy with gemcitabine versus observation
  in patients with resected pancreatic cancer (PC).
  J Clin Oncol 26 2008 (May 20 suppl abstr
  LBA4504).
• Ishikawa O, Ohigashi H, Imaoka S. Is the
  long-term survival rate improved by preoperative
  irradiation prior to Whipple's procedure for
  adenocarcinoma of the pancreatic head? Arch Surg.
  1994 Oct129(10)1075-80
• Hoffman JP, Lipsitz S, Pisansky T et al. Phase
  II trial of preoperative radiation therapy and
  chemotherapy for patients with localized,
  resectable adenocarcinoma of the pancreas an
  Eastern Cooperative Oncology Group Study. JCO
  1998 Jan 16(1)317-23
• Evans DB, Rich TA, Byrd DR, et al. Preoperative
  chemoradiation and pancreaticoduodenectomy for
  adenocarcinoma of the pancreas. Arch Surg. 1992
  Nov127(11)1335-9
• Pisters PWT, Abbruzzese JL, Janjan NA, et al.
  Rapid-fractionation preoperative chemoradiation,
  pancreaticoduodenectomy, and intraoperative
  radiation therapy for resectable pancreatic
  adenocarcinoma. JCP 1998 Dec 16(12)3843-50
• Pisters PWT, Wolff RA, Janjan, NA et al.
  Preoperative paclitaxel and concurrent
  rapid-fractionation radiation for resectable
  pancreatic adenocarcinoma toxicities, histologic
  response rates, and event-free outcome. JCO 2002
  May 20(10)2537-44

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References

• Talmonti MS, Small W, Mulcahy MF et al. A
  multi-institutional phase II trial of
  preoperative full-dose gemcitabine and concurrent
  radiation for patients with potentially
  resectable pancreatic carcinoma. Ann Surg Oncol
  13(2)150-8
• Evans DB, Varadhachary GR, Crane CH et al.
  Preoperative gemcitabine-based chemoradiation for
  patients with resectable adenocarcinoma of the
  pancreatic head. JCO 2008 Jul 26(21)3496-3502
• Varadhachary GR, Wolff RA, Crane CH et al.
  Preoperative gemcitabine and cisplatin followed
  by gemcitabine-based chemoradiation for
  resectable adenocarcinoma of the pancreatic head.
  JCO 2008, Jul 26(21)3487-95
• Henrich S, Pestalozzi BC, Schafer M, et al.
  Prospective phase II trial of neoadjuvant
  chemotherapy with gemcitabine and cisplatin for
  resectable adenocarcinoma of the pancreatic head.
  JCO 2008, May 26(15)2526-31
• Varadhachary GR, Wolff RA, Crane CH, et al.
  Preoperative gemcitabine (gem) and bevacizumab
  (bev)-based chemoradiation for resectable
  pancreatic adenocarcinoma. JCO26 2008 (May 20
  suppl abstr 4630)