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					Pancreatic Cancer
     Review


    Gina Vaccaro, MD
      May 20, 2009
Outline

   Anatomy
   Histologic types
   Epidemiology
   Precursor lesions
   Presentation
   Treatment
        Anatomy of the pancreas




DePinho, Nature Reviews, 2002
        Anatomy of the pancreas




DePinho, Nature Reviews, 2002
Histology

   Ductal adenocarcinoma, PDAC (>85%)
   Acinar cell carcinoma
   Pancreatic Neuroendocrine Tumor
   Cystic neoplasms
   Other- Lymphoma (NHL)
DePinho, Nature Reviews, 2002
DePinho, Nature Reviews, 2002
Ductal Adenocarcinoma by the Numbers

     33,730 cases/yr in US
     30,000 deaths/yr
     7th- 8th decade of life- peak incidence
     72 years- median age at diagnosis
     4th- most common cause of Ca-related
      death in US
     15-20%- 5 yr survival if resectable
     3%- 5 yr survival, all stages
     2007 Estimated US Cancer Cases*
                                           Men               Women
                                          766,860            678,060
Prostate                      29%                                            26%       Breast
Lung & bronchus               15%                                            15%       Lung & bronchus
Colon & rectum                10%                                            11%Colon & rectum
Urinary bladder                7%                                             6%       Uterine corpus
Non-Hodgkin                    4%                                             4%       Non-Hodgkin
   lymphoma                                                                              lymphoma
Melanoma of skin               4%                                             4%       Melanoma of skin
Kidney                         4%                                             4%       Thyroid
Leukemia                       3%                                             3%       Ovary
Oral cavity                    3%                                             3%       Kidney
Pancreas                       2%                                             3%       Leukemia
All Other Sites               19%                                            21%       All Other Sites



*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2007.
    2007 Estimated US Cancer Deaths*


Lung & bronchus             31%           Men      Women     26%   Lung & bronchus
                                         289,550   270,100
Prostate                      9%                             15%   Breast
Colon & rectum                9%                             10%   Colon & rectum
Pancreas                      6%                             6%    Pancreas
Leukemia                      4%                             6%    Ovary
Liver & intrahepatic          4%                             4%    Leukemia
    bile duct
                                                             3%    Non-Hodgkin
Esophagus                     4%                                    lymphoma
Urinary bladder               3%                             3%    Uterine corpus
Non-Hodgkin                  3%                              2%    Brain/ONS
   lymphoma
                                                             2%     Liver & intrahepatic
Kidney                        3%                                      bile duct
All other sites             24%                              23%   All other sites



ONS=Other nervous system.
Source: American Cancer Society, 2007.
Predisposing Factors

   Age
   Smoking
   Chronic pancreatitis
   Obesity
   Diabetes mellitus
   None?
Familial Syndromes

   Hereditary Breast and Ovarian cancer
    (BRCA2)
   Peutz-Jeghers (LKB1)
   Familial atypical multiple mole
    melanoma (p16INK4a)
   Lynch syndrome (MSH2, MLH1, etc.)
   Hereditary pancreatitis (PRSSI)
Familial Syndromes

   Account for < 20% of the familial aggregation
    of PC
   National Familial Pancreas Tumor Registry
    (Hopkins)- 1200 families
   Familial PC- at least two 1st degree relatives
        Risk is 18X baseline
   Second degree relatives in familial PC
    kindreds have increased risk (3.7% vs. 0.6%)
Precursor Lesions

   PanIN (Pancreatic intraepithelial neoplasia)

   MCN (Mucinous cystic neoplasm)

   IPMN (Intraductal papillary mucinous
    neoplasm)
              Genetic Progression Model




DePinho, Nature Reviews, 2002
Regeneration 
Tumorigenesis




DePinho, Nature Reviews, 2002
KRAS mutation is necessary, but not sufficient

       Activating mutations are the 1st known
        genetic alterations
       Occur sporadically in normal pancreatic
        tissue
       Detected in ~30% of early neoplasms
       Nearly 100% of advanced PDAC
       Mice with pancreas-specific
        KRASG12Ddevelop PanIN, can progress to
        PDAC in the appropriate tumor suppressor
        background.
            A Target Rich Environment




DePinho, Gen Dev, 2006
Presentation

   Abdominal pain (Bad sign)
   Jaundice (Head lesions)
   Weight loss
   New onset diabetes mellitus
   Pancreatic enzyme insufficiency
    (diarrhea, floating/fatty stools)
Diagnosis

   FNA of the primary mass or distant
    metastases
   FNA of the primary is obtainable with
    EUS (endoscopic ultrasound)
   EUS is also useful for staging, invasion
    into surrounding vessels (SMA, SMV)
   Determination of resectability
Case 1
   66 yo female presented with upper
    abdominal pain
   Non-smoker, father has pancreatic cancer
   Started on PPI by PCP
   Pain continued, developed anorexia, 8 lb
    weight loss
   U/S- intra and extra hepatic biliary ductal
    dilitation
   CT- 1.4cm pancreatic head mass, 18mm
    CBD, dilated pancreatic duct
Case 1

   EUS- 2 x 1.8cm pancreatic head
    mass, 18 mm CBD, no nodes
   FNA- adenocarcinoma
   Staged T3N0
   No involvement of critical vascular
    structures.
   Underwent “Whipple” resection
Case 1

   Pathology:
      2.5 cm ductal adenocarcinoma
      T4N1 (1/19 nodes)
      Positive SMA and radial margin
      Angiolymphatic and perineural invasion

      Poor prognosis- 5 yr survival 10-20%

      Recommendation- Adjuvant
      chemotherapy, chemoradiation (6 months)
Case 2
   62 yo male presented with L flank
   Presented to urgent care, MD palpated
    an abdominal mass
   CT done- 11 x 8 cm mass in the body
    of the pancreas, no mets, obliteraion of
    portal, splenic, SMV
   Also noted to have L renal stone
   Patient has no symptoms, no weight
    loss, no pain
Case 2
    Case 2
   EUS/FNA- low grade neuroendocrine
    neoplasm
   Disease is not resectable
   Prognosis is good, median survival >5yrs
   Options:
       Observation
       Somatostin analog
       Chemotherapy
       Biologic therapy
Extent of disease at presentation

Localized/Resectable (15-20 %)         MS 15-19 mo
Locally Advanced/Unresectable (40 %)   MS 8-12 mo
Metastatic (40 %)                      MS 3-6 mo
 Staging (AJCC 2002)
Primary Tumor (T)                                  Stage Grouping
TX       Primary tumor cannot be assessed          Stage 0 Tis N0 M0
T0       No evidence of primary tumor
Tis      Carcinoma in situ (also PanIN 3)          Stage IA T1 N0 M0
T1       Tumor limited to pancreas, <=2cm          Stage IB T2 N0 M0
T2       Tumor limited to pancreas, >2cm
T3       Tumor extends beyond pancreas w/o         Stage IIA T3   N0   M0
         involvement of celiac axis or SMA         Stage IIB T1   N1   M0
T4       Tumor invades celiac axis or SMA                    T2   N1   M0
         (unresectable)                                      T3   N1   M0
Regional Lymph Nodes (N)
NX       Regional lymph nodes cannot be assessed   Stage III T4 Any N M0
N0       No regional lymph node metastases
N1       Regional lymph node metastases            Stage IV Any T Any N M1
Distant Metastasis (M)
MX       Distant metastasis cannot be assessed
M0       No distant metastasis
M1       Distant metastasis
     Five-year Relative Survival (%)* during Three Time Periods
     By Cancer Site
    Site                                             1975-1977            1984-1986            1996-2002
    All sites                                           50                    53                   66
    Breast (female)                                        75                    79                      89
    Colon                                                  51                    59                      65
    Leukemia                                               35                    42                      49
    Lung and bronchus                                      13                    13                      16
    Melanoma                                               82                    86                      92
    Non-Hodgkin lymphoma                                   48                    53                      63
    Ovary                                                  37                    40                      45 †
    Pancreas                                                 2                     3                      5
    Prostate                                               69                    76                  100
    Rectum                                                 49                    57                      66
    Urinary bladder                                        73                    78                      82

*5-year relative survival rates based on follow up of patients through 2003.
†Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates.
Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and
Population Sciences, National Cancer Institute, 2006.
Why is pancreatic cancer
   so hard to treat?
Factors to Overcome

   No adequate screening test
   High incidence of metastatic disease at
    presentation
   Fulminant clinical course
   Lack of adequate systemic therapies
   Chemotherapy resistant
   Radiation resistant
   Lack of understanding of the biology
Resectable Disease
Criteria for Unresectability

   Determined by multi-disciplinary evaluation
   Extrapancreatic involvement
    – (extensive peripancreatic nodal involvement and/or distant
      mets)
   Encasement or occlusion of the SMV or SMV-portal
    vein confluence
    – (SMV reconstruction may be feasible)
   Direct involvement of SMA, IVC, aorta, celiac axis
Surgery
(tumors of head, neck or uncinate process)
   Pancreaticoduodenectomy (Whipple)
   Operative mortality <2-3% in major surgical centers
Surgery
(tumors of body or tail)

   Often present late with larger tumors and frequent metastases
   Distal pancreatectomy +/- splenectomy
Chemotherapy
5-fluorouracil

           Pyrimidine analog
           In use for over 40 yrs
           Thymidylate synthase
            inhibitor
           Pancreatic, colon,
            breast, esophageal,
            gastic cancer, etc.
Gemcitabine

        Nucleoside analog
        Difluorinated analog of
         deoxycytidine
        Pancreas, breast, lung
         and ovarian
Adjuvant Therapy
Adjuvant therapy
   Rationale:
    High risk of local and systemic recurrence
    Overall poor prognosis
   5-yr survival after resection:
    25-30% node-neg vs. 10% node-pos
   Current standard:
    No universally accepted standard approach
Adjuvant therapy
   5 major randomized trials
   GITSG, EORTC, ESPAC-1, RTOG 9704,
    CONKO-1
   Over 1200 patients studied
   Significant methodological differences
   Chemoradiotherapy in N. America
    (GITSG, RTOG)
   Chemotherapy alone in Europe
    (EORTC,ESPAC-1, CONKO)
5-fu based chemoradiation

Trial     RT dose        Chemo        MS (Mo)        1 yr %   2 yr %

GITSG     40 Gy(split)   Bolus 5fu   20 (p=.01)      63       42
          None           None        11              49       15
EORTC     40 GY(split) CI 5-fu       17.1 (p=.099)   65       37
          None           None        12.6            40       23


ESPAC-1   2x2 factorial design
                         ESPAC-1 (5-fu)

                                Chemoradiotherapy vs. none
                                MS              15.9 vs. 17.9 mos
                                2-yr survival   29 vs. 41 %
                                5-yr survival   10 vs. 20 %



                                Chemotherapy vs. none
                                MS              20.1 vs. 15.5 mos
                                2-yr survival   40 vs. 30 %
                                5-yr survival   21 vs. 8 %

Neoptolemos, NEJM 2004
Kaplan-Meier estimates of survival according to whether or not patients
Received chemoradiotherapy (Panel A) or chemotherapy (Panel B)


Neoptolemos, NEJM 2004
ESPAC-1 Limitations

   Trial design (2 x 2 factorial)
   Possible selection bias
   Suboptimal radiation dose
   Only 70% received 40 Gy
   Uses 5-fu based chemotherapy
   Design delays initiation of adjuvant
    chemotherapy in the combination arm
Gemcitabine-based adjuvant
therapy
   RTOG 9704 (ASCO 2006)
    442 subjects
    All received chemoradiation (50.4 Gy) + CI 5-fu
    2 Arms: Additional 5-fu
               Additional Gemcitabine

    No overall difference in aggregate survival
    Head lesions only  Gemcitabine arm superior
               MS 20 vs. 17 mos
               3-yr OS 32 vs. 21 % (p=0.047)
Gemcitabine-based adjuvant
therapy
   CONKO-001
    368 subjects
    Randomized to Obs vs. Gemcitabine x 6 cycles
    10 % never received chemotherapy
    62 % received all 6 cycles
    Gr 3/4 toxicity 7.7 % in Gem arm vs. 2.5 % in Obs
    Median DFS 13.4 vs. 6.9 mos (p<0.001)
    No difference in overall survival (22 vs. 20 mos)
    QOL similar in both groups
Disease-free and Overall Survival (Intent-to-Treat Analysis)

Oettle, JAMA 2007
Adjuvant therapy (Conclusions)

   Benefit of adjuvant chemotherapy is clear
   Gemcitabine is better than 5-fu as adjuvant
    chemotherapy
   Role of chemoradiation therapy is uncertain
   Clinical trial participation should be
    encouraged
   Molecularly-targeted therapies, vaccines are
    under investigation
Future Directions

   Phase III: ESPAC-3
    5-fu/LV vs. Gem vs. Obs
   Phase II: Addition of targeted agents to
    Gemcitabine
    –   Bevacizumab
    –   Erlotinib
    –   Erbitux
    –   Capecitabine
    –   Oxaliplatin
Neoadjuvant Therapy
Rationale for Neoadjuvant therapy

   Intact vasculature permits maintenance of
    oxygenation in tissue necessary for
    radiation-induced necrosis
   Improved delivery of chemotherapy to tumor
   May downstage tumor
   20-30% of resected patients are unable to
    receive adjuvant therapy
   Saves patients with occult metastases from
    morbidity of unnecessary surgery
Neoadjuvant therapy

   No randomized studies comparing to
    adjuvant
   Small, Phase II, mostly single instituiton
   5-fu and Gemcitabine chemoradiation have
    been studied
   Neoadjuvant chemoradiation can be given
    safely without excess surgical morbidity
 ACOSOG Z5041


Gemcitabine-Erlotinib

      Surgery

Gemcitabine-Erlotinib
 Locally Advanced,
Unresectable Disease
Locally advanced, unresectable

   40% of newly diagnosed patients
   Most with adherence to adjacent structures (celiac
    or SM vessels)
   Median survival 8-12 mos
   Optimal treatment is controversial
   Treatment options:
        RT alone
        Chemotherapy alone
        Concurrent chemoradiation (+/- surgery)
Chemoradiation > RT alone

   GITSG (Morertel, Cancer 1981)
   194 patients
   Randomized to:
    High dose RT
    Moderate dose RT + 5-fu
    High dose RT + 5-fu
   1-yr survival:
    11 % (60 Gy)
    38 % (40 Gy + 5-fu)
    36 % (60 Gy + 5-fu)
Chemoradiation > RT alone

   Medicare/SEER (Krzyzanowska, JCO 2003)
   Large, retrospective cohort
   1696 patients treated between 1991-96

   Adjusted mean survival duration (weeks):
    Chemoradiation         47
    RT alone               29
    Chemo alone            27
    No therapy             15
   Supports the use of chemoradiation over either
    modality alone
RT + Gemcitabine


   NCCN states “Radiation is usually given in
    combination with 5-fu chemotherapy.
    Recent evidence suggests that concurrent
    gemcitabine and radiation can yield similar
    outcomes.”
Treatment of Metastatic
       Disease
Efficacy endpoints

   Traditional tumor measurements to assess
    RR are often inadequate in the primary
    tumor site.
   Characteristic desmoplastic reaction and
    inflammatory response
   Recent trials have included QOL endpoints
   “Clinical benefit” and survival may be more
    accurate determinants of efficacy.
Fluorouracil
   Extensively studied since 1950’s
   LV-modulated 5-fu (infusional and bolus)
        RR 0- 9%      MS 10-24 wks

   Capecitabine (Cartwright, JCO 2002)
   Phase II study, 42 patients
   Chemotherapy-naive
   24% achieved clinical benefit (pain intensity,
    analgesic use, KPS)
   7% PR
   Well tolerated, 17% Gr 3 HFS
Gemcitabine
   Nucleoside analog structurally similar to cytarabine
   Pivotal Trial (Burris, JCO 1997)
   126 patients randomized:
         Gem 1000mg/m2 IV qwk 7/8, then 3/4
         5-fu 600mg/m2 IV qwk
   Treatment was blinded to patients, not to investigators
   Primary efficacy measure= Clinical benefit response
   Composite of pain, KPS and weight
   Clinical benefit required improvement >= 4 weeks
   RR, TTP, OS
Gemcitabine
   No confirmed objective responses
   Clinical benefit response 23.8% in Gem arm,
        4.8% in 5-fu arm (P= .0022)
   Median survival 5.65 vs. 4.41 mos (P= .0025)
Gemcitabine Combinations
   Gemcitabine has been combined with many other
    active cytotoxic agents:
         5-fu
         Cisplatin
         Docetaxel
         Oxaliplatin
         Irinotecan
         Etc…


    No survival benefit has been seen over
                   Gem alone
Nieto, The Oncologist, 2008
Molecularly targeted
      therapy
(Hochster, Cancer 2006)
Nieto, The Oncologist, 2008
Targeting EGFR
Gemcitabine + Cetuximab
   SWOG S0205 (Philip, ASCO 2007)
   Phase III study, 735 patients
Targeting VEGF
Gemcitabine + Bevacizumab
   Overexpression of VEGF/VEGFR are common
   Phase II data promising for Gem/Bev combo
   Phase III trial from CALGB 80303




    (Kindler, ASCO 2007)
Gemcitabine + Erlotinib
   Expression of EGFR is common, poor prognosis
   Phase III study from NCIC (Moore, JCO 2007)
   569 patients randomized to:
       Gemcitabine 1000mg/m2 weekly +/-
       Erlotinib 100mg po daily
   Few objective responses (8.6 vs. 7.9%)
   Overall survival 6.2 vs. 5.9 mos favoring
    combination
   1-yr survival 23 vs. 17% (p=.023)
   Adjusted HR for death in erlotinib 0.82 (p=.038)
   FDA approved in 2005 in combination with
    gemcitabine
(Moore, JCO 2007)
Gemcitabine + Erlotinib


   1st evidence of a survival benefit of EGFR-
    TKI plus chemotherapy in any form of
    cancer
   1st Phase III trial to demonstrate significant
    improvement in survival beyond that seen
    with Gemcitabine alone in pancreatic cancer
Ongoing Trials

   Orathecin (rubitecan)- Oral Topo I inhibitor
   GV1001- Telomerase peptide vaccine
   AG-013736- Oral VEGFR/PDGFR-B inhibitor
   Sorafenib- Oral Raf/VEGFR/PDGFR-B/CKIT
   Aflibercept- VEGF Trap
   AZD0530- Oral Abl/Src kinase inhibitor
   PTK787/ZK 222584- VEGFR-TKI
   Romidepsin (Depsipeptide)- HDAC inhibitor
   MGCD0103 (MG-0103)- HDAC inhibitor
Conclusions


   Pancreatic cancer remains a clinical challenge
   Current therapies offer only modest benefits
   Numerous studies incorporating new,
    targeted agents have offered little/no benefit
    over Gemcitabine alone.
   Rationally-designed combinations based on
    tumor biology may be more effective.
   Clinical trials

				
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