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Gastrointestinal Cancers - NCCTG Patient Advocates

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					Gastrointestinal Cancers

      Steven R. Alberts, MD
        Medical Oncology
Overview
   Frequency of GI Cancers
   Esophageal and Stomach Cancer
   Pancreatic Cancer
   Liver Cancer
   Colon and Rectal Cancer
Esophageal and Stomach
Cancer
Adenocarcinoma of the Esophagus -
An Evolving Story

   Progressive decline in stomach cancer
    since early 1900’s
   Recent dramatic increase in
    adenocarcinomas of the esophagus and
    gastroesophageal junction
Esophagus and GE Junction
Occurrence of Esophageal and
Gastric Cancer

   New Cases in 2006
       Esophagus 14,550
            Men 11,260
            Women 3,290
       Stomach 22,280
            Men 13,400
            Women 8,880
       One-third of stomach cancers from GE
        Junction and Cardia
    Jemal A, et al. CA Cancer J Clin 56:106-1309, 2006
Cancer Deaths in the US, 1930-2002
        Esophageal Cancer Incidence Trends
            SEER, 1974-78 to 1994-98
                                                  Male                                                   Female
                                            20                                                      20
                                                                    >350-fold increase in
                                            10                                                      10
                                                                        esophageal
           Rate per 100,000 person-years




                                             5                                                      5
                                                                      adenocarcinoma

                                                                     Squamous Cell Carcinoma - Black
                                             1                       Squamous Cell Carcinoma - White 1
                                                                     Adenocarcinoma - White
                                                                     Adenocarcinoma - Black
                                            0.5                                                    0.5




                                            0.1                                                    0.1


                                           0.05                                                   0.05



                                           0.02                                                   0.02
Brown & Devesa,                               1970 1980 1990 2000                                    1970 1980 1990 2000
2002                                          Year of diagnosis                                         Year of diagnosis
                                Age-Specific Incidence Rates
                           30
                                White Males, SEER, 1995-1999

                           25
                                                                                              Esophageal
Incidence per 100,000 py




                                                                                              adenoca

                           20
                                                                                              Gastric cardia
                                                                                              adenoca
                           15
                                                                                              Esophageal
                                                                                              squamous cell
                           10


                            5


                            0
                                40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84   85+
    Progression of
Esophageal Adenocarcinoma

Gastroesophageal Reflux Disease

Metaplasia/Barrett’s Esophagus

     Low Grade Dysplasia

     High Grade Dysplasia

       Adenocarcinoma
   Population Attributable Risks
              U.S. Multicenter Study


Risk Factor                   PAR (95% CI)

Smoking: ever                 40   (26-56)
BMI: upper 3 quartiles        41   (24-61)
Reflux symptoms               30   (20-42)
Fruits & vegetables           15   (6 -35)
   (<2 times/day)
All factors combined          79   (67-87)
Engel LS, et al. JNCI 2003.
Helicobacter pylori
Blaser MJ. J Infect Dis, vol 179, pp 1523-30.
    5-year survival for patients
      with esophageal cancer

   Stage   I: 79%
   Stage   IIA: 38%
   Stage   IIB: 27%
   Stage   III: 14%
   Stage   IV: 5%
Treatment for Advanced Stage
Cancer
Chemotherapy
   Multiple options for metastatic
    disease
       5-FU/CDDP, ELF, FAMTX, FAM, ECF, etc
       Survival and quality of life benefit for
        chemotherapy (7.5+ - 12 mo) versus best
        supportive care (3 - 4 mo) in 4 randomized
        trials
        (Ann Oncol 8:163-8, 1997)
Stomach Cancer -
Chemotherapy
   ECF - Current “Standard” Therapy
       Epirubicin 50 mg/m2 day 1
       Cisplatin 60 mg/m2 day 1
       5-FU 225 mg/m2/day days 1-21
ECF
      EOX
Treatment for Early Stage
Cancer
Stomach Cancer - Surgery
   Subtotal or total gastric resection
   Limited (D0, D1) or extended (D2)
    lymph node dissection
   Japanese extended radical
    lymphadenectomy
       5-year survival rate reportedly increased
        from 20% to 30-50%
Adjuvant Chemoradiotherapy
   Intergroup 0116
       Randomized trial of adjuvant
        chemotherapy and radiation versus
        observation
       Patients undergoing curative resection for
        stomach or gastroesophageal junction ACA

         (Proc Am Soc Clin Oncol 19:1a, 2000)
    Postoperative Therapy – INT
    0116
       Randomization after potentially curative
        surgery


    Observation


R
    5-FU + LV x        Radiation     5-FU + LV x
    1 cycle            + 5-FU        2 cycle
Adjuvant Chemoradiotherapy
   Intergroup 0116 Outcome
       3.3 years of median follow-up
                            Adjuvant   Observation
    3-year overall survival   49%        32%
      (p=0.001)
    median survival (mos)     42         27   (p=0.03)


       44% improvement in relapse free survival
        and 28% improvement in median survival
    CALGB 80101: Adjuvant therapy
    after Resection of Gastric or GEJ ACA


     5-FU/CF        CI 5-FU + RT      5-FU/CF x 2

R
        ECF        CI 5-FU + RT         ECF x 2



     534 eligible patients required to detect a 30%
     improvement in overall survival (alpha  0.05)
    Magic Study: Neoadjuvant ECF

R
A             ECF X3         Surgery      ECF X3
  N = 250
N
D
O
M
I N = 250       Surgery
Z
E Patients with resectable distal esophageal and gastric
  adenocarcinoma
            Survival
                   1.0

                   0.9
                                                      Logrank p-value = 0.009
                   0.8                                 Hazard Ratio = 0.75
                   0.7                                  (95% CI 0.60 - 0.93)
                   0.6

                   0.5

                   0.4

                   0.3
                             Events Total
                   0.2       149     250          CSC
                             170     253          S
                   0.1

                   0.0
                         0      12       24           36         48   60   72
Patients at risk                        Months from randomisation
          CSC        250       168          111       79        52    38   27
          S          253       155          80        50        31    18   9
Esophageal and Stomach
Cancer
   Summary
       Benefit from chemotherapy in both
        curative and non-curative settings
       Role of radiation in curative setting unclear
       Need to test new targeted agents
Pancreatic Cancer
Occurrence of Pancreatic Cancer

   New Cases in 2006 – 33,730
   Deaths in 2006 – 32,300

    Jemal A, et al. CA Cancer J Clin 56:106-1309, 2006
Pancreatic Cancer -
Classification
   Histologic Type
       Carcinoma                 90-95%
            Adenocarcinoma
            Adenosquamous carcinoma
            Cystadenocarcinoma
            Mucinous carcinoma
            Giant cell carcinoma
       Islet cell          5%
       Acinar cell       1-2%
       Lymphoma and sarcoma
Pancreatic Carcinoma
   Less than 25% of patients will have
    potentially resectable tumors
       50% of surgical patients undergo curative
        resection
   50-70% recurrence rate after resection
    Pancreatic Cancer Treatment
   Resectable                    Not resectable
(10-15% of cases)



                Locally advanced               Metastatic
                    ( 40% of patients)   ( 45-50% of patients)

   Surgery
± adjuvant RT         Radiotherapy                 CT
   and CT             Chemotherapy                BSC
                        RT + CT
Metastatic Pancreatic Cancer
Pancreatic Carcinoma -
Gemcitabine
   Phase III Trial: Gemcitabine vs 5-FU
    Primary end-point: Improvement in disease-
    related signs and symptoms
            Gemcitabine group: 63 patients
            5-FU group: 63 patients


    (H. A. Burris et al. J Clin Oncol. 1997;15(6):2403-13)
Pancreatic Carcinoma -
Gemcitabine
   Phase III Trial: Gemcitabine vs 5-FU
    Primary end-point
                                    Gemcitabine       5-FU
            Decrease in pain     23.8%      4.8%
                                   (p=0.0022)
           No differences seen in weight gain or PS

    (H. A. Burris et al. J Clin Oncol. 1997;15(6):2403-13)
Pancreatic Carcinoma -
Gemcitabine
   Phase III Trial: Gemcitabine vs 5-FU

       Secondary end-points
          Tumor Response

                            Gemcitabine 5-FU
           Partial response    5.4%      0%
           Stable disease     39.0%     19%


        (H. A. Burris et al. J Clin Oncol. 1997;15(6):2403-13)
Pancreatic Carcinoma -
Gemcitabine
   Phase III Trial: Gemcitabine vs 5-FU
    Secondary end-points
            Survival
                                              Gemcitabine    5-FU
             Median (months)                     5.65        4.41
             Progression free                    2.33        0.92

    (H. A. Burris et al. J Clin Oncol. 1997;15(6):2403-13)
Gemcitabine in Combination
with Other Agents
Chemotherapy              Targeted Agents
     Oxaliplatin             Erlotonib
     Cisplatin               C-225
     5-Fluorouracil          Bevacizumab
     Capecitabine            PS-341
Resected Pancreatic Cancer
Pancreatic Cancer - Adjuvant
Therapy
   Chemoradiation
       5-Fluorouracil
       External beam radiation
       Median survival
            Surgery alone: 10.9 months
            Chemoradiation: 21 months
    Postoperative Therapy –
    RTOG 9704
       Benefit limited to head of pancreas
        cancers
                                    Overall Survival
                                    20.6 months

                       Radiation    5-FU x 3 weeks
    5-FU x 3 weeks
                       + 5-FU       (3 cycles)

R                                   16.9 months

    Gemcitabine x 3    Radiation    Gemcitabine x 3
    weeks              + 5-FU       weeks (3 cycles)
Pancreatic Cancer
   Summary
       Chemotherapy of limited benefit in both
        curative and non-curative settings
       Desperate need for new agents
Liver and Biliary Tract Cancers
Liver and Biliary Tract Cancers
   New Cases in 2006 – 27,080
   Deaths in 2006 – 19,460
Hepatocellular Carcinoma -
Epidemiology

   Approximately 350,000 new cases/year
    worldwide
   Males account for 2/3 of all cases
   70 percent of all HCC occurs in Asia
Hepatocellular Carcinoma -
Epidemiology

      Incidence of HCC in U.S. varies by ethnic/racial group
       (rate per 100,000)
       Group              Male Female
       White               2.39    1.02
       Black               4.85    1.58
       Japanese            5.86    2.42
       Chinese            11.68 3.76
       Korean             20.06 3.92

SEER
Hepatocellular Carcinoma -
Risk Factors

   Hepatitis B Virus (HBV)
   Hepatitis C Virus (HCV)
   Aflatoxins
   Alcohol
   Oral Contraceptives
Hepatocellular Carcinoma -
Risk Factors

   Risk Factors (%) by Region

Risk Factor       U.S.       Japan   Africa
HBV               10-15       20       60
HCV                 60        50      <10
Aflatoxin            0         0     Important
Alcohol           10-15       20        ?
OBC                 10
Hepatocellular Carcinoma -
Hepatitis B

   Development of HCC

    - 70-90% develops in background of cirrhosis
    - 10-40% of regenerative nodules appear to be
      monoclonal
    - Cirrhosis is not required
    - Long interval between infection and
      development of HCC
Hepatocellular Carcinoma -
Hepatitis C

   Greater degree of inflammation and hepatocyte turnover
    than seen with HBV
   Time from infection to cirrhosis:
     21 + 10 years
   Time from infection to HCC:
    29 + 13 years
   Annual incidence of HCC in HCV-related cirrhosis: 4-7%
   No documented childhood cases
Hepatocellular Carcinoma -
Treatment

   Primary resection: 15-30%
    - 5-year survival 27-49%
    - most important predictor: presence of cirrhosis
   Transplantation: 5-10%
    - small HCC in setting of advanced cirrhosis
    - recurrence most common cause of death
Hepatocellular Carcinoma -
Treatment

   Chemoembolization
   Percutaneous ethanol injection
   Cryosurgery
   Radiofrequency ablation
   Chemotherapy
Biliary Tract Cancers
   Account for about one-third of “liver”
    cancers
   Appear to be increasing in frequency
   Etiology unclear
       Primary sclerosing cholangitis
Biliary Tract Cancers
   Treatment options
       Surgery
       Chemotherapy
       Transplant
Biliary Tract Cancers
   Surgery
       60-80% recurrence after surgery
       Postoperative radiation and/or
        chemotherapy of limited benefit
Biliary Tract Cancers
   Chemotherapy
       Gemcitabine
           20% response rate
           Overall survival: 10 months
Biliary Tract Cancers
   Liver Transplant
       80% survival at 5 years
            Mayo series using pretransplant chemotherapy
             and radiation
       Only 40-50% of potential patients make it
        to surgery
Liver Cancers
   Summary
       Limited treatment options
       Frequent problem of underlying liver
        disease
       Care generally requires coordinated
        multidisciplinary care
Colon and Rectal Cancer
Annual Age-adjusted Cancer Incidence
Rates US, 1975 to 2002
Cancer Deaths in the US, 1930-2002
Colorectal Cancer
   New cases in 2006 – 148,610
       Men: 72,800
       Women: 75,810
   Deaths in 2006 – 55,170
                     CRC Stage at Diagnosis

              21% Stage IV                                          14% Stage I




                                                                                  28% Stage II
                                     37% Stage III



Treatment Algorithms: Colorectal Cancer 5th Edition. Datamonitor 2003.
Stage IV Colon Cancer
   Spread of colon cancer beyond colon and
    local lymph nodes
   “Incurable”
   Goals of treatment
       Palliation
       Increased life expectancy
NCI Treatment Guidelines
   Resection or bypass of obstructing mass
   Surgical resection of isolated metastases
   Palliative chemotherapy and/or radiation
    therapy
   Clinical trials
Evolution of Therapy

     Era of 5-Fluorouracil (5-FU)
         1950’s thru 1980’s
Stage IV Colon Cancer: 5-FU
   Role of 5-FU for metastatic disease
   5-FU + Leucovorin
       No previous Rx: 23%
       Median survival: 12 months
   Toxicity, grade > 3
       Stomatitis: 26%
       Diarrhea: 15%
                                     Meta-Analysis, JCO, 1992
Evolution of Therapy

   Era of New Chemotherapy Agents
               1990’s
     Randomized Comparison
                                      IFL
Stratification:          R   CPT-11: 125 mg/m2/wk x 4 wks, q 6 wks
                         A     5FU: 500 mg/m2/wk x 4 wks, q 6 wks
 PS (0 vs 1, 2)         N      LV: 20 mg/m2/wk x 4 wks, q 6 wks
                         D
 Age
                         O            Mayo 5-FU/LV
  (< 65 yr vs > 65 yr)
                         M
                                5FU: 425 mg/m2/d x 5 d, q 4 wks
 Time from initial      I       LV: 20 mg/m2/d x 5 d, q 4 wks
  diagnosis              Z
  (< 6 mo vs > 6 mo)     A
                         T
 Prior adjuvant         I            Weekly CPT-11
  therapy                O   CPT-11: 125 mg/m2/wk x 4 wks, q 6 wks
  (yes vs no)            N
Saltz Trial - Median Survival

                CPT-11/5-FU/LV   5-FU/LV     CPT-11

                     N=231               N=226
N=226
Median (mo)            14.8       12.6           12.0

Log-rank test        p=0.04
New Agents – Oxaliplatin
   Initially developed in Europe
   Response rate as a single agent: 10%
   Response when combined with 5-FU
    and leucovorin: 28-53%
    Cost-Effectiveness Analysis of
    FOLFOX4 vs IFL in N9741
R          IFL:
A     Irinotecan +
N                             IFL     FOLFOX      p-value
         5-FU/LV
D
O                     OS    15.0 mo   19.5 mo     0.0001
M      FOLFOX4:
I     Oxaliplatin +   TTP    6.9 mo    8.7 mo     0.0014
Z       5-FU/LV
A                     RR     31%       45%        0.002
T
I         IROX:
O     Irinotecan +
                             795 patients
N      oxaliplatin

                                    Goldberg et al, JCO 2004
Evolution of Therapy

         The 21st Century
Targeted Agents and Individualized
             Therapy
The New Revolution in Cancer
Care

   Plateau in benefits of chemotherapy
   Recognition that not all tumors and not
    all people are built the same
      Agents Targeting the VEGF Pathway

    Anti-VEGF
                                       VEGF                           Soluble
    antibodies
                                                                       VEGF
   (bevacizumab)
                                                                     receptors
                                                                   (VEGF-TRAP)


                                                                   Anti-VEGFR
                                                                    antibodies
                                                                    (IMC-1121b)
                            P      P          P     P
                            P      P          P     P
                           VEGFR-1            VEGFR-2
                                                                 Small-molecule
                             Endothelial cell                   VEGFR inhibitors
                                                           (PTK787, SU-11248, AZ2171)

VEGF Educational Resource Network Slide Curriculum; Reprinted with permission from the
                          Health Science Center for Continuing Medical Education, NY.
   Bevacizumab in
   First-Line MCRC (AVF2107g)
                 R
                 A       IFL + placebo
                             (N=411)                     PD
                 N
                 D
   Previously    O    IFL + bevacizumab
untreated MCRC   M       (5 mg/kg, q2w)                  PD
    (N=923)      I           (N=402)
                 Z
                 A
                 T   5-FU/LV + bevacizumab
                 I       (5 mg/kg, q2w)                  PD
                 O           (N=110)
                 N
                       Primary endpoint:
                             Survival

                       Hurwitz et al. N Engl J Med. 2004;350:2335.
     Efficacy: 2 Arms
                              IFL +            IFL +
                             Placebo        Bevacizumab
                            (N=411)           (N=402)               P Value

Median survival (mo)          15.6                20.3               <0.001


PFS (mo)                      6.24                10.6               <0.001

ORR (%)                        35                   45                0.004


Duration of response (mo)     7.1                 10.4                0.001

                                     Hurwitz et al. N Engl J Med. 2004;350:2335.
Cetuximab Inhibits Binding of EGF and Other Ligands

   Cetuximab Mechanism of Action
                        Blocks receptor dimerization,
             Antibody   tyrosine kinase phosphorylation,
              Binds
                        and signal transduction




                                         Receptor
                                       Internalized
CALGB/SWOG 80405: Proposal for Phase III
First-line Therapy of Metastatic CRC



                                   Cetuximab
“Dealer’s Choice”
      FOLFOX                      Bevacizumab
      FOLFIRI

                                  Cetux + Bev

 • Primary endpoint: OS
• 6 different treatment options
  Achievements and Goals in the Treatment of
  Advanced Colorectal Cancer

BSC 1980s
5-FU/LV 1990s
5-FU/LV/CPT 2000
5-FU/LV/Oxali 2000
FOLFOX/ FOLFIRI
FUFOX 2001

FOLFOX/FOLFIRI
+ targeted therapy                           median
                                             overall
                                            survival
                     0   6   12   18   24   (months)
Stage 0 and I Colon Cancer
   Limited penetration of the colon
   No lymph node involvement
   Expected survival after surgery of over 80
    percent
Stage II Colon Cancer
   Penetration trough the wall
   No lymph node involvement
   Expected recurrence rate 10 to 30 percent
Treatment Guidelines
   NCI
       Partial colectomy
       Consider clinical trial
   Mayo
       Partial colectomy
       Adjuvant chemotherapy for high risk patients
    Colon Stage II – Adjuvant
    E5202: High Risk Stage II (Open)
                    Expect 2 weeks
                   for tissue review
                                           mFOLFOX6
              High Risk
R             • MSS + 18q LOH          R
e             • MSI-L + 18q LOH
g                                           mFOLFOX6
i    Tumor block                           + bevacizumab
      assessment
s
     for 18q/MSI
t
e
              Low Risk
r
              • MSS, no 18q LOH
              • MSI-L, no 18q LOH          Observation
              • MSI-H +/- 18q LOH
Stage III Colon Cancer
   Any depth of penetration into or through the
    wall
   Lymph node involvement
   50 to 75 percent risk of recurrence
NCI Treatment Guidelines
   Partial colectomy
   Adjuvant therapy or clinical trial
  Prognostic Factors
                    DNA ploidy        CEA    Surgical skill

   Dendritic cell                                    Socioeconomic
      counts                                             status

  Alleles:                                                      Perforation
CCND1 870A                                                      Occlusion
BRCA1 LOH
                                                              No. of nodes
                                                               examined
    Invasion:
      Depth                                               No. of nodes
    Lymphatic
                                       Mutations:           positive
     Venous
    Perineural                            p53
                                                    MSI/ MSS
     Serosal
                    Differentiation      K-ras
                                                    LOH 18q
                                         Mad2
    Estimates of 5 year DFS (%) with
    Surgery

  Nodal             T stage   Low Grade High Grade
  Status
                               S          S
  0 nodes            T3       74          70
                     T4       63          57
                    T1-T2     71          67
  1-4 nodes          T3       53          46
                     T4       37          30
                    T1-T2     51          44
  > 5 nodes          T3       27          21
                     T4       13           9
7 studies; n=3341                       Gill et al, JCO 2004
                     Disease-free Survival (ITT)
                     Stage II and Stage III Patients
                     1.0
                     0.9
                     0.8                                                                 3.5%
                     0.7
   DFS probability




                     0.6                                                                 8.6%
                     0.5
                                                              7.2%
                     0.4
                     0.3       HR [95% CI]:                          FOLFOX4 – 451 Stage II
                     0.2       0.82 [0.60 – 1.13] Stage II           LV5FU2 – 448 Stage II
                               0.75 [0.62 – 0.89] Stage III          FOLFOX4 – 672 Stage III
                     0.1
                                                                     LV5FU2 – 675 Stage III
                     0.0
                           0    6    12    18    24    30      36   42   48   54   60   66
Data cut-off: January 16, 2005                        Months
Ongoing US Cooperative Group Trials Adjuvant
Therapy of Colon Cancer

Intergroup N0147
                        mFOLFOX6 6m
  Stage III colon
  cancer (N=2300)
                       mFOLFOX6 6m +
                        Cetuximab 6m


  NSABP C-08
                        mFOLFOX6 6m
  Stage II/III colon
  cancer (N=2700)
                       mFOLFOX6 6m +
                       Bevacizumab 12m
Colorectal Cancer
   Summary
       Dramatic improvements in the last decade
       Many patients with metastatic disease
        living for more than 2 years
       Increasing chance for cure

				
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