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  • pT1 10 nodes, pT2 20, pT3 30 nodes
  • Over 80% of patients received cisplatin-based chemotherapy and 5040 cGy of radiationTiming of biopsies not discerned in the study

ASCO 2010 Review: Gastric and Esophageal Cancer ASCO 2010 Review: Gastric and Esophageal Cancer Presentation Transcript

  • Recent Advances in the Treatment of Gastric and Esophageal Cancers
    Jeffrey S. Rose, MD
    The Ohio State University
    October 8, 2010
  • Esophageal and Gastric Cancer Incidence (US)
    Esophageal Cancer 2010
    16,640 new cases, 14,500 deaths
    89% fatality rate
    Over 70% adenocarcinoma
    Gastric Cancer 2009
    21,130 new cases, 10,620 deaths
    50% fatality rate
    Increasing incidence of cardia tumors
    American Cancer Society
  • Incidence (cont)
    SEER database: 1975-2004
    White males
    463% increase in incidence of adenocarcinoma
    1.01-5.69/100,000
    50% decrease in SCC
    White females
    335% increase in incidence of adenocarcinoma
    0.17-0.74/100,000
    29% decrease in SCC
    Brown. JNCI 2008
  • What’s New: Gastroesophageal Junction Cancer Staging
    AJCC 6 staging guideline has been criticized as a poor predictor of survival
    Emphasizes the importance of depth of invasion (T) and the involvement of lymph nodes based on anatomic location
    Multiple studies demonstrate the number of involved lymph nodes may better predict survival
  • What’s New: Gastroesophageal Junction Cancer Staging
    Retrospective review of 336 patients with resected ACA and SCC at MSKCC compared AJCC 6 staging with # of involved lymph nodes
    Rizk N, et al. J Thorac Cardiovasc Surg. 2006.
  • Nodal Status Matters
    Rizk N, et al. J Thorac Cardiovasc Surg. 2006.
  • Survival Improves if >18 Lymph Nodes Removed
    Rizk N, et al. J Thorac Cardiovasc Surg. 2006.
  • Staging: WECC/AJCC 7
    Essential changes:
    Inclusion of tumor grade
    Addition of N1, N2 and N3 based on # of LN involved (1-3, 4-6 or >6)
    M1 changed to nonregional lymph node involvement or distant metastasis
  • Staging: WECC/AJCC 7
    Stage 0: T0N0M0, Any Grade; TisN0M0, Any Grade
    Stage IA:T1N0M0, Grade 1-2
    Stage IB: T1N0M0, Grade 3-4; T2N0M0, Grade 1-2
    Stage IIA: T2N0M0, Grade 3-4
    Stage IIB: T3N0M0/T0-2N1M0, Any Grade
    Stage IIIA: T0-2N2M0, Any Grade; T3N1M0, Any Grade; T4aN0M0, Any Grade
    Stage IIIB: T3N2M0, Any Grade
    Stage IIIC: T4aN1-2M0, Any Grade; T4bAnyNM0, Any Grade; Any TN3M0, Any Grade
    Stage IV: AnyTAnyNM1, Any Grade
  • Staging: WECC/AJCC 7 Validation for GEJ ACA
    Single institution cohort at MDACC comparing WECC/AJCC 7 to both gastric and esophageal AJCC 6 staging systems
    449 GEJ ACA patients (Siewert I-III) treated with neoadjuvant therapy followed by surgery or surgery alone
    All staging systems predictive
    For GEJ ACA: WECC/AJCC 7 > AJCC 6 Esoph > AJCC 6 Gastric
    CONCLUSION: Incorporating the number of positive lymph nodes within the staging system appears to better predict survival
    Gaur P, et al. Ann Thorac Surg. 2010.
  • Assessment of Response Following Neoadjuvant Therapy-Biopsy
    Endoscopic biopsy after CRT has been used to determine response
    156 patients at MSKCC received CRT for local-regionally advanced esophageal cancer -> biopsy -> resection
    118 patients had no tumor identified on endoscopic biopsy:
    69% had local disease at time of surgery
    Negative biopsy better predicted a pCR for squamous cell carcinoma versus adenocarcinoma (54.3% vs 13.6% P< 0.001).
    Nodal status of surgical specimens did not correlate
    Survival was equivalent
    CONCLUSION: A negative endoscopic biopsy is not a useful predictor of a pCR after CRT, final nodal status, or overall survival
    Sarkaria IS, et al. Ann Surg. 2009.
  • Assessment of Response Following Neoadjuvant Therapy-PET/CT
    PET is useful in restaging after CRT to exclude distant metastasis
    Multiple studies are looking at prognostic value after CRT or chemotherapy
    Preliminary results suggest that PET/CT can potentially be a prognosticator for OS, but data on meaningful prediction of response are lacking
  • Assessment of Response Following Neoadjuvant Therapy-PET/CT
    Retrospective analysis of 152 patients with Esoph/GEJ ACA treated with CRT and surgery
    >52% SUV decrease was associated with improved OS (43% vs 72% at 3 y)
    Pathologic response with <50% residual cancer associated with longer OS
    % SUV decrease not associated
    In multivariate analysis, SUV decrease only prognostic factor of OS
    Javeri H et al. Cancer. 2009
  • Assessment of Response Following Neoadjuvant Therapy-PET/CT
    Javeri H et al. Cancer. 2009
  • Assessment of Response Following Neoadjuvant Therapy
    CONCLUSIONS:
    No role for repeat endoscopy with biopsy
    PET/CT useful for excluding distant disease, but not ready as a prognostic test
  • Definitive Therapies:CROSS Study: Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric junction cancer: Results from a multicenter randomized phase III study
    A. V. Gaast, P. van Hagen, M. Hulshof, D. Richel, M. I. van Berge Henegouwen, G. A. Nieuwenhuijzen, J. T. Plukker, J. J. Bonenkamp, E. W. Steyerberg, H. W. Tilanus, CROSS Study Group
  • Phase III study comparing preoperative chemoradiotherapy (CRT) followed by surgery versus surgery in patients with esophageal or GE junction cancer (T2-3/N0-1)
    Preoperative CRT with weekly paclitaxel 50 mg/m2 and carboplatin AUC = 2 for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery versus surgery
    363 pts were enrolled with adeno/squamous/other carcinoma 273/86/4
    CROSS Study
  • CROSS Study
  • Overall Survival
  • Preoperative CRT-ACA
  • Preoperative CRT-SCC
  • Neo-adjuvant CRT: Conclusion
    Neo-adjuvant CRT/trimodality therapy is the standard of care for resectable ACA of the esophagus
    CRT alone may be sufficient for certain patients with SCC
    Surgery aids in decrease of local recurrence, but does not improve survival
    Herskovic A et al. N Engl J Med 1992;26:1593-98, Tepper JE et al. ASCO 2006, Gaast AV et al. ASCO 2010
  • Advanced Disease
    Last Year, We Were “On Target”. One Year Later?
    Yes, with Herceptin
    Probably, with Cetuximab
    No, with Avastin
  • CALGB 80403 / ECOG 1206: Randomized Phase II Study of Standard Chemotherapy + Cetuximab for Metastatic Esophageal Cancer
    PC Enzinger, BA Burtness, DR Hollis,
    D Niedzwiecki, DH Ilson, AB Benson 3rd,
    RJ Mayer, RM Goldberg
  • Background
    Cetuximab: a chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor (EGFR)
    EGFR expression in ~80% (30-90%) esophageal cancer, ~40% gastric cancer
    EGFR expression correlates with prognosis in esophagogastric ACA and SCC
    KRAS mutations occur in ~2% (0-9%) of esophageal cancers
    Mukaida. Cancer 1991; Itakura. Cancer 1994; Yacoub. Mod Pathol 1997; Torzewski. Anticancer Res 1997; Koyama.
    J Cancer Res Clin Oncol 1999; Lea. Carcinogenesis 2006
  • Background
  • ARM A: (ECF + cetuximab); 1 cycle = 21 days
    Cetuximab 400  250mg/m2 IV, weekly
    Epirubicin 50 mg/m2 IV, day 1
    Cisplatin 60mg/m2 IV, day 1
    Fluorouracil 200mg/m2/day, days 1-21
    ARM B: (IC + cetuximab); 1 cycle = 21 days
    Cetuximab 400  250mg/m2 IV, weekly
    Cisplatin 30 mg/m2 IV, days 1 and 8
    Irinotecan 65 mg/m2 IV, days 1 and 8
    Stratification:
    ECOG 0-1 vs 2
    ADC vs. SCC
    ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days
    Cetuximab 400  250mg/m2 IV, weekly
    Oxaliplatin 85 mg/m2 IV, day 1
    Leucovorin 400 mg/m2, day 1
    Fluorouracil 400 mg/m2 IV bolus, day 1
    Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)
    Treatment Schema
    Primary endpoint RR
  • Progression-Free Survival
    Median PFS:
    ECF-C 5.9
    IC-C 5.0
    FOLFOX-C 6.7
  • Overall Survival
    Median OS:
    ECF-C 11.5
    IC-C 8.9
    FOLFOX-C 12.4
  • P
    -
    value
    p=0.03
    p=0.03
    p=0.05
    p=0.05
    p=0.06
    p=0.06
    4%
    17%
    17%
    Pain
    Pain
    9%
    9%
    1%
    1%
    3%
    3%
    Pulmonary
    Pulmonary
    4%
    4%
    1%

    1%

    0%
    0%
    Vascular
    Vascular
    6%
    6%
    7%
    7%
    4%
    4%
    p=0.01
    Death; no CTCAE defined
    Death; no CTCAE defined
    6%
    6%
    0%
    0%
    0%
    0%
    Total (
    Heme
    + Non
    -
    Heme
    )
    Total (
    Heme
    + Non
    -
    Heme
    )
    75%
    75%
    86%
    86%
    79%
    79%
    P
    -
    value
    ECF
    -
    C
    ECF
    -
    C
    IC
    -
    C
    IC
    -
    C
    FOLFOX
    -
    C
    FOLFOX
    -
    C
    Non
    -
    Hematologic
    Non
    -
    Hematologic
    66%*
    66%*
    77%**
    77%**
    65%
    65%
    Constitutional symptoms
    Constitutional symptoms
    13%
    13%
    18%
    18%
    17%
    17%
    Dermatologic
    Dermatologic
    16%
    16%
    11%
    11%
    19%
    19%


    Gastrointestinal
    Gastrointestinal
    28%
    28%
    42%
    42%
    22%
    22%
    Infection
    Infection
    13%
    13%
    8%
    8%
    7%
    7%
    Metabolic
    Metabolic
    16%
    16%
    34%
    34%
    22%
    22%
    Neurologic
    Neurologic
    12%
    12%
    4%
    p=0.01
    * Includes 4 deaths
    ** Includes 2 deaths
    † Indicates a death
    Toxicity
  • Response
    Survival
    Response
    Survival
    ECF
    41-45%
    8.9-9.9 mos
    ECF-C
    57.8%
    11.5 mos
    IC (Phase II)
    57-58%
    9-14.6 mos
    IC-C
    45.6%
    8.9 mos
    FOLFOX
    40-41%
    7.1-10.7 mos
    FOLFOX-C 53.6%
    12.4 mos
    15%
    -10%
    Vs.
    2.5mo
    -2mo
    *Lorenzen. Ann Oncol 2009
    Discussion: Is there a signal for cetuximab in esophageal cancer?
  • Conclusions
    All 3 regimens > 40% RR
    IC-C: appeared to have lowest response and survival & most adverse events
    ECF-C: appeared to have highest response, but highest treatment-related mortality and most treatment-related modifications
    FOLFOX-C: good response and survival and best tolerated
  • EOX
    REAL 3*
    EOX + Panitumumab
    Cape / Cis
    EXPAND**
    Cape / Cis + Cetuximab
    * http://clinicaltrials.gov/ct2/show/NCT00824785
    **http://clinicaltrials.gov/ct2/show/NCT00678535
    Studies on the Horizon
  • AVAGAST: a randomized, double-blind placebo- controlled, phase III study of first-line capecitabine and cisplatin + bevacizumab or placebo in patients with advanced gastric cancer (AGC)
    Y-K Kang, A Ohtsu, E Van Cutsem, SY Rha, A Sawaki, SR Park, H-Y Lim, J Wu, B Langer, MA Shah on behalf of AVAGAST investigators
  • Rationale for Bevacizumab in AGC
    Angiogenesis important for tumor growth, progression and metastases
    Bevacizumab:
    Humanized monoclonal antibody to VEGF
    Promising results in Phase II studies in AGC
    Shah et al. 2006
  • R
    AVAGAST: A Randomized Double-Blind, Placebo- Controlled Phase III Study
    Capecitabine*/Cisplatin (XP)
    + Placebo q3w
    Locally advanced
    or metastatic gastric cancer
    Capecitabine*/Cisplatin (XP)
    + Bevacizumab q3w
    Primary endpoint OS
    Cape 1000mg/m2 oral bid, d1–14, 1-week rest
    Cisplatin 80mg/m2 d1
    Bevacizumab 7.5 mg/kg d1
    Maximum of 6 cycles of cisplatin
    Cape and bevacizumab/placebo until PD
  • Overall Response
  • Progression-Free Survival
    XP + Placebo
    XP + Bev
    1.0
    0.9
    0.8
    0.7
    HR = 0.80
    95% CI 0.68–0.93
    p = 0.0037
    0.6
    0.5
    0.4
    6.7
    0.3
    0.2
    5.3
    0.1
    0.0
    12
    0
    15
    18
    21
    24
    3
    9
    6
    Study month
    387
    387
    279
    306
    145
    201
    86
    123
    55
    71
    32
    38
    3
    3
    15
    11
    0
    0
    XP + Placebo
    XP + Bev
  • Overall Survival
    XP + Placebo
    XP + Bev
    1.0
    0.9
    0.8
    0.7
    HR = 0.87
    95% CI 0.73–1.03
    p = 0.1002
    0.6
    0.5
    12.1
    0.4
    0.3
    10.1
    0.2
    0.1
    0.0
    12
    0
    15
    18
    21
    24
    3
    9
    6
    Study month
    271
    291
    146
    178
    98
    104
    15
    19
    54
    50
    0
    0
    343
    355
    204
    232
    387
    387
    XP + Placebo
    XP + Bev
  • Regional Differences in Efficacy
  • Conclusions
    Primary endpoint of OS not met
    Secondary efficacy endpoints (PFS, best ORR) significantly improved, indicating clinical activity of bev + chemo in AGC
    Apparent greater benefit in America>Europe>Asia
    No unexpected / new safety signals for bev
    Further analysis ongoing, including preplanned biomarker analysis
  • Other Therapeutic Options in Advanced Disease
    GE junction:
    FLO vs FLOT (abs 4013)
    Improved PFS, RR, not OS
    Increased, but expected, toxicity
    DCF vs Modified DCF (abs 4014)
    Improved PFS, RR and OS
    53% vs 30% hospitalized for toxicity
    Gastric:
    Granite-1 study looking at Everolimus. 56% DCR in phase II study.
    TOGA: QoL not affected
  • Conclusions
    Cetuximab looks promising, not ready for clinical practice (REAL-3/EXPAND)
    No role for Bevacizumab in gastric cancer
    All patients with gastric and GEJ ACA should have her2neu status assessed
    DCF active but still toxic, even when modified and administered with GCSF
  • Thank You and GO BIG RED!