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Cco Gi 2008 Cr Slideset Cco Gi 2008 Cr Slideset Presentation Transcript

  • January 25-27, 2008 Orlando, Florida CCO Independent Conference Coverage of the 2008 Gastrointestinal Cancers Symposium* *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from
  • About These Slides
    • These slides accompany CCO’s online Independent Conference Coverage of the 2008 Gastrointestinal Cancers Symposium
    • Our thanks to the presenters who gave permission to include their original data
    • The full program is available on the Clinical Care Options for Hematology/Oncology Web site: clinicaloptions.com/GI2008
    • Users are encouraged to use these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
    • These slides may not be published or posted online without permission from Clinical Care Options
    Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
    • Alan P. Venook, MD Professor of Clinical Medicine Department of Hematology and Oncology Division of Medical Oncology University of California, San Francisco San Francisco, California
    Faculty Participating in Slide Development
  • Contents
    • Colorectal Cancers
    • Esophageal and Stomach Cancers
      • Esophageal cancers
      • Gastric Cancer
      • Gastrointestinal Stromal Tumors (GIST)
    • Pancreas, Small Bowel, and Hepatobiliary Tract Cancers
      • Pancreatic Cancer
      • Hepatocellular Carcinoma
      • Cholangiocarcinomas
  • Colorectal Cancers
  • PACCE Trial: Oxaliplatin Arm Patients with metastatic colorectal cancer and ECOG ≤ 1 (N = 823) Oxaliplatin-CT (eg, FOLFOX)/ Bevacizumab + Panitumumab (n = 413) Interim analysis at 231 PFS events Panitumumab discontinued Oxaliplatin-CT (eg, FOLFOX)/ Bevacizumab (n = 410) Median follow-up: 54 weeks Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273.
  • PACCE Trial Oxaliplatin Arm: PFS Median (Months) Ox-CT/Bev + Pmab Ox-CT/Bev 0 2 4 6 8 12 10 Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273. 11.1 9.6 59 52 PFS Events, % 1.27 (1.05-1.53) Ox-CT/Bev + Pmab -- Ox-CT/Bev HR (95% CI) Regimen
  • PACCE Trial Oxaliplatin Arm: Toxicity
    • More serious adverse events reported with panitumumab plus oxaliplatin chemotherapy/bevacizumab
      • Skin toxicity most frequent
    Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273. 38 60 Any serious adverse event Grade 3/4 toxicity < 6 17
    • Dehydration
    24 24
    • Neutropenia
    4 < 6 10 13 1 Ox-CT/Bev ( n = 397) 10 11 18 24 36 Ox-CT/Bev + Pmab (n = 407)
    • Nausea
    Grade 3/4 Toxicity, %
    • Skin toxicity
    • Diarrhea
    • Infections
    • Low potassium
  • PACCE Trial Oxaliplatin Arm: Summary
    • Adding panitumumab to oxaliplatin chemotherapy with bevacizumab did not prolong PFS
      • 9.6 (panitumumab) vs 11.1 months (no panitumumab)
    • Trend toward inferior PFS and OS
    • Toxicity frequent in both arms; incidence of serious adverse events higher with oxaliplatin chemotherapy/ bevacizumab/panitumumab
      • 60% (panitumumab) vs 38% (no panitumumab)
    • Majority of patients in both arms withdrew from study due to nonprogressive events
    Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273.
  • PACCE Trial Irinotecan Arm Patients with metastatic colorectal cancer and ECOG ≤ 1 (N = 230) Irinotecan chemotherapy (eg FOLFIRI)/ Bevacizumab (n = 115) Irinotecan chemotherapy (eg FOLFIRI)/ Bevacizumab + Panitumumab (n = 115) Median follow-up: 9 months Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279.
  • PACCE Trial Irinotecan Arm: PFS Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279. PFS Events, n (%) Median, mos (95%CI) 54 (47) 43 (37) 10.1 (8.2-13.7) 11.7 (9.0-13.2) Pmab + Bev/Iri-CT Bev/Iri-CT HR: 1.21 (95% CI: 0.80-1.82)* *Descriptive only Censored No Pmab Censored Pmab 115 74 23 7 1 0 0 0 0 4 1 2 7 6 6 23 32 34 19 76 29 0 0 115 0 5 10 15 20 25 Months 0 20 40 60 80 100 Patients (%)
  • PACCE Trial Irinotecan Arm: Toxicity
    • More serious adverse events when panitumumab added to irinotecan chemotherapy/bevacizumab
    • Skin toxicity most frequent
    Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279. Grade 3/4 toxicity 33 54 Any serious adverse event 9 14
    • Infections
    21 17
    • Neutropenia
    4 6 6 9 0 Iri-CT/Bev ( n = 113) 11 12 14 28 37 Iri-CT/Bev + Pmab (n = 111 )
    • Nausea
    Toxicity, %
    • Skin toxicity
    • Diarrhea
    • Dehydration
    • Low potassium
  • PACCE Trial Irinotecan Arm: Summary
    • Adding panitumumab to irinotecan chemotherapy and bevacizumab did not prolong PFS
      • 10.1 (panitumumab) vs 11.7 months (no panitumumab)
    • Toxicity frequent in both arms; incidence of serious adverse events higher in patients receiving panitumumab
      • 54% (panitumumab) vs 33% (no panitumumab)
    Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279.
  • FFCD 2001-02 Trial: 5-FU ± Irinotecan
    • One arm of a 2-arm of randomized phase III trial compared 5-FU/irinotecan with 5-FU alone in frontline therapy in elderly patients (75 years of age or older) with metastatic colorectal cancer
      • Interim descriptive analysis (N = 142 patients followed ≥ 8 weeks)
    • Response by RECIST criteria high with a 5-FU/irinotecan regimen compared with 5-FU alone in frontline therapy
      • ORR: 88% for 5-FU/irinotecan vs 69% for 5-FU alone
    • PD more prevalent in 5-FU-alone arm
      • 25% for 5-FU vs 9% for 5-FU/irinotecan
    • 60-day mortality: 12.7%
      • Primary cause of death: disease progression
    Mitry E, et al. GI Cancers Symposium 2008. Abstract 281.
  • FFCD 2001-02 Trial: Toxicity
    • Neutropenia and diarrhea more frequent in 5-FU/ irinotecan arm
    • Toxicity manageable, investigators concluded
    Mitry E, et al. GI Cancers Symposium 2008. Abstract 281. 48 16 Any grade 3/4 toxicity 98 93 Any adverse event 57 57 Death 16 9 28 5-FU/IR (n = 67) 0 1 1 5-FU (n = 75 ) Toxicity, %
    • Neutropenia
    • Neutropenia with fever
    • Diarrhea
  • CONcePT Trial Design Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280. Patients with metastatic colorectal cancer (N = 140) *Treat to failure. † 8 cycles with oxaliplatin, 8 cycles without oxaliplatin, 8 cycles with oxaliplatin. Continuous Oxaliplatin* mFOLFOX7 + bevacizumab + placebo (n = 34) Continuous Oxaliplatin* mFOLFOX7 + bevacizumab + Ca 2+ /Mg 2+ (n = 35) Intermittent Oxaliplatin † mFOLFOX7 + bevacizumab + placebo (n = 36) Intermittent Oxaliplatin † mFOLFOX7 + bevacizumab + Ca 2+ /Mg 2+ (n = 35)
  • CONcePT Trial Results: Sequentially Confirmed* Responses
    • Trend toward better response with intermittent oxaliplatin compared with continuous oxaliplatin dosing (evaluable patients)
      • OR: 1.96 (95% CI: 0.86-4.54; P = .089)
    Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280. 21 36 45 43 46 48 48 39 32 16 7 18 0 25 50 75 100 Placebo Ca+/Mg+ Placebo Ca+/Mg+ Continuous Oxaliplatin Intermittent Oxaliplatin PD SD PR *Responses confirmed by RECIST criteria on sequential assessments. Patients, %
  • CONcePT Trial: Summary
    • Prophylactic Ca 2+ /Mg 2+ did not influence tumor response
    • Trend toward shorter time to first response with prophylactic Ca 2+ /Mg 2+
      • 32.7 weeks with placebo vs 24.0 weeks with Ca 2+ /Mg 2+
    • Trend toward higher response rates with intermittent oxaliplatin (intent-to-treat population)
      • Without Ca 2+ /Mg 2+ : 45% (intermittent) vs 21% (continuous)
      • With Ca 2+ /Mg 2+ : 34% (intermittent) vs 29% (continuous)
    • Results on peripheral sensory neuropathy pending
    Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280.
  • X-ACT Trial Design Twelves C, et al. GI Cancers Symposium 2008. Abstract 274. Bolus 5-FU/Leucovorin 5-FU 425 mg/m 2 + LV 20 mg/m 2 on Days 1-5, every 28 days (n = 983) Capecitabine 1250 mg/m 2 twice daily on Days 1-14, every 21 days (n = 1004) Chemotherapy-naive patients with operable stage III colorectal cancer and resection ≤ 8 weeks (N = 1987) Median follow-up: 6.8 years
  • X-ACT Trial: 5-Year DFS Twelves C, et al. GI Cancers Symposium 2008. Abstract 274. 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Months 0 0.2 0.4 0.6 0.8 1.0 Test of noninferiority: P < .0001 Test of superiority: P = .0682 Estimated Probability HR: 0.88 (95% CI: 0.77-1.01) NI margin: 1.20 Capecitabine (n = 1004) 5-FU/LV (n = 983) 5-Year DFS 60.8% 56.7% ITT population
  • X-ACT Trial Key Findings
    • Trend toward superior 5-year DFS and OS with capecitabine treatment
      • DFS: 60.8% vs 56.7% ( P = .0682)
      • OS: 68.4% vs 71.4% ( P = .06)
    • Hand-foot syndrome common toxicity with capecitabine
      • Associated with higher DFS and OS
      • Possible clinical marker for optimal capecitabine exposure
    Twelves C, et al. GI Cancers Symposium 2008. Abstract 274.
  • Adherence to Follow-up Guidelines After Curative Resection
    • Guidelines
      • ≥ 2 office visits each year
      • ≥ 2 CEA tests each year
      • > 1 colonoscopy within 3 years
      • Yearly CT scans for poorly differentiated cancer
    • Medicare claims evaluated between 1992 and 2001
      • Adherence to guidelines between 6 and 42 months after diagnosis
      • 33,906 patients identified
    Cooper GS, et al. GI Cancers Symposium 2008. Abstract 284.
    • 9.9% of patients met guidelines
    • 77.2% did not meet guidelines
    • 12.9% of patients were in excess of guidelines; met guidelines but also had CT scan for other level of differentiation and/or PET scan
    • Older age and local stage cancer predicted under use of guidelines
    Adherence to Follow-up Guidelines: Results Cooper GS, et al. GI Cancers Symposium 2008. Abstract 284. 0 20 40 60 80 100 Office Visits Colonoscopy CES CT Poorly Differentiated CT Other Level of Differentiation PET Scan Patients, %
  • KRAS Status and Response to Panitumumab: Phase III Trial Analysis Amado RG, et al. GI Cancers Symposium 2008. Abstract 278. Panitumumab 6 mg/kg every 2 weeks + Best Supportive Care (n = 231) Best Supportive Care* (n = 232) Colorectal cancer patients stratified by ECOG 0-1 vs 2 and region (N = 463) *Optional crossover to panitumumab upon disease progression.
  • PFS by KRAS Status and Treatment Amado RG, et al. GI Cancers Symposium 2008. Abstract 278.
    • The relative effect of panitumumab vs best supportive care was significantly greater in patients with WT vs mutant KRAS
    • The quantitative-interaction test comparing the magnitude of the relative treatment effect on PFS between WT and mutant KRAS was statistically significant ( P < .0001)
    • PFS was significantly greater for panitumumab treatment compared with best supportive care in the WT KRAS group (stratified log-rank test: P < .0001).
    Mutant KRAS WT KRAS Pmab + BSC BSC alone 7.4 7.3 HR: 0.99 (95% CI: 0.73-1.36) Proportion Event Free Weeks 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 HR: 0.45 (95% CI: 0.34-0.59) Stratified log-rank test: P < .0001 Proportion Event Free Weeks 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Pmab + BSC BSC alone 12.3 7.3 Median PFS Median PFS
  • OS by KRAS Status and Treatment Amado RG, et al. GI Cancers Symposium 2008. Abstract 278. Median OS (Months) 8.1 7.6 4.9 4.4 0 2 4 6 8 10 WT KRAS WT KRAS Mutant KRAS Mutant KRAS Pmab BSC Pmab BSC
  • KRAS Mutation Status and Response to Panitumumab: Summary
    • OS shorter in patients with KRAS mutation regardless of treatment
      • HR: 0.67 (95% CI: 0.55-0.82)
    • Incidence of disease progression following panitumumab nearly 2-fold higher in patients with mutant KRAS
      • 70% for mutant KRAS vs 36% for WT KRAS
    • Panitumumab monotherapy appears effective only in patients WT KRAS
    • KRAS mutational status does not influence PFS following best supportive care
    • KRAS genotyping recommended for metastatic colorectal cancer patients
    Amado RG, et al. GI Cancers Symposium 2008. Abstract 278.
  • Circulating Tumor Cells Predict Survival
    • Baseline CTCs in metastatic colorectal cancer patients entering new systemic therapy predicts PFS and OS
    Cohen SJ, et al. GI Cancers Symposium 2008. Abstract 299. < .0001 9.5 23.6 .0008 5.6 8.5 187 ECOG PS 0 .0155 9.4 15.0 .0738 4.7 7.0 210 ECOG PS 1-2 .0001 12.1 23.1 .0880 7.7 8.7 213 Age < 65 yrs .0005 10.5 18.6 .0178 6.3 8.6 235 Bevacizumab < .0001 7.4 14.8 < .0001 2.8 7.1 200 Age ≥ 65 yrs < .0001 6.2 14.8 .0016 2.3 5.4 117 Second/third-line treatment .0001 5.9 15.9 < .0001 2.3 6.7 99 Irinotecan 18.1 17.3 21.2 < 3 CTC Median OS, Mos 11.6 9.5 11.6 ≥ 3CTC .0008 < .0001 .0001 P Value Median PFS, Mos Oxaliplatin Liver metastasis First-line treatment Parameter 242 302 296 n .1200 7.5 8.7 4.2 6.3 ≥ 3CTC .0002 .0246 P Value 8.5 8.7 < 3 CTC
  • Genes Predictive for Colon Cancer Recurrence
    • NSABP C-01/C-02 observational arm (N = 765)
    • Patients treated with surgery alone
    • 59 genes prognostic for disease recurrence
      • Up to an 11-fold difference in risk between individual expressed genes
      • Genes involved in a number of biological pathways including cell cycle regulation, cell proliferation, and invasion
    • Multigene algorithm developed and will be validated
    Lavery I, et al. GI Cancers Symposium 2008. Abstract 302.
  • Insurance Status and Colorectal Cancer Stage at Diagnosis
    • Analysis of data from National Cancer Data Base
    • N = 493,419; 50 years of age or older
    • Uninsured and Medicaid patients 100% and 50%, respectively, more likely to be diagnosed with late-stage colorectal cancer
    Halpern MT, et al. GI Cancers Symposium 2008. Abstract 275 0.0 0.5 1.0 1.5 2.0 2.5 Uninsured Medicaid Medicare < 65 Yrs Medicare > 65 Yrs Stage II vs I Stage III/IV vs I OR for Advanced-Stage Colorectal Cancer Diagnosis
  • Insurance Status and Colorectal Cancer Stage at Diagnosis: Summary
    • Uninsured and Medicaid patients at risk for late-stage colorectal cancer diagnosis
    • Supplementing Medicare with private insurance reduces this risk
    • Groups more likely to be diagnosed with advanced-stage colorectal cancer include
      • Blacks
      • Females
      • Persons with low socioeconomic or education status
      • Persons receiving care at nonteaching/research hospitals
    • Underserved populations need better access to screening and better screening
    Halpern MT, et al. GI Cancers Symposium 2008. Abstract 275
  • Esophagus and Stomach Cancers
  • Barrett’s Esophagus and Metabolic Syndrome
    • N = 180: 102 Barrett’s Esophagus and 78 GERD
    • Mean age 56 years
    Power DG, et al. GI Cancers Symposium 2008. Abstract 2. Patients (%) 0 20 40 60 80 100 BMI > 25 Central Adiposity DeMeester Score Metabolic Syndrome Elevated CRP Barrett’s Esophagus GERD P = .007 P = .05 P = .04
  • Barrett’s Esophagus and Metabolic Syndrome: Summary
    • Metabolic syndrome prevalent in Barrett’s Esophagus (46%) and GERD (32%) patients
    • High prevalence of long segment Barrett’s Esophagus (> 3 cm) in patients with
      • Central adiposity (93%)
      • Metabolic syndrome (62%)
      • BMI > 30 (42%)
      • Hyperinsulinemia (20%)
      • Elevated IL-4 (4%)
    • Inflammation and insulin resistance due to metabolic syndrome may contribute to Barrett’s Esophagus progression to adenocarcinoma
    Power DG, et al. GI Cancers Symposium 2008. Abstract 2.
  • OE02 Update: Design Allum WH, et al. GI Cancers Symposium 2008. Abstract 9. Preoperative Chemotherapy Then Surgery Cisplatin 80 mg/m 2 on Day 1 + 5-FU 1 g/m 2 /day for 4 days, two 4-day courses 3 weeks apart (n = 400 ) Patients with resectable esophageal cancer (N = 802) Median follow-up: 5.9 years Surgery Alone (n = 402) Median follow-up: 6.1 years
  • OE02 Update: DFS
    • DFS from randomization + 6 months
    Allum WH, et al. GI Cancers Symposium 2008. Abstract 9. 02 00 121 162 83 115 65 85 50 67 41 54 32 41 26 33 17 21 8 14 No. at risk 0.75 1.00 0.50 0.25 0 Survival 0 1 4 6 8 9 Years DFS by Treatment Arm HR: 0.82 (95% CI: 0.71-0.95; P = .003) Chemotherapy then surgery Surgery alone Surgery alone Chemotherapy then surgery 7 5 2 3
  • OE02 Update: Results
    • 5-year OS
      • 17% surgery alone vs 23% chemotherapy then surgery ( P = .03)
    • Survival rates dependent on resection status but not histology
    • 3-year survival by MRC
      • R0: 42%
      • R1: 18%
      • R2: 9%
      • Unresected: 1%
    Allum WH, et al. GI Cancers Symposium 2008. Abstract 9. Survival by Resection Status (All Patients) Survival Rate Months From Randomization R0 R1 R2 Unresected 1.0 0.8 0.6 0.4 0.2 0 0 12 24 36 48 60 72 84 96 108 120
  • JCOG 9907: Study Design Ando N, et al. GI Cancers Symposium 2008. Abstract 10. Treatment-naive patients aged younger than 75 years with squamous cell carcinoma of thoracic esophagus, T1-3/N0-1/M0, and ECOG PS 0-2 (N = 330) 5-FU/Cisplatin 5-FU 800 mg/m 2 on Days 1-5 Cisplatin 80 mg/m 2 on Day 1 (n = 164) Surgery Transthoracic esophagectomy with lymphadenectomy ≥ D2 (n = 166) Postoperative chemotherapy Preoperative chemotherapy Surgery Transthoracic esophagectomy with lymphadenectomy ≥ D2 5-FU/Cisplatin 5-FU 800 mg/m 2 on Days 1-5 Cisplatin 80 mg/m 2 on Day 1
  • JCOG 9907: PFS, OS Ando N, et al. GI Cancers Symposium 2008. Abstract 10. Second Interim Analysis Unadjusted 2-sided log-rank P = .013 HR by Cox model: 0.64 (95% CI: 0.45-0.91; P = .014) Unadjusted 1-sided stratified Log- rank P = .0444 > .0254 (alpha) HR: 0.76 (94.91% CI: 0.56-1.04) OS Postop 5-yr OS: 38.4% Preop 5-yr OS: 60.1% Years After Randomization 0 1 2 3 4 5 6 7 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 PFS Postop median PFS: 2 yrs Preop median PFS: 3 yrs Years After Randomization 0 1 2 3 4 5 6 7 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
  • JCOG 9907: Summary
    • Survival benefit with preoperative chemotherapy
    • Fewer patients in postoperative chemotherapy arm received chemotherapy
      • 70.5% postoperative vs 88.4% preoperative
    • 2-fold greater incidence of grade 3/4 mucositis and leucopenia in postoperative chemotherapy group
    • Preoperative chemotherapy provided greater benefit for patients with stage II disease
    • Preoperative chemotherapy led to downstaging and R0 resection and therefore is recommended for patients with resectable (stage II/III) esophageal cancer
    Ando N, et al. GI Cancers Symposium 2008. Abstract 10.
  • Second-Line Cetuximab in Esophageal Cancer: SWOG Phase II Trial
    • Survival benefit of second-line cetuximab in patients with metastatic esophageal adenocarcinoma
    • Cetuximab treatment regimen
      • Initial dose: 400 mg/m 2 IV
      • Subsequent doses: 250 mg/m 2 IV over 1 hour every 7 days
    • Adverse events observed in 64% of patients
      • Considered manageable
      • Approximately 50% of patients had dose modification
    Gold PJ, et al. GI Cancers Symposium 2008. Abstract 96.
  • Second-Line Cetuximab in Esophageal Cancer SWOG Phase II Trial: Results
    • Primary endpoint — 23 patients surviving > 6 months — not met
    • 6-month survival rate: 36%
    Gold PJ, et al. GI Cancers Symposium 2008. Abstract 96. 4 1.8 1.8 0 1 2 3 4 OS PFS TTF Months 0 20 40 60 80 100 Not evaluable PD SD PR Response Rate (%) 5% 7% 11% 76% N = 55
  • Phase III IRIS Study: Design Imamura H, et al. GI Cancers Symposium 2008. Abstract 5. S-1 Oral Fluoropyrimidine 80 mg/m 2 /day on Days 1-28, every 6 weeks (n = 160) Patients aged 20-75 years with nonresectable and advanced gastric cancer and ECOG PS 0-2 (N = 315) Irinotecan + S-1 (IRIS) Irinotecan 80 mg/m 2 /day IV on Days 1 and 15 + S-1 80 mg/m 2 /day given on Days 1-21, every 5 weeks (n = 155 ) Median follow-up 10.4 months Median follow-up 12.6 months
  • Phase III IRIS Study: Response by RECIST
    • 187 patients evaluated for objective response
    • ORR higher in IRIS ( P = .035). ORR represents PR rate—no CR observed
    Imamura H, et al. GI Cancers Symposium 2008. Abstract 5. 27 41 38 43 32 13 0 20 40 60 80 100 S-1 (n = 93) IRIS (n = 94) Not evaluable PD SD PR Response Rate (%)
  • Phase III IRIS Study: Survival Results
    • Higher response rates with IRIS treatment equated to slightly longer time to treatment failure, but not to significantly longer OS
    Imamura H, et al. GI Cancers Symposium 2008. Abstract 5. .2327 12.8 10.5 OS, mos 44.9 3.6 S-1 (n = 160) 52.0 1-yr survival, % .1565 4.5 Time to treatment failure, mos P Value IRIS (n = 155) Outcome
  • AMC 0201 Adjuvant Mitomycin C: Design Kang Y, et al. GI Cancers Symposium 2008. Abstract 6. Mf Mitomycin C 20 mg/m 2 + short-term Doxifluridine 600 mg/m 2 /day x 3 cycles (n = 424) Chemotherapy-naive patients aged 18-70 years with advanced gastric cancer and D2 dissection, M0 (N = 855) MFP Mitomycin C + long-term Doxifluridine x 14 cycles + Cisplatin 60 mg/m 2 on Day 1, every 4 weeks x 6 months (n = 431) Median follow-up 3.2 years Randomization 3-6 weeks postsurgery
  • AMC 0201 Adjuvant Mitomycin C: Recurrence-Free Survival Kang Y, et al. GI Cancers Symposium 2008. Abstract 6. HR: 1.067 (95% CI: 0.845-1.346) Log-rank test: P = .59 Recurrence-Free Proportion Months 0 0 0.2 0.4 0.6 0.8 1.0 12 24 36 48 60 72 MFP Mf 58.1 63.3 5-yr RFS 32.4 31.6 Total recurrence 64.9 67.0 3-yr RFS MFP (n = 431) Mf (n = 424) Outcome, %
  • Adjuvant Mitomycin C: Summary
    • Extending doxifluridine and adding cisplatin to adjuvant mitomycin C safe, but efficacy not improved
    • 5-year recurrence-free survival and OS rates similar between treatment arms
      • Recurrence-free survival: 63.3% in Mf arm vs 58.1% in MFP arm
      • OS: 64.5% in Mf arm vs 64.8% in MFP arm
    • More than 30% of patients in each arm had disease recurrences, the majority of which were distant
    Kang Y, et al. GI Cancers Symposium 2008. Abstract 6.
  • Phase II Trial of Sorafenib in Imatinib- and Sunitinib-Resistant GIST Nimeiri HS, et al. GI Cancers Symposium 2008. Abstract 7. 3 1 2 14 3 11 0 5 10 15 20 Overall (N = 24) IM-RES (n = 6) IM/SU-RES (n = 18) SD PR ORR 71% ORR 67% ORR 72% ORR Patients (n)
    • Conclusions
    • Sorafenib proves active in imatinib- and imatinib/sunitinib- resistant GIST patients
    • Overall sorafenib well tolerated, but dose reductions frequent
    • Accrual ongoing
    Phase II Trial of Sorafenib in Imatinib- and Sunitinib-Resistant GIST: PFS, OS Nimeiri HS, et al. GI Cancers Symposium 2008. Abstract 7. 5.1-open 13.0 Median OS, mos 62 5.3 All Patients (N = 24) 37-78 1-yr survival, % 3.2-open Median PFS, mos 95% CI Survival
  • ACOSOG Z9000: Phase II Study of Adjuvant Imatinib in GIST
    • High-risk GIST patients (N = 107)
      • Multiple lesions or ≥ 10 cm
      • KIT positive
    • Oral imatinib initiated after surgery (median 59 days)
      • 400 mg/day for 12 months
    • No severe adverse events
      • < 20% had grade 3 toxicity
    • Overall survival 99% at 1 year, 97% at 2 years and at 3 years
    • Recurrence-free survival 94% at 1 year, 73% at 2 years, 61% at 3 years
      • Recurrence rate high among patients with KIT exon 9 mutation
    • Recurrence-free survival prolonged vs historical controls
    DeMatteo RP, et al. GI Cancers Symposium 2008. Abstract 8.
  • Imatinib Pharmacokinetics and Response in GIST Patients (Trial B2222) Demetri GD, et al. GI Cancers Symposium 2008. Abstract 3. Imatinib 400 mg/day (n = 73) GIST patients (N = 147) Imatinib 600 mg/day (n = 74 ) Imatinib 800 mg/day Imatinib 800 mg/day PD PD PK data collected prospectively Correlation with clinical outcomes analyzed retrospectively
  • Response to Imatinib in GIST by C min Quartiles Demetri GD, et al. GI Cancers Symposium 2008. Abstract 3.
    • Patients in lowest imatinib exposure quartile (Q1) had shorter TTP (median: 11.3 months) than patients in the upper 3 quartiles (30.6 months; P = .0029)
    • Patients in lowest imatinib exposure quartile (Q1) exhibited somewhat lower rates of clinical benefit (ie, CR + PR + SD) than patients in the upper 3 quartiles
    7 (19) 29 (81) Q2-Q3, n (%) (n = 36) Q4, n (%) (n = 19) Q1, n (%) (n = 18) 3 (16) 6 (33) PD/unknown 16 (84) 12 (67) CR + PR + SD Imatinib C min Quartiles (n = 73) Response
  • Trial B2222: Summary
    • Survival not different between treatment arms
      • Median PFS: 57 months; median OS: 21 months
      • OS varied by KIT exon 11 mutation
        • OS: 63 months with KIT exon 11 and 8 months with no mutation ( P = .005)
    • Trend toward higher rates of clinical benefit with higher imatinib exposure
      • Q1: 67%; Q2/3: 81%; Q4: 84%
    • Higher imatinib exposure provided greater clinical benefit for patients with KIT exon 11 mutation
      • Q1 67% vs Q2/3 + Q4 100% ( P = .009)
    Demetri GD, et al. GI Cancers Symposium 2008. Abstract 3.
  • Pancreas, Small Bowel, and Hepatobiliary Tract Cancers
  • ACOSOG Z05031: Chemoradiation in Resected Pancreatic Cancer Patients
    • Chemoradiation regimen
      • Radiation 5040 cGy/cisplatin/ 5-FU
      • Postchemoradiation 5-FU
    • Phase II study
    • 93 patients planned; 89 patients accrued; 80 evaluable
    • Study accrual terminated due to toxicity concerns
    • Median follow-up: 28 months
    Picozzi VJ, et al. GI Cancers Symposium 2008. Abstract 125. 8
    • Febrile neutropenia
    12
    • Thrombocytopenia
    39
    • Neutropenia
    Hematologic toxicity 24
    • Stomatitis
    30
    • Anorexia
    36
    • Nausea
    Gastrointestinal toxicity 22
    • Vomiting
    25
    • Diarrhea
    27
    • Dehydration
    ACOSOG Toxicity, %
  • Chemoradiation in Resected Pancreatic Cancer Patients: OS Picozzi VJ, et al. GI Cancers Symposium 2008. Abstract 125. 18-month OS 67% 90 100 80 70 60 50 40 30 20 10 0 Survival (%) 0 1 2 3 Time (Yrs) 18-month OS 67%
  • Adjuvant Chemoradiation in Pancreatic Adenocarcinoma
    • Retrospective analysis of 2 patient arms
      • Johns Hopkins (n = 618)
      • Mayo Clinic (n = 474)
    • Patients underwent pancreaticoduodenectomy, followed by chemoradiation or observation
      • One half of the patients (53.4%) received 5-FU – based adjuvant chemoradiation
    • Median OS: 18.8 months
    Hsu CC, et al. GI Cancers Symposium 2008. Abstract 124.
  • Adjuvant Chemoradiation in Pancreatic Adenocarcinoma: Survival Hsu CC, et al. GI Cancers Symposium 2008. Abstract 124. 0 0.8 1.0 0.6 0.4 0.2 Survival, proportion 0 1 2 3 4 5 Follow-up (Yrs) mOS 2-yr OS 5-yr OS CRT 21.1 mo 44.7% 22.3% Obs 15.5 mo 34.6% 16.1% ( P < .001) Observation only (n= 509) Adjuvant chemoradiation (n = 583) RR: 0.74 (95% CI 0.62-0.87)
  • CFTR Mutation and Risk of Pancreatic Cancer
    • CFTR gene mutations associated with other pancreatic diseases; association to pancreatic cancer unknown
    • Case-control study
      • Patients (n = 948) recruited through Mayo Clinic Pancreas Biospecimen Resource from 2000-2006
      • Controls (n = 13,340) derived from prenatal counseling samples
      • Analysis limited to white patients/controls due to higher frequency of CFTR gene mutations
    McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187.
  • CFTR Mutation and Risk of Pancreatic Cancer: Incidence and Age of Onset McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187. CFTR carrier Noncarrier 0 12 24 36 48 60 72 Overall Ever Smokers Never Smokers Age of Pancreatic Cancer Onset (Yrs) 0 2 4 6 8 < 60 < 55 < 50 Incidence of CFTR Mutation (%) Age (Yrs)
  • CFTR Mutation and Risk of Pancreatic Cancer: Summary
    • Carrying just 1 CFTR mutation increases risk for pancreatic cancer
    • Age of onset of pancreatic cancer influenced by smoking in CFTR mutation carriers only
    • Known CFTR carriers should be counseled not to smoke
    McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187.
    • SNPs in 8 genes involved in gemcitabine metabolism
      • Cytidine deaminase ( CDA )
      • Deoxycytidine kinase ( dCK )
      • Ribonucleotide reductase ( RRM1 )
      • Deoxycytidylate deaminase ( DCTD )
      • Human concentrative ( hCNT ) 1, 2, and 3
      • Equilibrative nucleoside transporter ( hENT1 )
    SNPs and Gemcitabine Activity and Toxicity Javle MM, et al. GI Cancers Symposium 2008. Abstract 126.
  • Combined SNP Genotypes and Survival Javle MM, et al. GI Cancers Symposium 2008. Abstract 126. Combined Genotype: hCNT1 (16AA/AG); hCNT2 (17CC); hENT1 (913CC) Number of alleles: P = .008 Combined Genotype: CDA (111C); CDA (76AA); RRM1 (42GG); DCTD (47AG) Number of alleles: P = .052 Cumulative Survival, % 100 80 60 40 20 0 0 20 40 60 80 100 Time (Mos) Cumulative Survival, % 3 1-2 0 100 80 60 40 20 0 0 20 40 60 80 100 Time (Mos) 3 1-2 0
  • SNPs and Gemcitabine: OS by Genotype Javle MM, et al. GI Cancers Symposium 2008. Abstract 126. 0 10 20 30 40 CC CT TT AA AG GG CDA C111T RRM1 G42A Median OS (Mos) n = 48 n = 17 n = 3 n = 15 n = 56 n = 97
  • SNPs and Gemcitabine Activity and Toxicity: Summary
    • Genetic variants of genes involved in gemcitabine metabolism have prognostic value in gemcitabine treatment of pancreatic cancer
    • SNPs associated with lower drug toxicity correlated with poor efficacy
      • CDA 111CC and dCK 1205TT alleles associated with poor survival but a lower incidence of neutropenia
    • Tailored therapy according to genetics on horizon
    Javle MM, et al. GI Cancers Symposium 2008. Abstract 126.
  • Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation
    • Phase II study of preoperative therapy
    • Patients with localized pancreatic cancer (N = 29)
      • ECOG PS 0-1
    Small W, et al. GI Cancers Symposium 2008. Abstract 131. Cycle 1 21 days Gemcitabine Days 1 and 8 1000 mg/m2 Bevacizumab Days 1 and 15 10 mg/kg Cycle 2 28 days Gemcitabine Days 1, 8, and 15 1000 mg/m2 Bevacizumab Days 8 and 21 10 mg/kg Radiotherapy Days 1-5, 8-12, 15-19 Cycle 3 21 days Gemcitabine Days 1 and 8 1000 mg/m2 Bevacizumab Day 8 10 mg/kg
  • Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation Small W, et al. GI Cancers Symposium 2008. Abstract 131. 53 48 36 45
    • 1-yr OS, %
    6 5 4 15
    • Progressed or died, n
    67 50 38 68
    • 6-mo PFS, %
    10.0 11.8 10.2 10.2
    • Median duration, mos
    PFS NA 11.8 10.2 11.8
    • Median duration, mos
    OS 36 50 38 41
    • 1-yr PFS, %
    13 82 All (N = 29) 4 71 Resectable (n = 7) 5 75 Unresectable (n = 12) 4
    • Died, n
    89 Borderline (n = 10)
    • 6-mo OS, %
    Survival
  • Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation
    • Chemoradiation combination of gemcitabine/ bevacizumab/radiation well tolerated
      • Only 1 patient did not complete 3 cycles of therapy
    • Radiographic CR seen in 2 patients
      • CR (2), PR (3), SD (18), PD (5)
    • 6 patients underwent resection; 2 had pathologic CR (33%)
    Small W, et al. GI Cancers Symposium 2008. Abstract 131.
  • SHARP: Sorafenib in Patients With Advanced HCC and HCV Infection Bolondi L, et al. GI Cancers Symposium 2008. Abstract 129.
    • Post hoc analysis of subpopulation in phase III trial of sorafenib vs placebo
    14.0 7.6 44.1 Sorafenib (n = 93) HCV-Positive Patients 7.9 2.8 30.6 Placebo (n = 85) 10.7 5.5 43.5 Sorafenib (n = 299) Overall SHARP Population 2.8 Median TTP, mos 7.9 31.6 Placebo (n = 303) Median OS, mos Disease recurrence, % Outcome
  • Sorafenib in Patients With HCC and Child-Pugh A and B Cirrhosis
    • Phase II study
    • Sorafenib 400 mg twice daily
    • Areas under the curve
      • Child-Pugh A 25.4 mg/hour/L and Child-Pugh B 30.3 mg/hour/L
    Abou-Alfa GK, et al. GI Cancers Symposium 2008. Abstract 140. 0 10 20 30 40 50 TTP OS Child-Pugh A (n = 21) Median (Wks) Child-Pugh B (n = 7)
  • Sorafenib Plus Doxorubicin in HCC Phase II Study: Design Abou-Alfa GK, et al. GI Cancers Symposium 2008. Abstract 128. Treatment-naive patients with advanced HCC, Child-Pugh A, and ECOG PS 0-2 (N = 96) Placebo/Doxorubicin* Doxorubicin 60 mg/m 2 IV every 21 days (n = 49) Sorafenib/Doxorubicin* Sorafenib 400 mg twice daily Doxorubicin 60 mg/m 2 IV every 21 days (n = 47) *After 18 weeks, patients allowed to continue on single-agent sorafenib or placebo until disease progression.
  • Sorafenib Plus Doxorubicin in HCC Phase II Study: Results Abou-Alfa GK, et al. GI Cancers Symposium 2008. Abstract 128. 4.8 6.5 2.8 8.6 13.8 6.9 0 3 6 9 12 15 TTP OS PFS Placebo Sorafenib Median (Mos) ( P = .0129) ( P = .076)
    • Retrospective analysis of SEER database
    Surgery and Adjuvant Radiation in Cholangiocarcinomas (CCA): Survival Shinohara ET, et al. GI Cancers Symposium 2008. Abstract 143. 4 8 12 16 Radiation and Surgery Surgery Radiation No Treatment Extrahepatic CCA Intrahepatic CCA Median OS (Mos) n = 701 n = 1372 n = 475 n = 2210 n = 286 n = 948 n = 396 n = 2209 0
  • Surgery and Adjuvant Radiation in CCA: Prognostic Factors
    • Treatment, race, and stage independent predictors for survival in multivariate analysis for extrahepatic and intrahepatic CCA
    • Year of diagnosis independent predictor of survival for intrahepatic CCA only
    Shinohara ET, et al. GI Cancers Symposium 2008. Abstract 143. 0.59-0.77 0.68 0.58-0.75 0.66
    • Radiation
    0.44-0.54 0.49 0.47-0.57 0.52
    • Surgery
    0.34-0.47 0.40 0.42-0.52 0.47
    • Radiation and surgery
    1.21-1.53 1.31 1.13-1.50 1.30 Black vs white 0.59 0.48 HR Extrahepatic CCA 0.54-0.65 0.43-0.53 95% CI 0.66 0.51 HR Intrahepatic CCA Multivariate Analysis 0.46-0.56 Localized vs distant disease 0.60-0.73 95% CI Regional vs distant disease Treatment vs no treatment Factor
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    • topic areas in gastrointestinal cancers
    • Colorectal Cancers
    • Esophageal and Gastric Cancers
    • Pancreas, Small Bowel, and Hepatobiliary Tract Cancers
    • clinicaloptions.com/GI2008
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