1、Advances in Pancreatic Cancer JIANGSU CANCER HOSPITAL MEDICAL ONCOLOGY DEPARTMENT CHEN JIA 2010.4.26 Epidemiology Risk Factors Clinical Presentation Surgical Management and Adjuvant Strategies Systemic Therapy for Advanced Disease Cytotoxic Combinations Targeted Therapy Outline Jemal A, et al. CA Ca
2、ncer J Clin. 2007;57:43-66. Fourth leading cause of cancer death in North America 2007 estimated deaths in United States: 33,370 Peak incidence in 7th and 8th decades of life Average age at diagnosis: 60-65 years Slightly higher incidence in men vs women (RR: 1.35) Higher incidence (by 30% - 40%) in
3、 African American men Epidemiology of Pancreatic Cancer Adapted from: American Cancer Society. Cancer Facts 57:43-66. Pancreatic cancer accounts for 2% of cancer cases (and 6% of cancer deaths) per year in the United States1 Incidence and death rates due to pancreatic cancer remain stable Mortality
4、rates parallel incidence 2006: 33,730 new cases and 32,300 deaths Few long-term survivors Poor responses to combined modality treatment High risk of recurrence following surgery Pancreatic Cancer: Scope of the Clinical Problem Pancreatic Cancer: Scope of the Clinical Problem (contd) 5-year survival:
5、 5-year history of diabetes mellitus, type II Familial syndromes Account for 15% to 20% of cases2 1 family member affected: 18 times risk3 3 family members affected: 57 times risk Pancreatic Cancer: Risk Factors (contd) 1. Yeo TP, et al. Principles and Practice of Oncology, 7th ed. 2006;26:176-275.
6、2. Klein AP, et al. Cancer J. 2001;7:266-273. 3. Harrisons Principles of Internal Medicine. 16th ed. Syndrome Molecular/Genetic Defect Hereditary pancreatitis 7q35 Hereditary nonpolyposis colorectal cancer (Lynch syndrome II) hMSH2, hMLH1 Hereditary breast and ovarian cancer BRCA2 Familial atypical
7、multiple mole melanoma (FAMM) p16 (9p21) Peutz-Jeghers syndrome STK11/LKB1 (19p13) Ataxia-telangiectasia (ATM) syndrome 11q22-23 Klein AP, et al. Cancer J. 2001;7:266-273. Familial Syndromes Component Symptom Local Epigastric/back pain Constitutional Fatigue Anorexia Weight loss Biliary obstruction
8、Jaundice Pruritus Pale stools Pancreatic insufficiency Malabsorption Symptom complex is vague, which often delays presentation and diagnosis Majority (80%) of patients present with unresectable disease Pancreatic head tumors may present earlier Patients develop jaundice due to biliary obstruction Cl
9、inical Presentation AJCC Staging TUMOR Tis: in situ carcinoma T1: 2 cm T3: beyond pancreas T4: involves celiac axis or superior mesenteric artery (unresectable) NODE N0: no lymph node metastases N1: regional lymph node metastases METASTASES M0: no distant metastases M1: distant metastases present St
10、age 0 Tis, N0, M0 Stage IA T1, N0, M0 Stage IB T2, N0, M0 Stage IIA T3, N0, M0 Stage IIB T1-3, N1, M0 Stage III T4, any N, M0 Stage IV Any T, any N, M1 unresectable AJCC Cancer Staging Manual, 6th ed. . 1. Yeo CJ, et al. Ann Surg. 2002;236:355-366. Curative If patient is considered resectable, preop
11、erative tissue diagnosis is not required Even in experienced centers, morbidity can be 40% to 50%1 Mortality rates 5% Palliative bypass Helps delay complications from malignant biliary and small bowel obstruction Performed in patients planned for curative surgery deemed unresectable intraoperatively
12、 (usually because of peritoneal metastases) Surgery in Pancreatic Cancer: Two Main Approaches Surgery in Pancreatic Cancer: Curative Procedures Whipple procedure or pancreaticoduodenectomy Pylorus-sparing surgery Right-sided tumors Distal pancreatectomy Islet cell tumors (tail, body of pancreas) Tot
13、al pancreatectomy No survival advantage, more morbidity1 Lillemoe KD. Ann Surg. 1995;221:133-148. Surgery in Pancreatic Cancer: Palliative Procedures1 Gastrojejunostomy For patients (up to 20%) who develop gastric outlet obstruction Hepato- or choledochojejunostomy For biliary obstruction Cholecysto
14、jejunostomy Not recommended because of high rates of reobstruction Liu YB, et al. World J Gastroenterol. 2006;12:765-767. A Role for Adjuvant Therapy? Rationale for local and systemic treatment modalities in adjuvant setting Surgical failure (ie, disease recurrence) is common 80% of patients will de
15、velop progressive disease within 12 months of surgery1,2 Disease progression occurs both locally and in distant sites 1. Mu DQ, et al. World J Gastroenterol. 2004;10:906-909. 2. Shibata K, et al. Pancreas. 2005;31:69-73. GITSG1 Survival advantage for chemoradiation followed by 5-FU for 1 year, but E
16、arly termination, and Slow accrual (43 patients in 8 years) EORTC2 No survival benefit for chemoradiation, but no maintenance chemotherapy 1. Kaiser MH, et al. Arch Surg. 1985;120:899-903. 2. Klinkenbijl JH. Ann Surg. 1999;230:776-782. Adjuvant Therapy: Historical Lack of Consensus 1. Neoptolemos JP
17、, et al. NEJM. 2004;350:1200-1210. 2. Oettle H, et al. J Am Med Assoc. 2007;297:267-277. Two recent randomized clinical trials demonstrated benefit ESPAC-11 N = 289 (4-arm study also evaluating chemoradiation) Observation vs 5-FU/LV (Mayo) 5-year survival: 8% vs 21% (P = .009) CONKO-0012 N = 368 Obs
18、ervation vs gemcitabine (Days 1, 8, and 15 of 4-week cycle x 6 months) Disease-free survival: 6.9 vs 13.4 months 5-year disease-free survival: 5.5% vs 16.5% Adjuvant Chemotherapy ESPAC-1: Survival CONKO-001: Disease-Free Survival Oettle H, et al. J Am Med Assoc. 2007;297:267-277. Adjuvant Chemothera
19、py: Outcomes Neoptolemos JP, et al. NEJM. 2004;350:1200-1210. Months CumulativeDisease Free Survival 100% 75% 50% 25% 0% 0 100% 75% 50% 25% 0% 12 24 36 48 60 72 Chemotherapy No chemotherapy Months Survival (%) 84 72 60 48 36 24 12 0 observation gemcitabine Patients with pancreatic adenocarcinoma who
20、 have undergone potentially curative resection (N = 289) Observation (n = 69) Chemoradiotherapy 20 Gy to tumor over 2 weeks plus 5-FU 500 mg/m2 on Days 1-3 of radiotherapy x 2 cycles (n = 73) Chemotherapy Leucovorin 20 mg/m2 plus 5-FU 425 mg/m2, Days 1-5 of 28 x 6 cycles (n = 75) Combination Chemora
21、diotherapy Chemoradiotherapy followed by chemotherapy, administered as above (n = 72) Neoptolemos JP, et al. NEJM. 2004;350:1200-1210. Adjuvant Chemoradiotherapy: ESPAC-1 Study Adjuvant chemoradiotherapy: lower median survival vs no chemoradiotherapy Median Survival No chemoradiotherapy: 17.9 months
22、 Chemoradiotherapy: 15.9 months HR: 1.28 (95% CI: 0.99-.66); P = .05 Neoptolemos JP, et al. NEJM. 2004;350:1200-1210. Adjuvant Chemoradiotherapy: ESPAC-1 Study 0 100 75 50 25 0 12 24 36 48 60 72 Months Survival, %Chemoradiotherapy No chemoradiotherapy Conventional cytotoxic agents 5-FU Gemcitabine C
23、ombination regimens Targeted therapies EGFR inhibitors Antiangiogenic agents Systemic Therapies Gemcitabine Antimetabolite prodrug Inhibits DNA synthesis Intracellular conversion into 2 active metabolites with complementary mechanisms of action Diphosphate: blocks thymidylate synthase (thereby inhib
24、iting conversion of cytosine to deoxy derivative) Triphosphate: blocks incorporation of thymidine nucleotides into DNA F F O O N N NH2 HO HO Gemcitabine: Common Adverse Events Myelosuppression Paraesthesias Rash Abnormal liver enzyme levels Gemcitabine vs 5-FU in Unresectable Pancreatic Cancer: Clin
25、ical Trial Design Gemcitabine 1000 mg/m2 weekly x 7, off x 1, then weekly x 3 of 4 weeks (n = 63) 5-FU 600 mg/m2 weekly (n = 63) Patients with untreated, unresectable pancreatic cancer (75% stage IV), KPS 80, morphine 10 mg/d, MPAC pain intensity score 20 (N = 126) Burris HA, et al. J Clin Oncol. 19
26、97;15:2403-2413. Gemcitabine vs 5-FU in Unresectable Pancreatic Cancer: Outcomes *Clinical benefit response (primary study outcome) is a composite score of pain, performance status, and weight. Burris HA, et al. J Clin Oncol. 1997;15:2403-2413. Outcomes in gemcitabine arm vs 5-FU arm Clinical benefi
27、t response:* 23.8% vs 4.8% (P = .002) Median survival time: 5.7 vs 4.4 months (P = .003) 1-year overall survival rate: 18% vs 2% Log-rank test P = .0009 Gemcitabine (n = 63) 5-FU (n = 63) Overall survival at 1 year Gemcitabine: 18% 5-FU: 2% Median overall survival Gemcitabine: 5.65 months 5-FU: 4.41
28、 months Burris HA, et al. J Clin Oncol. 1997;15:2403-2413. Gemcitabine vs 5-FU in Unresectable Pancreatic Cancer: Overall Survival 0 100 2 4 6 8 10 12 Survival Time (Months) % PatientsSurviving14 16 18 20 90 80 70 60 50 40 30 20 10 0 Many regimens have been evaluated Platinum agents Taxanes Topoisom
29、erase inhibitors Fluoropyrimidines (oral and intravenous) Large, well-designed, randomized clinical trials No significant improvements in outcomes Cytotoxic Combinations With Gemcitabine Study Drug Regimen Response Rate, % Median Survival, mos 1-Year Survival, % Rocha Lima CM, et al1 Gem alone vs ge
30、m + irinotecan 4.4 16.1 6.6 6.3 22 21 Oettle H, et al2 Gem alone vs gem + pemetrexed 7.1 14.8 6.3 6.2 20 21 Louvet C, et al3 Gem alone vs gem + oxaliplatin 17.3 26.8 7.1 9.0 28 35 Colucci G, et al4 Gem alone vs gem + cisplatin 9.2 26.4 5 7.5 NA 1. Rocha Lima CM, et al. J Clin Oncol. 2004;22:3776-3783. 2. Oettle H, et al. Ann Oncol. 2005;16:1639-1645. 3. Louvet C, et al. J Clin Oncol. 2005;23:3509-3516. 4. Colucci G, et al. Cancer. 2002;94:902-910. Gemcitabine Combination Regimens
