Скачать презентацию Pancreatic Cancer Review Gina Vaccaro MD May 20 Скачать презентацию Pancreatic Cancer Review Gina Vaccaro MD May 20

ad7d9839a03773e4961f9cde3f9c1a04.ppt

  • Количество слайдов: 85

Pancreatic Cancer Review Gina Vaccaro, MD May 20, 2009 Pancreatic Cancer Review Gina Vaccaro, MD May 20, 2009

Outline Anatomy n Histologic types n Epidemiology n Precursor lesions n Presentation n Treatment Outline Anatomy n Histologic types n Epidemiology n Precursor lesions n Presentation n Treatment n

Anatomy of the pancreas De. Pinho, Nature Reviews, 2002 Anatomy of the pancreas De. Pinho, Nature Reviews, 2002

Anatomy of the pancreas De. Pinho, Nature Reviews, 2002 Anatomy of the pancreas De. Pinho, Nature Reviews, 2002

Histology Ductal adenocarcinoma, PDAC (>85%) n Acinar cell carcinoma n Pancreatic Neuroendocrine Tumor n Histology Ductal adenocarcinoma, PDAC (>85%) n Acinar cell carcinoma n Pancreatic Neuroendocrine Tumor n Cystic neoplasms n Other- Lymphoma (NHL) n

De. Pinho, Nature Reviews, 2002 De. Pinho, Nature Reviews, 2002

De. Pinho, Nature Reviews, 2002 De. Pinho, Nature Reviews, 2002

Ductal Adenocarcinoma by the Numbers n n n n 33, 730 cases/yr in US Ductal Adenocarcinoma by the Numbers n n n n 33, 730 cases/yr in US 30, 000 deaths/yr 7 th- 8 th decade of life- peak incidence 72 years- median age at diagnosis 4 th- 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 766, 860 Women 678, 060 Prostate 29% 26% 2007 Estimated US Cancer Cases* Men 766, 860 Women 678, 060 Prostate 29% 26% Breast Lung & bronchus 15% Lung & bronchus Colon & rectum 10% 11% Colon & rectum Urinary bladder 7% 6% Uterine corpus Non-Hodgkin lymphoma 4% 4% Non-Hodgkin 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 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 289, 550 Women 270, 2007 Estimated US Cancer Deaths* Lung & bronchus 31% Men 289, 550 Women 270, 100 26% Lung & bronchus 15% Breast Colon & rectum Prostate 9% Colon & rectum 9% 10% Pancreas 6% 6% Pancreas Leukemia 4% 6% Ovary Liver & intrahepatic bile duct 4% 4% Leukemia Esophagus 4% 3% Non-Hodgkin lymphoma Urinary bladder 3% 3% Uterine corpus Non-Hodgkin lymphoma 3% 2% Brain/ONS Kidney 3% 2% Liver & intrahepatic bile duct All other sites 24% ONS=Other nervous system. Source: American Cancer Society, 2007. 23% All other sites

Predisposing Factors Age n Smoking n Chronic pancreatitis n Obesity n Diabetes mellitus n Predisposing Factors Age n Smoking n Chronic pancreatitis n Obesity n Diabetes mellitus n None? n

Familial Syndromes Hereditary Breast and Ovarian cancer (BRCA 2) n Peutz-Jeghers (LKB 1) n Familial Syndromes Hereditary Breast and Ovarian cancer (BRCA 2) n Peutz-Jeghers (LKB 1) n Familial atypical multiple mole melanoma (p 16 INK 4 a) n Lynch syndrome (MSH 2, MLH 1, etc. ) n Hereditary pancreatitis (PRSSI) n

Familial Syndromes n n Account for < 20% of the familial aggregation of PC Familial Syndromes n n Account for < 20% of the familial aggregation of PC National Familial Pancreas Tumor Registry (Hopkins)- 1200 families Familial PC- at least two 1 st degree relatives Risk is 18 X baseline Second degree relatives in familial PC kindreds have increased risk (3. 7% vs. 0. 6%)

Precursor Lesions n Pan. IN (Pancreatic intraepithelial neoplasia) n MCN (Mucinous cystic neoplasm) n Precursor Lesions n Pan. IN (Pancreatic intraepithelial neoplasia) n MCN (Mucinous cystic neoplasm) n IPMN (Intraductal papillary mucinous neoplasm)

Genetic Progression Model De. Pinho, Nature Reviews, 2002 Genetic Progression Model De. Pinho, Nature Reviews, 2002

Regeneration Tumorigenesis De. Pinho, Nature Reviews, 2002 Regeneration Tumorigenesis De. Pinho, Nature Reviews, 2002

KRAS mutation is necessary, but not sufficient n n n Activating mutations are the KRAS mutation is necessary, but not sufficient n n n Activating mutations are the 1 st known genetic alterations Occur sporadically in normal pancreatic tissue Detected in ~30% of early neoplasms Nearly 100% of advanced PDAC Mice with pancreas-specific KRASG 12 Ddevelop Pan. IN, can progress to PDAC in the appropriate tumor suppressor background.

A Target Rich Environment De. Pinho, Gen Dev, 2006 A Target Rich Environment De. Pinho, Gen Dev, 2006

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

Diagnosis FNA of the primary mass or distant metastases n FNA of the primary Diagnosis FNA of the primary mass or distant metastases n FNA of the primary is obtainable with EUS (endoscopic ultrasound) n EUS is also useful for staging, invasion into surrounding vessels (SMA, SMV) n Determination of resectability n

Case 1 n n n 66 yo female presented with upper abdominal pain Non-smoker, Case 1 n n n 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. 4 cm pancreatic head mass, 18 mm CBD, dilated pancreatic duct

Case 1 EUS- 2 x 1. 8 cm pancreatic head mass, 18 mm CBD, Case 1 EUS- 2 x 1. 8 cm pancreatic head mass, 18 mm CBD, no nodes n FNA- adenocarcinoma n Staged T 3 N 0 n No involvement of critical vascular structures. n Underwent “Whipple” resection n

Case 1 n Pathology: 2. 5 cm ductal adenocarcinoma T 4 N 1 (1/19 Case 1 n Pathology: 2. 5 cm ductal adenocarcinoma T 4 N 1 (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 n Presented to urgent care, Case 2 62 yo male presented with L flank n Presented to urgent care, MD palpated an abdominal mass n CT done- 11 x 8 cm mass in the body of the pancreas, no mets, obliteraion of portal, splenic, SMV n Also noted to have L renal stone n Patient has no symptoms, no weight loss, no pain n

Case 2 Case 2

Case 2 EUS/FNA- low grade neuroendocrine neoplasm n Disease is not resectable n Prognosis Case 2 EUS/FNA- low grade neuroendocrine neoplasm n Disease is not resectable n Prognosis is good, median survival >5 yrs n Options: Observation Somatostin analog Chemotherapy Biologic therapy n

Extent of disease at presentation Localized/Resectable (15 -20 %) Locally Advanced/Unresectable (40 %) Metastatic Extent of disease at presentation Localized/Resectable (15 -20 %) Locally Advanced/Unresectable (40 %) Metastatic (40 %) MS 15 -19 mo MS 8 -12 mo MS 3 -6 mo

Staging (AJCC 2002) Primary Tumor (T) TX Primary tumor cannot be assessed T 0 Staging (AJCC 2002) Primary Tumor (T) TX Primary tumor cannot be assessed T 0 No evidence of primary tumor Tis Carcinoma in situ (also Pan. IN 3) T 1 Tumor limited to pancreas, <=2 cm T 2 Tumor limited to pancreas, >2 cm T 3 Tumor extends beyond pancreas w/o involvement of celiac axis or SMA T 4 Tumor invades celiac axis or SMA (unresectable) Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N 0 No regional lymph node metastases N 1 Regional lymph node metastases Distant Metastasis (M) MX Distant metastasis cannot be assessed M 0 No distant metastasis M 1 Distant metastasis Stage Grouping Stage 0 Tis N 0 M 0 Stage IA T 1 N 0 M 0 Stage IB T 2 N 0 M 0 Stage IIA T 3 N 0 M 0 Stage IIB T 1 N 1 M 0 T 2 N 1 M 0 T 3 N 1 M 0 Stage III T 4 Any N M 0 Stage IV Any T Any N M 1

Five-year Relative Survival (%)* during Three Time Periods By Cancer Site Breast (female) 75 Five-year Relative Survival (%)* during Three Time Periods By Cancer Site Breast (female) 75 79 89 Colon 51 59 65 35 42 49 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 1984 -1986 53 Lung and bronchus 1975 -1977 50 73 78 82 Site All sites Leukemia 1996 -2002 66 *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? Why is pancreatic cancer so hard to treat?

Factors to Overcome n n n n No adequate screening test High incidence of Factors to Overcome n n n n 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 Resectable Disease

Criteria for Unresectability n n Determined by multi-disciplinary evaluation Extrapancreatic involvement – (extensive peripancreatic Criteria for Unresectability n n Determined by multi-disciplinary evaluation Extrapancreatic involvement – (extensive peripancreatic nodal involvement and/or distant mets) n Encasement or occlusion of the SMV or SMV-portal vein confluence – (SMV reconstruction may be feasible) n Direct involvement of SMA, IVC, aorta, celiac axis

Surgery (tumors of head, neck or uncinate process) n n Pancreaticoduodenectomy (Whipple) Operative mortality Surgery (tumors of head, neck or uncinate process) n n Pancreaticoduodenectomy (Whipple) Operative mortality <2 -3% in major surgical centers

Surgery (tumors of body or tail) n n Often present late with larger tumors Surgery (tumors of body or tail) n n Often present late with larger tumors and frequent metastases Distal pancreatectomy +/- splenectomy

Chemotherapy Chemotherapy

5 -fluorouracil n n Pyrimidine analog In use for over 40 yrs Thymidylate synthase 5 -fluorouracil n n Pyrimidine analog In use for over 40 yrs Thymidylate synthase inhibitor Pancreatic, colon, breast, esophageal, gastic cancer, etc.

Gemcitabine n n n Nucleoside analog Difluorinated analog of deoxycytidine Pancreas, breast, lung and Gemcitabine n n n Nucleoside analog Difluorinated analog of deoxycytidine Pancreas, breast, lung and ovarian

Adjuvant Therapy Adjuvant Therapy

Adjuvant therapy n Rationale: High risk of local and systemic recurrence Overall poor prognosis Adjuvant therapy n Rationale: High risk of local and systemic recurrence Overall poor prognosis n 5 -yr survival after resection: 25 -30% node-neg vs. 10% node-pos n Current standard: No universally accepted standard approach

Adjuvant therapy n n n 5 major randomized trials GITSG, EORTC, ESPAC-1, RTOG 9704, Adjuvant therapy n n n 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) n Chemotherapy alone in Europe (EORTC, ESPAC-1, CONKO)

5 -fu based chemoradiation Trial RT dose Chemo MS (Mo) GITSG 40 Gy(split) None 5 -fu based chemoradiation Trial RT dose Chemo MS (Mo) GITSG 40 Gy(split) None Bolus 5 fu None EORTC 40 GY(split) CI 5 -fu 17. 1 (p=. 099) None 12. 6 ESPAC-1 2 x 2 factorial design 20 (p=. 01) 11 1 yr % 2 yr % 63 49 42 15 65 40 37 23

ESPAC-1 (5 -fu) Chemoradiotherapy vs. none MS 15. 9 vs. 17. 9 mos 2 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 2 -yr survival 40 vs. 30 % 5 -yr survival Neoptolemos, NEJM 2004 20. 1 vs. 15. 5 mos 21 vs. 8 %

Kaplan-Meier estimates of survival according to whether or not patients Received chemoradiotherapy (Panel A) 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 n n n Trial design (2 x 2 factorial) Possible selection bias ESPAC-1 Limitations n n n 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 n RTOG 9704 (ASCO 2006) 442 subjects All received chemoradiation (50. Gemcitabine-based adjuvant therapy n 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 n CONKO-001 368 subjects Randomized to Obs vs. Gemcitabine x 6 Gemcitabine-based adjuvant therapy n 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 Disease-free and Overall Survival (Intent-to-Treat Analysis) Oettle, JAMA 2007

Adjuvant therapy (Conclusions) n n n Benefit of adjuvant chemotherapy is clear Gemcitabine is Adjuvant therapy (Conclusions) n n n 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 n n Phase III: ESPAC-3 5 -fu/LV vs. Gem vs. Obs Phase Future Directions n n 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 Neoadjuvant Therapy

Rationale for Neoadjuvant therapy n n n Intact vasculature permits maintenance of oxygenation in Rationale for Neoadjuvant therapy n n n 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 n n No randomized studies comparing to adjuvant Small, Phase II, mostly Neoadjuvant therapy n n 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 Z 5041 Gemcitabine-Erlotinib Surgery Gemcitabine-Erlotinib ACOSOG Z 5041 Gemcitabine-Erlotinib Surgery Gemcitabine-Erlotinib

Locally Advanced, Unresectable Disease Locally Advanced, Unresectable Disease

Locally advanced, unresectable n n n 40% of newly diagnosed patients Most with adherence Locally advanced, unresectable n n n 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 n n GITSG (Morertel, Cancer 1981) 194 patients Randomized to: Chemoradiation > RT alone n n 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 n n n Medicare/SEER (Krzyzanowska, JCO 2003) Large, retrospective cohort Chemoradiation > RT alone n n n 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 n NCCN states “Radiation is usually given in combination with 5 RT + Gemcitabine n 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 Treatment of Metastatic Disease

Efficacy endpoints n n Traditional tumor measurements to assess RR are often inadequate in Efficacy endpoints n n 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 n n n n Extensively studied since 1950’s LV-modulated 5 -fu (infusional and Fluorouracil n n n n 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 n n n n Nucleoside analog structurally similar to cytarabine Pivotal Trial (Burris, Gemcitabine n n n n Nucleoside analog structurally similar to cytarabine Pivotal Trial (Burris, JCO 1997) 126 patients randomized: Gem 1000 mg/m 2 IV qwk 7/8, then 3/4 5 -fu 600 mg/m 2 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 n n n No confirmed objective responses Clinical benefit response 23. 8% in Gemcitabine n n n 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 n Gemcitabine has been combined with many other active cytotoxic agents: 5 Gemcitabine Combinations n 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 Nieto, The Oncologist, 2008

Molecularly targeted therapy Molecularly targeted therapy

(Hochster, Cancer 2006) (Hochster, Cancer 2006)

Nieto, The Oncologist, 2008 Nieto, The Oncologist, 2008

Targeting EGFR Targeting EGFR

Gemcitabine + Cetuximab n n SWOG S 0205 (Philip, ASCO 2007) Phase III study, Gemcitabine + Cetuximab n n SWOG S 0205 (Philip, ASCO 2007) Phase III study, 735 patients

Targeting VEGF Targeting VEGF

Gemcitabine + Bevacizumab n n n Overexpression of VEGF/VEGFR are common Phase II data Gemcitabine + Bevacizumab n n n 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 n n n n Expression of EGFR is common, poor prognosis Gemcitabine + Erlotinib n n n n Expression of EGFR is common, poor prognosis Phase III study from NCIC (Moore, JCO 2007) 569 patients randomized to: Gemcitabine 1000 mg/m 2 weekly +/Erlotinib 100 mg 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) (Moore, JCO 2007)

Gemcitabine + Erlotinib n n 1 st evidence of a survival benefit of EGFRTKI Gemcitabine + Erlotinib n n 1 st evidence of a survival benefit of EGFRTKI plus chemotherapy in any form of cancer 1 st Phase III trial to demonstrate significant improvement in survival beyond that seen with Gemcitabine alone in pancreatic cancer

Ongoing Trials n n n n n Orathecin (rubitecan)- Oral Topo I inhibitor GV Ongoing Trials n n n n n Orathecin (rubitecan)- Oral Topo I inhibitor GV 1001 - Telomerase peptide vaccine AG-013736 - Oral VEGFR/PDGFR-B inhibitor Sorafenib- Oral Raf/VEGFR/PDGFR-B/CKIT Aflibercept- VEGF Trap AZD 0530 - Oral Abl/Src kinase inhibitor PTK 787/ZK 222584 - VEGFR-TKI Romidepsin (Depsipeptide)- HDAC inhibitor MGCD 0103 (MG-0103)- HDAC inhibitor

Conclusions n n n Pancreatic cancer remains a clinical challenge Current therapies offer only Conclusions n n n 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