Pancreatic Cancer. Maribel Tirado Gomez, MD Hematology and Medical Oncology

Transcription

1 Pancreatic Cancer Maribel Tirado Gomez, MD Hematology and Medical Oncology

2 Disclosures I have no actual or potential financial or commercial conflict of interest in relation to this presentation. Consulting Honoraria Merck

3 Agenda Epidemiology Pancreatic Cancer in Puerto Rico Risks Factors and Clinical Presentation Pre-treatment Evaluation Treatment Supportive Care

4 Epidemiology of Pancreatic Cancer

5 Epidemiology of Pancreatic Cancer Fourth leading cause of cancer death in North America 2018: 55,440 new cases and 44,330 deaths Peak incidence in 7 th and 8 th decades of life Average age at diagnosis: years Slightly higher incidence in men vs women (RR: 1.35) Higher incidence (30% - 40%) in African American men American Cancer Society. Cancer Facts & Figures Jemal A, et al. CA Cancer J Clin. 2007;57:43-66

6 Epidemiology of Pancreatic Cancer Stage for stage, pancreatic cancer is associated with the lowest survival rates of any major cancer type. By 2030, pancreatic cancer is expected to rise to the second leading cause of cancer-related mortality in the United States (after lung cancer). No screening test, thus the vast majority of patients are inoperable at time of diagnosis. Siegel RL, et al. CA Cancer J Clin. 2018;68:7-30 Rahib L, et al. Cancer Res. 2014;74: American Cancer Society. Cancer facts & figures 2017

7 Cancer Incidence in Puerto Rico Torres-Cintrón CR et. al. (2017). Cancer in Puerto Rico, PR Central Cancer Registry

8 Cancer Mortality in Puerto Rico Torres-Cintrón CR et. al. (2017). Cancer in Puerto Rico, PR Central Cancer Registry

9 Pancreatic Cancer in Puerto Rico Mean age at diagnosis: 68 years Period Incidence Mortality ,691 1,448 Male: 898 Female: Male: 187 Female: 164 Male: 747 Female: Male: 164 Female: year 3 years 5 years 0 Local Regional Distant Unknown Torres-Cintrón CR et. al. (2017). Cancer in Puerto Rico, PR Central Cancer Registry

10 Trend on Pancreatic Cancer Incidence in Puerto Rico Castañeda-Ávila M et. al. Epidemiology of Pancreatic Cancer in Puerto Rico ( ): Incidence, Mortality and Survival. Austin J Gastroenterol. 2016; 3(1): 1058

11 Risk Factors Environmental Smoking/Second hand Smoke Chronic pancreatitis Alcohol abuse Metabolic Obesity Diabetes Hyperglycemia/ metabolic syndrome Genetic (< 20% of cases) Up to 10% have firstdegree relative with disease BRCA1/2 positive Peutz-Jeghers syndrome: 26% cumulative risk at 70 yrs of age Ataxia-telangiectasia Familial adenomatous polyposis Lynch syndrome Edderkaoui M, et al. Front Physiol. 2014;5;490 Korsse SE, et al. J Med Genet. 2013;50:59-64 Hezel AF, et al. Genes Dev. 2006;20:

12 Clinical Presentation and Treatment

13 Clinical Presentation 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 Component Symptom Local Epigastric/back pain (~75%) Constitutional Biliary obstruction Pancreatic insufficiency Fatigue Anorexia Weight loss (85%) Depression: > 70%; highest of any GI cancer Jaundice (55%) Pruritus Pale stools (25%) Malabsorption

14 Initial Evaluation Imaging Transabdominal or endoscopic ultrasound ERCP MRCP CT or MRI (Pancreatic Protocol) Pathologic confirmation of adenocarcinoma (vs pnet) Serologic Evaluation Tumor markers: CA 19-9 Sensitivity, 70% - 92%; specificity, 68% - 92% ] Some pts are unable to express CA 19-9 due to lack of Lewis antigen Can be elevated in pts without pancreatic cancer Bilirubin, AST/ALT, lipase, amilase, CBC Lee ES, et al. World J Gastroenterol. 2014;20: Tummala P, et al. J Gastrointest Oncol. 2011;2:

15 Siegel R, et al. CA Cancer J Clin. 2012;62:10-29 Sun H. Sci Rep Oct 23;4:6747 Pancreatic Cancer by Stage Stage Classification % at Diagnosis 5-Yr Survival, % Localized 8 22 Locally advanced/ unresectable 27 9 Metastatic

16 Pancreas Anatomy

17 Clinical Staging of Pancreatic Cancer Criteria Evidence of extrapancreatic disease Resectable No evidence Borderline Resectable No evidence Localized Unresectable Lymph nodes beyond field of resection SMA encasement No evidence 180 > 180 SMV/portal vein Patent SMPV Impingement or short segment occlusion Unreconstructable occlusion Celiac encasement No evidence 180 (tail) > 180 (body/tail) Hepatic artery No arterial tumor contact Abutment or encasement Invasion or encasement Callery MP, et al. Ann Surg Oncol. 2009;16:

18 Whipple Procedure

19 Adjuvant Therapy Trial Arms Median OS, Mos P Value GITSG (N = 43) EORTC (N = 207) ESPAC-1 (N = 578) CONKO-001 (N = 368) RTOG (N = 451) ESPAC-3 (N = 1088) ESPAC-4 (N = 730) [2] RT/5-FU Obs RT/5-FU Obs 5-FU/LV No chemo RT/5-FU/LV No RT Gem Obs RT/5-FU + 5-FU RT/5-FU + Gem 5-FU Gem Gem/Cape Gem

20 Treatment Options for Metastatic Pancreatic Cancer

21 Gemcitabine vs 5-FU in Unresectable Pancreatic Cancer Gemcitabine Patients with untreated, unresectable pancreatic cancer (75% stage IV), KPS 80, Morphine 10 mg/d, MPAC pain intensity score 20 (N = 126) 1000 mg/m 2 weekly x 7, off x 1, then weekly x 3 of 4 weeks (n = 63) 5-FU 600 mg/m 2 weekly (n = 63) Burris HA, et al. J Clin Oncol. 1997;15:

22 % Patients Surviving Gemcitabine vs 5-FU in Unresectable Pancreatic Cancer Gemcitabine (n = 63) 5-FU (n = 63) Median overall survival Gemcitabine: 5.65 months 5-FU: 4.41 months Clinical Benefit Response Gemcitabine: 23.8% 5-FU: 4.8% Composite score of pain, performance status, and weight Overall survival at 1 year Gemcitabine: 18% 5-FU: 2% Log-rank test 10 P = Survival Time (Months) Burris HA, et al. J Clin Oncol. 1997;15:

23 Probability of Survival (%) Gemcitabine ± Erlotinib in Unresectable Pancreatic Cancer International, doubleblind, placebocontrolled, randomized phase III trial of gemcitabine + erlotinib or placebo (N = 569) Median PFS: 3.75 vs 3.55 months (P =.004) ORR: 8.6% vs 8.0% (P = NS) HR: 0.82 (95% CI: ; P =.038) Erlotinib (n = 285) Median: 6.24 mos 1-yr survival: 23% 20 Placebo (n = 284) Median: 5.91 mos 1-yr survival: 17% Mos 24 Moore MJ, et al. J Clin Oncol. 2007;25:

24 FOLFIRINOX vs Gemcitabine in Metastatic Pancreatic Cancer Stratified by ECOG PS (0 vs 1), center, tumor location (head vs other) Pts with untreated metastatic pancreatic cancer; ECOG PS 0/1; adequate BM, platelet count, liver and renal function (N = 342) FOLFIRINOX Oxaliplatin 85 mg/m 2 + LV 400 mg/m 2 + Irinotecan 180 mg/m FU bolus 400 mg/m 2, then 2400 mg/m 2 IV over 46 hrs (n = 171) Gemcitabine 1000 mg/m 2 weekly x 7 of 8, then weekly x 3 of 4 (n = 171) Conroy T, et al. N Engl J Med. 2011;364:

25 Baseline Characteristics Characteristic FOLFIRINOX (n = 171) Gemcitabine (n = 171) Median age, yrs (range) 61 (25-76) 61 (34-75) Male, n (%) 106 (62.0) 105 (61.4) ECOG PS, n (%) 0 1 Pancreatic tumor location, n (%) Head Body Tail 64 (37.4) 106 (61.9) 67 (39.2) 53 (31.0) 45 (26.3) 66 (38.6) 105 (61.4) 63 (36.8) 58 (33.9) 45 (26.3) Biliary stent, n (%) No 144 (84.2) 149 (87.1) Conroy T, et al. N Engl J Med. 2011;364:

26 OS (%) PFS (%) FOLFIRINOX vs Gemcitabine: OS and PFS OS PFS FOLFIRINOX Gemcitabine FOLFIRINOX Gemcitabine Mos Mos Median OS: 11.1 vs 6.8 mos HR: 0.57 (95% CI: ; P <.001) Median PFS: 6.4 vs 3.3 mos HR: 0.47 (95% CI: ; P <.001) Conroy T, et al. N Engl J Med. 2011;364:

27 FOLFIRINOX vs Gemcitabine: Adverse Events Grade 3/4 AE, % FOLFIRINOX (n = 171) Gemcitabine (n = 171) P Value Hematologic Neutropenia Febrile neutropenia Thrombocytopenia Nonhematologic Fatigue Vomiting Diarrhea Sensory neuropathy Elevated ALT < NS NS <.001 <.001 <.001 Conroy T, et al. N Engl J Med. 2011;364:

28 Deterioration (Probability) FOLFIRINOX vs Gemcitabine: Quality of Life Time until definitive deterioration > 20 points, EORTC-C30 global health status/qol questionnaire FOLFIRINOX Gemcitabine P < Mos Prolongation of QoL in pts treated with FOLFIRINOX compared with gemcitabine, despite greater toxicity Specifically, longer time to deterioration in: Global health status Physical, cognitive, and social functioning Symptoms such as fatigue, N/V, pain, and anorexia Gourgou-Bourgade S, et al. J Clin Oncol. 2013;31:23-29.

29 Management of AEs: Irinotecan Diarrhea Early diarrhea usually transient, consider treatment with atropine Late diarrhea (> 24 hours after infusion may be life threatening, treat promptly with loperamide, fluids, and electrolytes Delay chemotherapy for return to pretreatment bowel function with 24 hrs without need for antidiarrhea medication If grades 2-4 late diarrhea recurs, treat and decrease subsequent doses

30 Management of AEs: Irinotecan Neutropenia Manage complications promptly with antibiotics Omit irinotecan during a cycle if neutropenic fever occurs or if ANC < 1,000/mm 3 After patient recovers to ANC 1,000/mm 3, subsequent doses should be reduced depending on the level of neutropenia observed Growth factor prophylaxis can be used with FOLFIRINOX

31 Management of AEs: Oxaliplatin Neuropathy Distal paresthesia, voice an visual changes, laryngopharyngeal dysesthesias Reduce dose if persistent grade 2 neurosensory events do not resolve Consider discontinuing oxaliplatin if persistent grade 3 neurosensory events Recovery to normal can take up to 4 months Gastrointstinal Nausea/vomits/diarrhea Reduce dose after recovery from grade 3/4 GI toxicities

32 Management of AEs: Oxaliplatin Neutropenia Delay until neutrophils 1.5 x 10 9 /L after grade 4 neutropenia or febrile neutropenia and reduce next dose Growth factor prophylaxis can be used with FOLFIRINOX Thrombocytopenia Delay until platelets 75 x 10 9 /L after grade 3/4 thrombocytopenia and reduce next dose

33 Phase III MPACT Trial: Gemcitabine ± nab- Paclitaxel in Metastatic Pancreatic Cancer Stratified by KPS, region, liver metastasis Patients with metastatic pancreatic cancer, no previous treatment for metastatic disease, KPS 70, bilirubin ULN (N = 861) nab-paclitaxel 125 mg/m 2 IV q3w + Gemcitabine 1000 mg/m 2 on Days 1, 8, 15 q4w (n = 431) Gemcitabine 1000 mg/m 2 /wk for 7 wks, then on Days 1, 8, 15 q4w (n = 430) Treat until PD Primary objective: OS Secondary endpoints: PFS, ORR, safety Von Hoff DD, et al. N Engl J Med. 2013;369:

34 Proportion of Patients Without Progression MPACT Trial of Gemcitabine ± nab-paclitaxel in Metastatic Pancreatic Cancer: PFS nab-p + Gem Gem Events, n/n (%) Median (95% CI) PFS, Mos 75th Percentile 277/431 (64) 5.5 m ( ) /430 (62) 3.7 m ( ) 5.9 HR: % CI ( ; P = ) Pts at Risk, n nab-p + Gem Gem PFS Rate at 6 mos 12 mos nab-p + Gem 44% 16% Gem 25% 9% Mos % Increase 76% 78% Von Hoff DD, et al. N Engl J Med. 2013;369:

35 Proportion of Surviving Patients MPACT Trial of Gemcitabine ± nab-paclitaxel in Metastatic Pancreatic Cancer: OS nab-p + Gem Gem Events, n/n (%) Median (95% CI) OS, Mos 75th Percentile 333/431 (77) 8.5 m ( ) /430 (83) 6.7 m ( ) 11.4 HR: 0.72 (95% CI: ; P = ) Pts at Risk, n nab-p + Gem Gem Mos Von Hoff DD, et al. N Engl J Med. 2013;369:

36 Gemcitabine ± nab-paclitaxel: Adverse Events Event, % Gemcitabine + Nab- Paclitaxel (n = 421) Gemcitabine (n = 402) AE leading to death 4 4 Hematologic AEs grade 3 Neutropenia Leukopenia Thrombocytopenia Anemia Receipt of growth factors Febrile neutropenia 3 1 Nonhematologic AEs grade 3 in 5% of pts Fatigue Peripheral neuropathy Diarrhea Von Hoff DD, et al. N Engl J Med. 2013;369:

37 Management of AEs: Nab-Paclitaxel Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported Do not rechallenge after a severe hypersensitivity reaction Pneumonitis Occurs in ~ 4% of pts receiving nab-paclitaxel plus gemcitabine Monitor for signs and symptoms of pneumonitis Interrupt nab-paclitaxel and gemcitabine during evaluation of suspected pneumonitis

38 Management of AEs: Nab-Paclitaxel Nervous system Sensory neuropathy is dose and schedule dependent Grade 1/2 sensory neuropathy does not generally require dose modification If grade 3 sensory neuropathy develops, withhold treatment until resolution to grade 1 followed by a dose reduction for all subsequent courses

39 Management of AEs: Nab-Paclitaxel Hematologic effects Bone marrow suppression (primarily neutropenia) is dose dependent and a dose-limiting toxicity In clinical studies, grade 3/4 neutropenia occurred in 38% of pts with pancreatic cancer Sepsis occurred in 5% of pts (with or without neutropenia) who received nab-paclitaxel plus gemcitabine Biliary obstruction, or presence of biliary stent, were risk factors for severe or fatal sepsis If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics

40 Advanced Pancreatic Cancer The regimens of nab-paclitaxel + gemcitabine and FOLFIRINOX are both commonly used as first line therapy in advanced pancreatic cancer Benefits versus toxicities must be carefully balanced Performance status Age (> or < 75 years) Comorbid conditions (preexisting sensory neuropathy) Risk of endobiliary stent complications Patient preference Cost What to do after progression in these up-front regimens?

41 Nanoliposomal Irinotecan Nanoliposomal irinotecan Approved by FDA in combination with 5-FU/LV for treatment of pts with metastatic pancreatic cancer who progress after gemcitabine-based therapy Irinotecan: topoisomerase I inhibitor Liposomal formulation associated with preferentially increased tumor exposure to irinotecan Longer half-life, increased AUC, slower clearance, reduced volume of distribution vs free drug Roy AC, et al. Ann Oncol. 2013;24: Drummond DC, et al. Cancer Res. 2006;66:

42 Nanoliposomal Irinotecan ± 5-FU/LV Nal-IRI 120 mg/m 2 Q3W (n = 151) Pts with metastatic pancreatic cancer who progressed on gemcitabinebased therapy, KPS 70 (N = 417) 5-FU/LV 2000/200 mg/m 2 /wk x 4 Q6W (n = 119) Nal-IRI 80 mg/m FU/LV* 2400/400 mg/m 2 Q2W (n = 117) Wang-Gillam A, et al. Lancet. 2016;387:

43 Nanoliposomal Irinotecan ± 5-FU Tumor Response and Control Nal-IRI + 5-FU/LV (n = 117) 5-FU/LV (n = 119) Median PFS, months (95% CI) ORR, % (95% CI) CA19-9 reduction, % 3.1 ( ) 1.5 ( ) P = ( ) 1 (0-2.5) P < P =.0009 Wang-Gillam A, et al. Lancet. 2016;387:

44 OS (%) OS (%) Nanoliposomal Irinotecan ± 5-FU/LV Nal-IRI + 5-FU/LV Nal-IRI + 5-FU/LV 5-FU/LV Mos From Randomization Median OS: 6.1 vs 4.2 mos HR: 0.57 (95% CI: ; P =.0009) Nal-IRI Nal-IRI 5-FU/LV Mos From Randomization Median OS: 4.9 vs 4.2 mos HR: 0.93 (95% CI: ; P =.5545) Wang-Gillam A, et al. Lancet. 2016;387:

45 Nanoliposomal Irinotecan ± 5-FU/LV: Adverse Events AEs, % Nal-IRI + 5-FU/LV (n = 117) Safety Population 5-FU/LV Control (n = 134) Any Grade Grade 3/4 Any Grade Grade 3/4 Diarrhea Vomiting Nausea Decreased appetite Fatigue Neutropenia Anemia Hypokalemia Similar toxicities management as in non-liposomal Irinotecan Wang-Gillam A, et al. Lancet. 2016;387:

46 Microsatellite Instability and Mismatch Repair

47 Metastatic Pancreatic Cancer ASCO Clinical Practice Guideline Update Routine testing for dmmr or MSI-H is recommended, using IHC, PCR, or NGS for patients who are considered to be candidates for checkpoint inhibitor therapy PD-1 immune checkpoint inhibitor pembrolizumab is recommended as second-line therapy for patients who have tested positive for dmmr or MSI-H Pembrolizumab 200 mg IV q 3 weeks Sohal DPS et. al. J Clin Oncol Aug 20;36(24):

48 Immune Checkpoint Inhibitors

49 Supportive Care in Pancreatic Cancer

50 Venous Thromboembolism (VTE) Incidence of VTE is 4 to 7-fold higher in pancreatic cancer The likelihood of VTE is highest during the first 3 months after diagnosis of pancreatic cancer Treatment with chemotherapy further increases the risk. Chew H, et al. Arch Intern Med. 2006;166: Blom J et. Al. Eur J Cancer. 2006; 42:410-4 Maraveyas A et. Al. Eur J Cancer. 2012;48:

51 CONKO-004 N= 152 Gemcitabine 1,000 mg/m 2 Metastatic Pancreatic Cancer N=312 N=160 Gemcitabine 1,000 mg/m 2 + Enoxaparin 1 mg/kg ( 3 months) Enoxaparin 40 mg/d (3 months) Regimen svte Major Bleeding (%) TTP (wks) OS (wks) Gemcitabine Gemcitabine + Enoxaparin Riess H. et. Al. ASCO (18S): LBA 4506

52 Pain Opiod Analgesia Multidisciplinary Pain Management Pain Management Specialists Palliative Care Specialists Celiac plexus neurolysis (CPN) Partial or complete pain relief is achieved in 70% to 90% of patients

53 Malignant Biliary Obstruction Occurs in 70% to 90% of patients with pancreatic cancer (tumors in the head of the pancreas). Impact on Quality of Life Cholangitis Malabsorption Pruritus Hepatic failure Techniques Endoscopic Biliary Stent Percutaneous transhepatic biliary drainage

54 Pancreatic Exocrine Insufficiency Occurs in 80% to 90% of patients with pancreatic cancer. Nonspecific symptoms Abdominal cramping and maldigestion Steatorrhea Treatment: Pancreatic enzyme replacement Starting dose of 40,000 75,000 IU pancreatic lipase should be given with meals and 20,000 25,0000 IU with snacks

55 Gastric outlet obstruction 10% to 25% of pts Good performance status Gastrojejunostomy (open or laparoscopic) ± J-tube Consider enteral stent Poor performance status Enteral stent Venting PEG tube for gastric decompression

56 Cancer-Associated Anorexia- Cachexia Syndrome 80% of pancreatic cancer patients at the time of diagnosis Inappropriately accelerated catabolic rate with systemic inflammation and profound anorexia Altered taste perception, weakness, early satiety, nausea, and a loss of appetite despite profound weight loss Megestrol and increased caloric intake Marihuana

57 Depression Screen for Depression Suicide Ideas Advance Directives Pallitive medicine Evaluation Medication Psycotherapy

58 Conclusions Improvements in overall survival in pancreatic cancer have been seen in the last decade. Research Challenges Development of a screening test More effective and less toxic therapies Multidisciplinary and Patient-Centered approach is essential to manage this populations of patients appropriately.

59 Thanks! Maribel Tirado Gomez, MD x 1108