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Hepatocellular & Pancreatic Carcinomas

Moving Forward with Targeted Therapy & New Agents

Raúl H. Morales - Borges, MD, FICPS, FIACATH

Chairman of the Board of Trustees and Lecturer of Pathology, Immunology & Genetics

San Juan Bautista School of Medicine

Medical Director of The Ashford Institute of Hematology & Oncology

Attending Physician and Consultant

Ashford Presbyterian Comm. Hospital

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Epidemiology of Hepatobiliary Cancers

• They are composed by Hepatocellular Carcinoma (HCC), Gallbladder Cancer (GBC), Intra-hepatic Cholangio-carcinoma (IHCC), and Extra-hepatic Cholangiocarcinoma (EHCC). They are highly lethal.

• In 2008, approximately 21,370 persons in USA were diagnosed with liver or intra-hepatic bile duct cancer and 9,520 with GBC or other Bile Tract Cancer.

• Approximately 18,410 deaths from liver and intra-hepatic bile duct cancer and 3,340 deaths from GBC and other Bile Tract Cancer.

• By 2009, there are 22,620 estimated new cases & 18,160 deaths.

Clinical Practice Guidelines in Oncology by NCCN: Hepatobiliary Cancers. JNCCN April 2009, 7(4):350-391.

Cancer Facts and Figures 2009. Atlanta, GA; American Cancer Society: 2009.

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Epidemiology of Pancreatic Cancer• In 2009, an estimated 42,470 new cases of

pancreatic carcinoma (PC) were diagnosed in the United States. Unfortunately, only 15% to 20% of these cases were amenable.

• There are 35,240 estimated deaths for 2009.• Approximately half of patients with newly

diagnosed pancreatic carcinoma will have locally advanced disease, with a median survival of 6-11 months. Tsai S, Eckhauser F: Comparing chemoradiotherapy with other modalities for treating unresectable pancreatic carcinoma. AJHO November 2009, 8(11):553, 557.

Cancer Facts and Figures 2009. Atlanta, GA; American Cancer Society: 2009.

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Risk Factors for HCC

• Hepatitis B “HBV” (Asia, Africa)

• Hepatitis C “HCV” (Europe, Japan, USA)

• Autoimmune Hepatitis

• Primary Biliary Cirrhosis

• Excessive Alcohol Intake• Non-alcoholic

Steatohepatitis “NASH” (Diabetes mellitus, Metabolic Syndrome)

• Aflatoxin (Apergilus fungus)

• Hereditary Hemochromatosis

• Porphyria Cutanea Tarda

• Alpha1-Anti-Trypsin Deficiency

• Wilson’s Disease

JNCCN April 2009, 7(4): 350-391

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Incidence of HCC(From Underlying Chronic Liver Disease)

• 4 million persons in USA have Chronic HCV with an annual incidence rate of HCC of 2% to 8%.

• 1.5 million persons in USA have Chronic HBV.

• NASH has a prevalence of 3% to 5%.

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Risk Factors for Pancreatic Cancer

• Age (90% > 55 & 70% > 65)

• African-Americans (1.3- to 1.4-fold than Caucasians)

• Iceland, Finland, Northern USA

• Smoking (20% - 30%)• High meat and fat intake• Vitamin D deficiency• Genetic/hereditary factors

such as MEN, vHL, BRCA1, BRCA2, Gardner’s syndrome, Familiar Polyposis.

• Obesity, Cirrhosis, Diabetes mellitus, Stomach ulcers by H. pylori, Chronic Pancreatitis (from excessive alcohol intake and gallstones)

• Long-term exposure to gasoline, insecticides, pesticides, dyes

Raimondi S, Maisonneuve P, Lowenfels AB: Nat. Rev. Gastroenterol. Hepatol. Dec. 2009, 6: 699-708.

O’Reilly EM, McIntosh AC: Community Oncology Oct 2009, 6(10), Supp.2: 3-14.

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Screening for Hepatoma Pancreas Ca. • In High-Risk patients

with HBV or HCV or Chronic Hepatitis.

• Alpha Fetoprotein (AFP) and Ultrasonography (US) every 6 months

• High-Risk patients would likely benefit from biologic screening, before the general population, but studies are in phase I and II.

Lo Menzo E et al: Front Biosci (Schol

Ed), Jan 2010; 2:578-590. PE Chang et al: Gastroenterol 2008; 43:881-888.

Bruix J, Sherman M: Hepatology 2005; 42;1208-1236.

BH Zhang et al: J Cancer Res Clin Oncol 2004; 130:417.

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Early detection of Pancreatic CancerKlapman J and Malafa MP from

H. Lee Moffitt Cancer Center

• Endoscopic Ultrasound as Screening of high risk patients such as:– 2 or more first-degree relatives with PC or

hereditary syndromes such as:• Peutz-Jeghers syndrome

• Familial Breast Cancer Syndrome

• Familial Atypical Multiple Mole Melanoma Syndrome

Cancer Control Oct. 2008; 15(4): 280-287

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Clinical Picture: Signs & Symptoms

• Initially, no symptoms or related to their longstanding liver disease.

• Abdominal pain, weight loss, early satiety, jaundiced, hepatomegaly, palpable mass in the upper abdomen, ascites, and/or vascular bruit in advanced stage.

• Initially, no symptoms or non-specific ones like dyspepsia, abdominal discomfort.

• Jaundiced, pain, depression, fatigue, weight loss, anorexia, mal-absorption & steatorrhea, glucose intolerance, and/or left supraclavicular adenopathy in advanced stage.

Hepatocellular Cancer Pancreatic Cancer

DeVita, Hellman, Rosenberg: Cancer: Principles & Practice in Oncology.

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Diagnosis of HCC

• Typically made by liver imaging tests such as:– Ultrasonography (US)

– Computed Tomography (CT) scan

– Magnetic Resonance Imaging (MRI)

• Measurement of blood levels of alpha-fetoprotein (AFP).

• Final Diagnosis is confirmed by radiologically-guided fine needle aspiration and/or biopsy.

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AFP testing and HCC

• Serum AFP levels are normal in 40% of patients with HCC of less than 2 cm in diameter and in 28% of those with tumors 2 to 5 cm in diameter.

• Not all HCC, the Fibrolamellar type, for example, secrete AFP.

• AFP could also be elevated in germ-cell tumors, testicular neoplasms, pregnancy, and acute or chronic viral hepatitis.

• AFP is useful to evaluate response after loco-regional therapy: Oncologic Marker of Radiologic Response, Progression, and Survival.

A Riaz et al: JCO Dec. 2009; 27(34):5734-5742

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Diagnosis of Cancer of the Pancreas

• Helical “spiral” CT scan is considered to be the state-of-the-art in this regard and it’s great for pre-operative staging.

• Endoscopic Ultrasound (EUS) is good re: invasion of adjacent veins or lymph nodes and for fine needle biopsy.

• Endoscopic Retrograde Cholangiopancreatography (ERCP) helps re: duct patency or for placement of a biliary stent.

• Laparoscopy should be done only in certain cases of liver or peritoneal metastases and body or tail cancers.

• Fine Needle Aspiration and Biopsy should be reserved for non-operable cases.

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Serum Tumor Marker CA 19-9and Cancer of the Pancreas

• It is valuable for following the therapeutic response of patients with PC who have an elevated serum CA 19-9 level.

• It is of limited value as a screening marker.• It may be within normal range while the cancer is

still at a small and asymptomatic stage.• Can be elevated in benign biliary or pancreatic

conditions.

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Staging of HCC

Child-Pugh Scoring

Cancer of the Liver Italian Program (CLIP)Chinese University Prognostic Index (CUPI)

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Staging of PC

TNM Staging

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Management of HCC

• It is directed toward the cure or to palliate depending of the size, location, invasion or metastatic disease.

• If the tumor is limited to one lobule, less than 5 cm, no invasion of vascular zone, and the patient has good liver function, then he or she is a good candidate for surgical resection.

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Surgery for HCC

• 10% to 20% of the HCC can be completely removed by surgery with a mortality rate of 5%, but they have a recurrence rate of 50% to 60%.

• There are many surgical interventions available other than resection such as radiofrequency ablation, cryosurgery, intra-hepatic artery chemotherapy or chemo-embolization.

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Another Alternatives for HCC

• Percutaneous Ethanol Injection “PEI” (< 3 cm)

• Trans Arterial Catheter Embolization with Cisplatin, Lipiodol & Gelfoam (TACE)

• RFA (< 5 cm)

• Selective Internal Radiotherapy with TheraSphere (SIR)

• Intra-arterial administration of I-131 labeled Lipiodol

• High Frequency Focused Ultra-sonography (HIFU)

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Adjuvant Therapy for HCC

• None, because most of the cases are unresectable.

• There is one trial presented at ASCO 2005 with adjuvant oral synthetic retinoid for 12 months.

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Systemic Palliative Therapy

• Doxorubicin

• Cisplatin

• 5-FU

• Interferon

• Epirubicin

• Paclitaxel

MB Thomas et al: Ann Surg Oncol 2008; 15:1008-1014

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Targeted Therapy for HCC

• Sorafenib: oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis.

• SHARP trial: phase III, 602 patients– Median OS: 10.7 vs. 7.9 months

• Asian-Pacific Study: phase III, 226 patients– Median OS: 6.5 vs. 4.2 months

• NCCN Guidelines: category I for Child-Pugh class A or B, unresectable, extensive, not candidate for liver transplant or local disease but poor performance status or co morbidity or metastatic disease.

NEJM 2008; 359:378-390 Hepatology Nov. 13 of 2009

JNCCN 2009; 7(4): 397-403

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Combinations with Sorafenib

• Doxorubicin– Median time to progression: 9 vs. 5 months– Overall survival: 13.7 vs. 6.5 months

• Erlotinib– 1 patient with stable disease– G1/2: fatigue, diarrhea, skin toxicity, hypo-

phosphatemia

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Other Targeted Therapies• Erlotinib

• Erlotinib + Bevacizumab: – Median progression free survival of 9 months– Median overall survival of 15.65 months– G ¾ toxicity of 12.5% to 20%

• Sunitinib:– 37.5 mg/d: 38.5% SD & median progression free survival of

4.1 months– 50 mg/d: median time to progression of 21 weeks & median

overall survival of 45 weeks

Duran et al; Clin Cancer Res 2007; 13: 4849-4857.

MB Thomas et al: JCO 2009; 27:843-850.

AX Zhu et al: JCO 2007; 25(Suppl. 1): Abstract 4637.

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Transplantation for HCCBD Campos & JF Botha: JNCCN 2009; 7(4): 409-416

• Liver transplantation remains the best available form of treatment for small HCC in patients with cirrhosis class A.

• The allowed Pre-transplant neoadjuvant therapy include: RFA, TACE or PEI.

• Best experienced trials done in Milan (1996), Barcelona (1998), UCSF (2001) & UCLA (2006-2007).

• We need better development of Living Donor Liver Transplant Programs and better characterization of HCC re: biology, staging & prognosis.

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Management of PC

• Treatment of Potentially Resectable Disease:– Right sided tumors: Pancreaticoduodenectomy

– Left sided tumors: Distal or caudal pancreatectomy

• Palliative Surgery is appropriate in patients discovered to have unresectable disease at the time of planned resection or in good-risk patients whose tumor-related symptoms are poorly alleviated by nonoperative means.

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Surgery in PC

• Experience at the University of Erlangen in Germany of all resections of tumors in the head of the pancreas:

15% 1 – 2 cm

33.4% 2 – 3 cm

23.3% 3 – 4 cm

27.8% > 4 cm

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Experience at UCLA Medical Center

26% 1 – 2 cm

17% 2 – 3 cm

22% 3 – 4 cm

26% 4 – 5 cm

9% > 5 cm

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Palliative Surgery and Nonoperative in PC

• Hepatico- or choledochojejunostomy, choledochoduodenostomy, or cholecysto- jejunostomy for obstructive jaundice.

• ERCP with biliary cannulation and stent placement or Percutaneous transhepatic biliary drainage.

• Percutaneous or Endoscopic celiac nerve block.

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Pancreatic Cancer Adjuvant TherapyNo Survival Difference Between 5-FU/LV & Gemcitabine

• John P. Neoptolemus et al: Phase III European Study Group for Pancreatic Cancer-3 trial with 1,088 patients:– R0 or R1 resection

• LV 20mg/m2 IV Bolus followed by 5-FU 425mg/m2 IV Bolus for 5 days every 28 days OR

• Gemcitabine 1,000mg/m2 IV infusion on days #1,8 & 15 every 4 weeks for 6 months.

• The toxicity profile was significant superior on Gemcitabine compared to bolus 5-FU, but no survival difference found. ESPAC-4 with Gem+ Capecitabine will address the questions.

ASCO 2009

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Neoadjuvant Strategies• To date, the current data demonstrate that,

although neoadjuvant chemo radiotherapy can be administered safely, there is no clear survival advantage to this strategy compared to postoperative therapy.

• In the realm of marginally resectable patients, it remains to be seen whether there is a meaningful cohort of patients for whom this approach may represent an important therapeutic advantage based on “down-staging” and subsequent improved surgical outcomes.

Hoffman JP et al: JCO 1998; 16:317.

Breslin TM et al: Ann Surg Oncol 2001; 8:123.

Magnin V et al: Int J Radiat Oncol Biol Phys 2003; 55:1300.

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Chemo radiation (CRT) Approaches in Locally Advanced Disease

• Many Trials by GITSG, ECOG, and SWOG have been done with Radiation Alone or Chemotherapy (CT) Alone with 5-FU/LV or Chemo radiation with 5-FU/LV or Chemo radiation with different agent (mCCNU, Doxorubicin) and the improvement is modest with chemo radiation and the local control remains a significant challenge.

Earle CC et al: Can J Gastroenterol 2003; 17(3):161.

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CRT with 5-FU or Gemcitabine for Unresectable PC

• In terms of CT survival, CRT was found not to be superior to CT, while at the same time increasing toxicities.

• Giving CT as induction followed by CRT provides a survival benefit of 3-4 months.

• No prophylactic peripancreatic lymph nodes irradiation provides lower GI toxicity.

• 5-FU remains the standard chemotherapy over Gemcitabine as radio sensitizer.

Hughet F et al: JCO 2009; 27(13): 2269-2277.

Tsai S and Eckhauser F: AJHO Nov. 2009; 8(11): 553.

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Treatment of Metastatic and Recurrent Disease

• Based on studies of single-agent Gemcitabine published between 1996 and 1999, where the RR was around 10% - 12% and the clinical benefit response was around 23% - 27%, it was approved for the treatment of patients with advanced PC in the USA and many other countries and is considered the standard agent for the treatment of this disease, as well as the accepted control with which to compare new drugs and interventions.

Rothenberg et al: Ann Oncol 1996; 7: 347.

Burris et al: JCO 1997: 15: 2403.

Storniolo et al: Cancer 1999; 85: 1261.

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GEM + Oxaliplatin vs GEMGESCOR and GISCAD phase III trial

C Louvet et al: JCO 2005; 23:3509-3516

Response Rate 26.8% vs 17.3%

Clinical Benefit 38.2% vs 26.9%

Median Survival 9.0 mo. vs 7.1 mo.

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CT in Advanced PC

• Phase I of Capecitabine 1440 mg/m2 (d#1-21) + Gemcitabine 1000 mg/m2 (d#1,8 & 15) + Bevacizumab 5 mg/kg (d#1 & 15) + Erlotinib 100 mg/day every 28 days x 6 cycles with 12.5 mo median overall survival and 9 mo of progression-survival time with 10% - 20% G3/4 diarrhea, HFS, stomatitis & skin rash and 40% G3 neutropenia and lethargy.

Cunningham D et al: JCO Nov 30 of 2009, 27(33):5499-5505

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GEM-CAPas standard first-line option in locally-advanced and

metastatic PC

• 533 patients in two arms: GEM vs. GEM-CAP (Phase III).– Gem 1000mg/m2 per week x 7 with 1 week rest

then weekly x 3 every 4 weeks– Gem 1000mg/m2 per week x 3 every 4 weeks +

CAP 1660mg/m2/d (839mg/m2 po bid) x 3weeks with 1 week rest

D Cunningham et al: JCO 27:5513-5518.

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GEM vs GEM-CAPPARAMETER GEM GEM-CAP

Overall response 12.4% 19.1%

Progression-free survival

3.8 mo. 5.3 mo.

Overall survival 6.2 mo. 7.1 mo.

Anemia 6% 4%

Neutropenia 22% 35%

Thrombocytopenia 6% 11%

Fever 2% 4%

Lethargy 21% 21%

HFS 0% 4%

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CALGB 89904Phase II in Metastatic PC

• 245 eligible patients randomly assigned to 1 of 4 regimens:– Gem-Cisplatin– 5-FU+Gem– Gem-Docetaxel– Gem-Irinotecan

MH Kulke et al: JCO 27: 5506-5512

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CALGB 89904Parameter Gem-Cis FU-Gem Gem-

DocetaxelGem-

Irinotecan

ORR 67% 72% 65% 69%

CA 19-9 response

33% 42% 42% 33%

Time to tumor

progression

4.5 mo. 3.3 mo. 4.1 mo. 4.0 mo.

Overall survival

6.7 mo. 6.4 mo. 6.4 mo. 7.1 mo.

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Biweekly GEM plus ErlotinibA Ardavanis et al: Anticancer Res. Dec. 2009; 29(12):5211-5217

• 27 patients• GEM 2gm/m2 IV infusion every 2 weeks plus

Erlotinib 100mg po every day for 6 cycles.• ORR: 25.9%• Stable disease: 59.3%• 1-year-survival rate: 20%• Median Overall Survival Rate: 7.5 mo.• Time to Progression: 5.5 mo.• No Grade 4 Hematological and Non-

Hematological Toxicities seen.

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Liposomal Paclitaxel + GEMESMO Conference 11th World Congress on

Gastrointestinal CancerJune 24-27, 2009

• Manfred P. Lutz et al from Caritas Hospital in Germany reported a 4-arm study with 200 patients with 80% metastatic & 20% locally advanced PC:– EndoTAG-1: 11, 22, or 44 mg/m2 biw

– GEM 1000 mg/m2 weekly

– RR of 60%, 65%, and 52%, respectively, vs 43% with GEM alone.

– 1-year-OSR of 22%, 36%, and 33%, respectively, vs 17% GEM alone.

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Erlotinib in Advanced PC

• It is indicated in combination with Gemcitabine for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

Moor MJ et al: JCO 2007; 25: 1960-1966.

Vulfovich M, Rocha-Lima C: Expert Rev Anticancer Ther 2008; 8: 993-1002

M Hidalgo et al: JCO 2001; 19:3267-3279.

.

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Molecular Targeted Agents for PC

• Matrix metalloproteinase inhibitors such as Marimastat and BAY12-9566 have no utility in the treatment of Advanced PC.

• Ras inhibitors such as Tipifarnib has in vivo inhibition of farnesyl transferase activity but no objective response seen with no significant survival benefit.

•E M O’Reilly and AC McIntosh: Commun Oncol October 2009; 6(Num 10, suppl 2): 3-14

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Others…

• Cetuximab

• Volociximab

• Trastuzumab

• Bevacizumab

• Conatumumab

• Lapatinib

• Axitinib

• Imatinib

• Masitinib

• Nab-paclitaxel

• Micellar paclitaxel

• Ixabepilone

• Glufosfamide

• Talabostat

• TNFerade

• Everolimus

• Celecoxib

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Molecular Pathology & Targeting Therapy in PC

• K-Ras

• SHH

• CDKN2A

• TP53

• SMAD4

• DUSP6

T Furukawa et al: Mod Pathol Aug. 2005: 18(8): 1034-1042.

T Furukawa: Clin Gastroenterol Hepatol Nov. 2009; 7(11 Suppl):S35-9.

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Consensus Report of the NCI Gastrointestinal Cancer Steering

Committee • By Philip A. Philip et al as Special Article in JCO

27(33): 5660-5669 from 11/20/09.• Enhance research in molecular pathways for new

targets, new drug development.• Preclinical mouse tumor models for rational drug

therapy design.• Phase III clinical trials only if meaningful clinical

signal of efficacy and safety seen in Phase II trials.• Establishment of Biorepositories for research.• Development of Biomarkers in Animal Models.

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Summary

• HCC and PC are diseases with better therapies now than even in the past 5 – 10 years and their survival have been improved too. Although ongoing studies will help us to fulfill the unanswered hopes and expectations in their molecular diagnosis and new therapies development and availability.

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