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Systemic Treatment and Outcomes of Metastatic Pancreatic

Fengming Zhong, MD, PhD

Pancreatic cancer, usually diagnosed at an advanced stage, is one of the deadliest malignancies. Survival for patients with resectable at 5 years is 25% to 30%, and patients with metastatic pancreatic cancer usually die within 1 year of diagnosis.

ancreatic cancer Well-known risk factors for pancre- creatic cancer has 2 components: rates have been increasing atic cancer include tobacco use, chronic systemic treatment and among men and women since pancreatitis, obesity, diabetes, and al- supportive care. P2000. From 2006 to 2010, in- cohol use. Individuals with Lynch syn- cidence rates increased by 1.3% per drome and certain other hereditary Systemic Disease Treatment year, and the death rate for pancre- syndromes are at increased risk.3 Newer The standard of care at the VA for atic cancer increased by 0.4% per risk factors of interest include chronic patients with metastatic pancre- year. An estimated 39,590 deaths with hepatitis B, , atic cancer follows the national are expected to occur in 2014, with or . These risk fac- guidelines, including the National similar numbers expected in women tors have in common a backdrop of Comprehensive Cancer Network (19,420) and in men (20,170).1 inflammation, which may predispose (NCCN) guidelines.10 Pancreatic cancer incidence and the patient to developing pancreatic • For first-line , currently mortality rates vary across different cancer. recognized regimens include racial/ethnic groups, with the high- Whether veterans as a group are 5- (5-FU), with irino- est rates in African Americans and the at increased risk for developing pan- tecan, leucovorin, and lowest rates in Asian Americans/Pacific creatic cancer is unclear. One study (FOLFIRINOX), with Islanders. During 2005-2009, the inci- suggests there may be an increased albumin-bound paclitaxel, and dence rate (per 100,000 persons) was risk in obese veterans.4 Certain high- gemcitabine with erlotinib. Single- 15.3 for African Americans, 11.6 for risk groups among veterans have agent gemcitabine or supportive whites, and 8.8 for Asian Americans/ been identified, such as veterans care is for patients with poor per- Pacific Islanders. According to Surveil- with hepatitis C, diabetes, Gaucher formance status. lance, Epidemiology, and End Results disease, and women nurses from the • For second-line therapy, switching (SEER) 18, for the period 2007-2011, Vietnam War era.5-8 from a gemcitabine to a fluoropy- the incidence rate was 17.2 for black Comorbidity, an area of increas- rimidine-based regimen, and vice men and 14 for white men; the inci- ing interest, was not a predictor of versa is a recognized option. dence rate was 14.2 for black women survival in a pilot study from one VA • When possible, participation in and 10.7 for white women.2 medical center.9 clinical trials is recommended. Treatment for metastatic pancre- Dr. Zhong serves as staff physician, Hematology and MANAGEMENT OF METASTATIC atic cancer has not been satisfactory. , at VA New Jersey Health Care System and is an assistant professor for the Department of Medi- PANCREATIC CANCER In 1997, single-agent gemcitabine cine at Rutgers-New Jersey Medical School. Management of metastatic pan- was approved by the FDA and be-

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came the standard of care when Table. Comparison of the Results of the 3 Major Positive a randomized controlled trial of Trials in Advanced Pancreatic Cancer gemcitabine in symptomatic pa- Treatment Median OS Median PFS 1-Year tients showed an increased sur- Regimens (months) (months) ORR (%) Survival (%) vival compared with that of 5-FU.11 Gem + Erlotinib The median survival durations were vs Gem 6.24 vs 5.91 3.75 vs 3.55 8.6 vs 8.0 23 vs 17 5.65 and 4.41 months for gemcitabine- FOLFIRINOX vs treated and 5-FU-treated patients, Gem 11.1 vs 6.8 6.4 vs 3.3 31.6 vs 9.4 48.4 vs 20.6 respectively (P = .0025). Nab-paclitaxel + Many attempts to combine gem- Gem vs Gem 8.5 vs 6.7 5.5 vs 3.7 23.0 vs 7.0 35 vs 22 citabine with other Abbreviations: Gem, gemcitabine; FOLFIRINOX, combinations of fluorouracil, leucovorin, , and were unsuccessful until 2005 when oxaliplatin; OS, overall survival; PFS, progression-free survival; ORR, overall response rate. gemcitabine in combination with erlotinib was approved by the FDA proved in September 2013 by the List of New Agents as a first-line therapy. A random- FDA as first-line treatment for Erlotinib is an oral agent and a small ized trial showed a 2-week prolonga- patients with metastatic pancreatic molecule that inhibits the tyrosine tion in survival with the addition of cancer. kinase activity of the human epider- erlotinib. The median survival For second-line therapy, a recent mal growth factor receptor (EGFR or was 6.24 months in the com- phase 2 study of ruxolitinib and HER1) pathway. bination group compared with capecitabine demonstrated prolon- Albumin-bound paclitaxel 5.91 months in the gemcitabine gation of overall survival in patients (nab-paclitaxel) is effective in tu- group.12 Erlotinib is associated who had an elevated C-reactive pro- mors that overexpress the albumin- with increased skin toxicity and tein (CRP). In the high CRP sub- binding protein secreted protein, diarrhea. Interestingly, trials with group, 3- and 6-month survival was acidic and rich in cysteine (SPARC), many other targeted agents, such 48% and 42% with ruxolitinib, but such as , and used in as bevacizumab, have not demon- was 29% and 11% with placebo.16 pancreatic cancer (as this cancer strated any survival improvement.13 Further studies are planned. also overexpresses SPARC). It is In 2011, a French study showed Although these developments, hypothesized, but not yet proven, that the multidrug combination of summarized in the Table, are ex- that blockage of SPARC proteins in FOLFIRINOX in patients with good citing, determining how they will pancreatic cancer patients can af- performance status (Eastern Co- apply to clinical practice will re- fect tumor growth. The strategy operative Oncology Group Perfor- quire careful patient selection and here is to attack inflammatory stro- mance Status [ECOG PS] 0 or 1) shared decision making about an- mal tissue. Pegylated recombinant increased overall mean survival to ticipated toxicities. human hyaluronidase (PEGPH20) 11.1 months compared with 6.7 months in the gemcitabine group, but with more neutropenia, diar- Fast Facts... rhea, and sensory neuropathy.11 In 2013, a comparison of nab- ▶ For first-line therapy, currently recognized regimens include paclitaxel plus gemcitabine and 5-FU with irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX), gemcitabine alone for patients gemcitabine with albumin-bound paclitaxel, and gemcitabine with a Karnofsky performance-sta- with erlotinib. Single-agent gemcitabine or supportive care is tus score of 70 or more showed a for patients with poor performance status median survival of 8.5 months vs For second-line therapy, switching from a gemcitabine to a 6.7 months, with more neu- ▶  fluoropyrimidine-based regimen, and vice versa is a recognized tropenia, fatigue, and neuro- option toxicity in the combination group.14,15 This regimen was ap- ▶ When possible, participation in clinical trials is recommended

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represents another way to target the radiation treatments or use a block (ECOG PS 0 or 1), FOLFIRINOX tumor stroma.17 is not settled, but there is a consen- or gemcitabine plus nab-paclitaxel Ruxolitinib, a janus kinase (JAK) sus to consider these interventions are reasonable choices for first- inhibitor, decreases the production of earlier rather than later. line treatment. Gemcitabine plus inflammatory . nab-paclitaxel is an option for Immunotherapy research is ongo- IMPLEMENTATION IN THE VA the patients with modest perfor- ing, using anti-cytotoxic-leukocyte There are no major barriers for ob- mance status who cannot toler- associated 4 (anti-CTLA-4) taining the newer agents or com- ate the FOLFIRINOX regimen. For and cancer .18,19 binations at the VA when they are patients with poor performance Research is increasing along many indicated. Most of the agents in the status, gemcitabine as a single- different avenues, and many other Table are on the VA National For- agent or as supportive care may research approaches beyond the mulary, with the exception of nab- be offered. Although the new scope of this article are also under- paclitaxel and erlotinib. When the combination regimens are more way, funded by the NCCN, private requested agents are not in the for- effective than single-agent gem- foundations such as the Lustgarten mulary, the case is reviewed, and the citabine, the median survival is still Foundation, and other groups. agents are usually approved for use < 1 year. More effective therapy is if they are appropriate for treatment needed. Participation in clinical SUPPORTIVE CARE according to national guidelines. trials is encouraged. ● Supportive care aspects relevant to Patient education about the risks pancreatic cancer are biliary drainage and benefits of is im- Acknowledgements and pain control. portant because some patients may I want to thank my colleagues Dr. Vic- decide against chemotherapy based tor Chang and Dr. Basil Kasimis for Biliary Drainage on past undesirable experiences of their comments. It is often necessary to place stents relatives or friends with cancer. The to improve bilirubin levels to relieve major barrier to using the newer Author disclosures The author reports no actual or poten- atient education about the risks and benefits tial conflicts of interest with regard to this article. P of chemotherapy is important because some patients may decide against chemotherapy based Disclaimer on past undesirable experiences of relatives or The opinions expressed herein are those friends with cancer. of the author and do not necessarily reflect those of Federal Practitioner, jaundice as well as obtain tissue or regimens is the patient’s poor general Frontline Medical Communications cells for diagnosis.20 condition at diagnosis. If the diagno- Inc., the U.S. Government, or any of sis can be made earlier, before their its agencies. This article may discuss Pain Control general condition deteriorates signif- unlabeled or investigational use of Recent studies have shown that icantly, the patients will have more certain . Please review complete an inflammatory perineural inva- treatment options and an improved prescribing information for specific sion by pancreatic cancer cells outcome. More research is needed to drugs or combinations—includ- leads to increased arborization and find better treatments for this deadly ing indications, contraindications, hypertrophy of the sensory nerves, disease. warnings, and adverse effects—before helping to explain in part the se- administering pharmacologic therapy vere pain experienced by patients.21 CONCLUSIONS to patients. In addition to opioids, other Systemic chemotherapy provides options include benefit to patients with advanced REFERENCES 1.  Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, and an image-guided celiac plexus pancreatic cancer. For the patients 2014. CA Cancer J Clin. 2014;64(1):9-29. block.22 The timing of when to start with good performance status 2. Siegel R, Naishadham D, Jemal A. Cancer statistics,

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2013. CA Cancer J Clin. 2013;63(1):11-30. 10. National Comprehensive Cancer Network. NCCN 2013;369(18):1691-1703. 3. Solomon S, Das S, Brand R, Whitcomb DC. In- Guidelines in the treatment of pancreatic adeno- 16. Hurwitz H, Uppal N, Wagner SA, et al. A random- herited pancreatic cancer syndromes. Cancer J. carcinoma. http://www.nccn.org/professionals/physi ized double-blind phase 2 study of ruxolitinib 2012;18(6):485-491. cian_gls/pdf/pancreatic.pdf. Accessed June 15, 2014. (RUX) or placebo (PBO) with capecitabine (CAPE) 4. Samanic C, Gridley G, Chow WH, Lubin J, Hoover 11. Burris HA III, Moore MJ, Andersen J, et al. Im- as second-line therapy in patients (pts) with met- RN, Fraumeni JF Jr. Obesity and cancer risk among provements in survival and clinical benefit with astatic pancreatic cancer (mPC). Abstract 4000. white and black United States veterans. Cancer gemcitabine as first-line therapy for patients with J Clin Oncol. 2014;32(suppl):5s. Causes Control. 2004;15(1):35-43. advanced cancer: A randomized trial. 17. Provenzano PP, Cuevas C, Chang AE, Goel VK, 5. El-Serag HB, Engels EA, Landgren O, et al. Risk of J Clin Oncol. 1997;15(6):2403-2413. Von Hoff DD, Hingorani SR. Enzymatic targeting hepatobiliary and pancreatic after hepatitis 12. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib of the stroma ablates physical barriers to treatment C virus infection: A population-based study of U.S. plus gemcitabine compared with gemcitabine of pancreatic ductal adenocarcinoma. Cancer Cell. veterans. Hepatology. 2009;49(1):116-123. alone in patients with advanced pancreatic can- 2012;21(3):418-429. 6. Atchison EA, Gridley G, Carreon JD, Leitzmann cer: A phase III trial of the National Cancer Insti- 18. Le DT, Lutz E, Uram JN, et al. Evaluation of ipili- MF, McGlynn KA. Risk of cancer in a large cohort tute of Canada Clinical Trials Group. J Clin Oncol. mumab in combination with allogeneic pancreatic of U.S. veterans with diabetes. Int J Cancer. 2011; 2007;25(15):1960-1966. tumor cells transfected with a GM-CSF gene in 128(3):635-643. 13. Kindler HL, Niedzwiecki D, Hollis D, et al. Gem- previously treated pancreatic cancer. J Immunother. 7. Landgren O, Turesson I, Gridley G, Caporaso NE. citabine plus bevacizumab compared with gem- 2013;36(7):382-389. Risk of malignant disease among 1525 adult male citabine plus placebo in patients with advanced 19. Plate JM. Advances in therapeutic vaccines for pan- US Veterans with Gaucher disease. Arch Intern Med. pancreatic cancer: phase III trial of the Cancer and creatic cancer. Discov Med. 2012;14(75):89-94. 2007;167(11):1189-1194. Leukemia Group B (CALGB 80303). J Clin Oncol. 20. Sharaiha RZ, Widmer J, Kahaleh M. Palliation of 8. Kang HK, Cypel Y, Kilbourne AM, et al. Health- 2010;28(22):3617-3622. pancreatic ductal obstruction in pancreatic cancer. ViEWS: Mortality study of female US Vietnam 14. Conroy T, Desseigne F, Ychou M. Groupe Tumeurs Gastrointest Endosc Clin N Am. 2013;23(4):917-923. era veterans, 1965-2010. Am J Epidemiol. 2014; Digestives of Unicancer; PRODIGE Intergroup. FOL- 21. Bapat AA, Hostetter G, Von Hoff DD, Han H. Peri- 179(6):721-730. FIRINOX versus gemcitabine for metastatic pancre- neural invasion and associated pain in pancreatic 9. Kim K, Zhong F, Chang VT, et al. Clinical char- atic cancer. N Engl J Med. 2011;364(19):1817-1825. cancer. Nat Rev Cancer. 2011;11(10):695-707. acteristics and comorbidity of veterans with pan- 15. Von Hoff DD, Ervin T, Arena FP, et al. In- 22. Erdek MA, King LM, Ellsworth SG. Pain man- creatic cancer. J Clin Oncol. 2011;29(15)(suppl): creased survival in pancreatic cancer with agement and palliative care in pancreatic cancer. Abstract e14549. nab-paclitaxel plus gemcitabine. N Engl J Med. Curr Probl Cancer. 2013;37(5):266-272.

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topics covered in this update include: • Managing HIV Infection in the Health Care Workplace: 30 Years Later • Update on Integrase Strand Transfer Inhibitors for the Treatment of HIV • HIV and Hepatitis C Coinfection • Care at the Crossroads: Navigating the HIV, HCV, and Substance Abuse • Recent Advances in HIV Development

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