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Management of Metastatic Pancreatic Adenocarcinoma

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Management of Metastatic Pancreatic Adenocarcinoma Management of Metastatic Pancreatic Adenocarcinoma a,b c,d, Ahmad R. Cheema, MD , Eileen M. O’Reilly, MD * KEYWORDS Pancreatic cancer Metastatic disease Gemcitabine Nab-paclitaxel FOLFIRINOX Targeted agents Immune therapy KEY POINTS Progress in the treatment of pancreatic ductal adenocarcinoma (PDAC) has been incre- mental, mainly ensuing from cytotoxic systemic therapy, which continues to be a standard of care for metastatic disease. Folinic acid, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX) and gemcita- bine plus nab-paclitaxel have emerged as new standard therapies, improving survival in patients with good performance status. Novel therapeutics targeting the peritumoral stroma and tumor-driven immune suppres- sion are currently a major focus of research in metastatic disease. Identification of reliable and validated predictive biomarkers to optimize therapeutics con- tinues to be a challenge. Continued efforts toward better understanding of tumor biology and developing new drugs are warranted because a majority of patients succumb within a year of diagnosis, despite an increasing number of therapeutic options available today. INTRODUCTION In the year 2016, there will be approximately 53,000 estimated new individuals diag- nosed with PDAC in the United States, representing approximately 3% of all cancer Financial Disclosures: None (A.R. Cheema). Research support: Sanofi Pharmaceuticals, Celgene, Astra-Zenica, MedImmune, Bristol-Myers Squibb, Incyte, Polaris, Myriad Genetics, Momenta Pharmaceuticals, OncoMed. Consulting: Celgene, MedImmune, Sanofi Pharmaceutical, Threshold Pharmaceuticals, Gilead, Merrimack (E.M. O’Reilly). Funding support: Cancer Center Support Grant (P30 CA008748). a Department of Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Pl, New York, NY 10029, USA; b Department of Medicine, Mount Sinai St. Luke’s-West Hospital Center, 1111 Amsterdam Avenue, New York, NY 10025, USA; c Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York,NY10065,USA;d Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA * Corresponding author. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York, NY 10065. E-mail address: [email protected] Surg Clin N Am 96 (2016) 1391–1414 http://dx.doi.org/10.1016/j.suc.2016.07.011 surgical.theclinics.com 0039-6109/16/ª 2016 Elsevier Inc. All rights reserved. 1392 Cheema & O’Reilly cases.1 Despite the low incidence, pancreatic cancer is the fourth leading cause of cancer-related death among both men and women in the United States, with a high mortality-to-incidence ratio, and is expected to become the second leading cause of cancer-related mortality by 2030.2,3 PDAC is the most common histologic subtype, found in more than 85% of cases. Surgical resection is curative in a minority of patients; however, 70% to 80% of patients have unresectable disease, with more than 50% having distant metastases at the time of initial diagnosis, where the treat- ment goals are to control disease, palliate symptoms, and prolong survival.2 For PDAC, the expected 5-year survival for all patients is approximately 6% to 7% and less for patients who are diagnosed with metastatic disease de novo.2,4 Putative explanations for poor outcomes are generally attributed to the asymptomatic early stages of the disease, lack of effective screening tools, early metastatic dissemina- tion, relative resistance of the tumor to cytotoxic and targeted therapies, dense stroma, hypoxic microenvironment, and immune suppression. Over the past several years, tangible improvements in outcomes have been observed in patients with metastatic PDAC with the increasing use of new chemother- apeutic regimens. Gemcitabine plus albumin-bound paclitaxel and FOLFIRINOX have generated median overall survivals (OSs) ranging from 8.5 to 11.1 months for patients with good performance status.5,6 For patients with poor performance status, however, median OS is typically in the 3-month to 6-month range. Through extensive research over the past decade, remarkable advances have been made in understanding the molecular pathogenesis and underpinnings of PDAC. Major advances include elucidation of genetic alterations present in PDAC as well as defining the role of signaling pathways, peritumoral stroma, and immune system in tumor initiation, spread, and resistance to systemic therapies. Therefore, various targeted and immune therapies have been designed and are currently being investi- gated. Despite encouraging results in phase I/II studies, substantial impact in out- comes has not yet been observed. Therefore, PDAC remains a serious challenge for patients, families, and the scientific community. This review discusses the current management options for patients with metastatic PDAC, with particular emphasis on the current state of the art along with current clin- ical trials and a focus on novel agents and immune therapeutics. FIRST-LINE SYSTEMIC THERAPY Systemic therapy is the mainstay of treatment of patients with metastatic PDAC, with proved efficacy in terms of prolonging survival. Historically, 5-FU as a single agent or 5-FU–based regimens were the standard treatments for patients with advanced disease, until the advent of gemcitabine.7,8 Single-agent Gemcitabine Gemcitabine is an S-phase–specific pyrimidine antimetabolite that is converted by cellular kinases into difluorodeoxycytidine triphosphate. This active metabolite then competes with deoxycytidine to inhibit DNA synthesis.9 In 1997, gemcitabine was approved by the US Food and Drug Administration (FDA) as monotherapy for metastatic PDAC after Burris and colleagues10 demonstrated that gemcitabine was superior to 5-FU in patients with baseline Karnofsky performance scale score (KPS) greater than or equal to 50%; 126 patients with advanced PDAC were randomized to receive either gemcitabine (1000 mg/m2 over 30 minutes weekly for 7 weeks, fol- lowed by a week of rest, and then weekly for 3 of 4 weeks) or weekly bolus of 5-FU (600 mg/m2). Clinical benefit response, the principal endpoint of this trial, defined by Management of Metastatic Pancreatic Adenocarcinoma 1393 composite assessment of pain (pain intensity/analgesia consumption), KPS, and dry weight gain, was observed in 23.8% of patients receiving gemcitabine compared with 4.8% in those receiving 5-FU (P 5 .022). Furthermore, median OS was also better for gemcitabine arm (5.65 vs 4.41 months, P 5 .0015). Based on the results of this trial, gemcitabine was established as a standard of care for first-line chemotherapy in patients with metastatic PDAC. To enhance the efficacy of gemcitabine, conventional dosing over 30 minutes versus fixed dose rate (FDR), 10 mg/m2/min, administration has been evaluated. Based on a phase I and pharmacokinetics study, which demonstrated saturation of deoxycytidine kinase enzyme, which catalyzes conversion of gemcitabine to its active metabolite, it was hypothesized that slower/prolonged infusion (FDR) could maximize the intracel- lular accumulation of active metabolite and enhance the antitumor activity.11 A phase III randomized trial did not, however, demonstrate improvements in symptoms, median OS, progression-free survival (PFS), or 1-year or 2-year survival rates in patients who received FDR gemcitabine compared with standard-dose gemcitabine.12 Gemcitabine Combination Therapies Given the positive outcomes with single-agent gemcitabine, numerous clinical trials investigated gemcitabine-based combination therapies in an attempt to improve the efficacy over single-agent therapy. Until recently, however, the results have been largely disappointing. Although gemcitabine combination therapies were observed to be safe and associated with better response rates, no statistically significant improvement in OS, the principal endpoint of most studies, was shown (Table 1). In meta-analyses, however, a survival benefit with some gemcitabine-based combina- tions, mainly fluoropyrimidine and platinum agents, over gemcitabine monotherapy was identified,13–15 providing some support for the use of gemcitabine combinations in patients with a good functional status. Several studies have also investigated gemcitabine-based polychemotherapy regimens comprising multiple cytotoxic drugs. One such study (randomized phase III, n 5 99) was conducted by Reni and colleagues,16 who demonstrated superior out- comes in terms of 4-month PFS (primary endpoint) with cisplatin, epirubicin, 5-FU, and gemcitabine (PEFG) combination therapy over single-agent gemcitabine. Even though outcome was favorable in the PEFG group, hematological toxicity was concerning with significant number of patients developing greater than or equal to grade 3 neutro- penia and thrombocytopenia. Although this study favored the use of intensified chemotherapy, it did not receive much endorsement due to the limitations, including small sample size and principal endpoint of 4-month PFS (instead of OS), which made results difficult to generalize. Gemcitabine Plus Erlotinib Erlotinib, a tyrosine kinase (TYK) inhibitor of the epidermal growth factor receptor (EGFR), was the first drug to show survival benefit when administered in combination with gemcitabine. Moore and colleagues,17 in 2007, conducted a phase III trial, including 569 patients, randomized to receive gemcitabine plus erlotinib (100 mg/d or 150 mg/d) or gemcitabine alone in patients with
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