Since the US Food and Drug Administration’s approval of gemcitabine in 1996, numerous randomized trials have investigated treatment programs to further improve the quality of life and survival of patients with advanced pancreatic cancer. After little progress over the ensuing 15 years, 2 combination treatment programs recently conferred improved survival compared with gemcitabine monotherapy in patients with metastatic pancreatic cancer: FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel. Importantly, our understanding of the biology of pancreatic cancer continues to grow. This improved biologic understanding holds great promise for integrating new targeted and immune-modifying therapies into current treatment programs.
Key points
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Over 50% of patients with pancreatic cancer present with metastatic disease, when treatment is palliative and consists primarily of systemic chemotherapy.
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Recent studies have identified 2 combination chemotherapy programs that impart improved survival times compared with gemcitabine monotherapy for patients with adequate functional status: FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel.
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New treatment approaches that leverage a growing understanding of pancreatic cancer biology are under development, including those that modify tumor-associated stroma, inhibit signaling from mutant KRAS , augment host immune response to the cancer, and exploit defects in tumor DNA repair mechanisms.
Introduction
Among 46,420 estimated new cases of pancreatic cancer in the United States in 2014, the majority of patients are diagnosed with metastatic disease at presentation. Among the patients able to undergo a potentially curative resection, most experience disease relapse, necessitating palliative therapy. Thus, the 5-year survival rate among all patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) remains estimated at 6.7%, with pancreatic cancer projected to become the second leading cause of cancer death in the United States by 2020.
Since the US Food and Drug Administration (FDA) approval of gemcitabine monotherapy in 1996, multiple randomized trials have failed to demonstrate improved survival for combination chemotherapy programs in advanced PDAC. However, in the past several years, clinical trials of FOLFIRINOX and gemcitabine plus nab-paclitaxel have demonstrated improved outcomes compared with gemcitabine alone in patients with metastatic PDAC. Targeted therapies and immunotherapy building upon these new chemotherapy backbones hold great promise for future improvements in patient outcomes.
Introduction
Among 46,420 estimated new cases of pancreatic cancer in the United States in 2014, the majority of patients are diagnosed with metastatic disease at presentation. Among the patients able to undergo a potentially curative resection, most experience disease relapse, necessitating palliative therapy. Thus, the 5-year survival rate among all patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) remains estimated at 6.7%, with pancreatic cancer projected to become the second leading cause of cancer death in the United States by 2020.
Since the US Food and Drug Administration (FDA) approval of gemcitabine monotherapy in 1996, multiple randomized trials have failed to demonstrate improved survival for combination chemotherapy programs in advanced PDAC. However, in the past several years, clinical trials of FOLFIRINOX and gemcitabine plus nab-paclitaxel have demonstrated improved outcomes compared with gemcitabine alone in patients with metastatic PDAC. Targeted therapies and immunotherapy building upon these new chemotherapy backbones hold great promise for future improvements in patient outcomes.
Patient evaluation and prognostic markers
Suspicion for metastatic PDAC typically results from symptomatic complaints and the radiologic appearance of a pancreatic mass associated with a characteristic pattern of metastatic spread. Presenting symptoms relate either to the local effects of the primary pancreatic mass, such as with biliary obstruction, epigastric pain, and weight loss, or from symptoms due to metastatic deposits, which most commonly occur in the liver, peritoneum, and lungs. Initial evaluation consists of computed tomographic scan encompassing the chest, abdomen, and pelvis and biopsy of the primary tumor or a metastatic site to confirm invasive adenocarcinoma. Histologic evaluation is important because less-common malignancies can resemble metastatic PDAC but require distinct management. These malignancies include less-common pancreatic malignancies such as pancreatic neuroendocrine tumors and nonpancreatic malignancies such as high-grade lymphomas or metastatic implants to the pancreas.
Immunohistochemistry (IHC) of a metastatic biopsy can be helpful in confirming the diagnosis when the primary pancreatic mass is difficult to visualize on imaging studies. PDAC typically demonstrates reactivity against cytokeratin (CK) 7, CK19, and carcinoembryonic antigen (CEA) and often lacks reactivity to CK20. IHC analysis for loss of Smad4 expression, which occurs in approximately 50% of PDAC tumors, as well as mutation analysis of the KRAS oncogene, which is mutated at codons 12 or 61 in 80% to 95% of tumors, can also be useful in defining a pancreatic origin when the primary site is radiologically indistinct.
The serum markers carbohydrate antigen 19-9 (CA19-9) and CEA should be assessed at diagnosis, and if their levels are elevated, they can be followed serially during therapy as a disease surrogate. CA19-9 is a sialylated Lewis blood group antigen that requires fucosyltransferase 3 (FUT3) activity for its production. Almost 10% of the population bears a germline polymorphism in FUT3 , making them Lewis-antigen negative and incapable of producing CA19-9. For individuals capable of CA19-9 production, low serum CA19-9 levels at diagnosis and declines in CA19-9 levels with initiation of chemotherapy are associated with improved outcomes. Additional clinical, circulating, and histologic factors are associated with poorer prognosis in patients undergoing chemotherapy for metastatic PDAC, including older age, poor performance status, high serum C-reactive protein (CRP) levels, high metastatic burden, presence of peritoneal carcinomatosis, and high-grade histology.
Molecular alterations have also been associated with prognosis in PDAC. Pancreatic cancers are typified by genetic alterations in KRAS , TP53 , CDKN2A , and SMAD4 , with approximately 40% of tumors possessing alterations in all 4 genes. Initial studies have demonstrated a poorer prognosis for patients with tumors possessing a greater number of these alterations. Furthermore, a comprehensive sequencing analysis of resected pancreatic cancers identified a survival disadvantage to the presence of somatic alterations in axon guidance genes.
Gemcitabine
Gemcitabine is a nucleoside analog whose metabolic product, difluorodeoxycytidine triphosphate competes with deoxycytidine for incorporation into DNA, inhibiting DNA synthesis. US FDA approval of gemcitabine in 1996 for patients with advanced PDAC followed the report of a trial involving 126 patients randomized to weekly gemcitabine (1000 mg/m 2 weekly × 7 followed by a week of rest, and then weekly for 3 of every 4 weeks) or weekly bolus of 5-fluorouracil at 600 mg/m 2 . The primary outcome of the trial was clinical benefit as assessed by a composite of pain measurement, Karnofsky performance status (KPS), and weight loss. Clinical benefit was seen in 23.8% of patients receiving gemcitabine compared with 4.8% of those receiving 5-fluorouracil ( P = .0022). Median overall survival (OS) was superior in the gemcitabine group at 5.65 months compared with 4.41 months in the 5-fluorouracil group ( P = .0025). Furthermore, the 12-month survival rate was 18% for patients receiving gemcitabine versus 2% for those receiving 5-fluorouracil. This trial established single-agent gemcitabine as the standard of care for first-line treatment of patients with advanced PDAC.
Strategies to Improve Gemcitabine Effectiveness
In an attempt to improve upon the efficacy of weekly gemcitabine at 1000 mg/m 2 administered over 30 minutes, prolonged gemcitabine infusions were evaluated. A phase 1 pharmacokinetic study demonstrated saturation of the rate-limiting deoxycytidine-kinase-driven enzymatic conversion of gemcitabine to its active metabolite with an optimal dose rate of 10 mg/m 2 /min. Thus, it was hypothesized that prolonged infusion of gemcitabine could maximize production of the active nucleotide analog and improve efficacy for a given dose of gemcitabine. A fixed dose rate (FDR) gemcitabine strategy of 10 mg/m 2 /min over 150 minutes was assessed in phase 2 trials and suggested improved response rates compared with standard infusion rates. Nevertheless, a randomized phase 3 clinical trial demonstrated no statistically significant improvement in survival for FDR gemcitabine compared with standard gemcitabine infusion in patients with advanced PDAC.
One mechanism that may explain de novo resistance of PDAC to gemcitabine is low tumor expression of human equilibrative nucleoside transporter 1 (hENT1), a transporter protein that facilitates gemcitabine entry into cells. CO-101 is a lipid-drug conjugate of gemcitabine that allows hENT1-independent entry of gemcitabine into tumor cells. A large phase 2 trial dichotomized patients with metastatic PDAC into hENT1-high and hENT1-low subgroups based on tumor staining for hENT1 by IHC, with the hypothesis that patients with low hENT1 expression may derive benefit from CO-101. Unfortunately, no difference was observed in survival between patients who received gemcitabine and those who received CO-101 in the hENT1-low subgroup or the overall study population.
Gemcitabine Treatment Doublets
Gemcitabine-based chemotherapy doublets have been extensively explored in patients with advanced PDAC, with the goal of improving upon the modest efficacy of gemcitabine monotherapy ( Table 1 ). The combination of gemcitabine with 5-fluorouracil or its orally available prodrug capecitabine failed to demonstrate statistically significant improvements in OS in several individual trials. However, a meta-analysis of 3 randomized trials evaluating gemcitabine plus capecitabine versus gemcitabine monotherapy in patients with advanced PDAC demonstrated statistical significance with a hazard ratio (HR) of 0.86 (95% confidence interval [CI], 0.75–0.98). Nevertheless, the improvement in median OS with the combination was less than 1 month (6.2 vs 7.1 months) and patients receiving gemcitabine plus capecitabine experienced increased neutropenia and hand-foot syndrome. The oral fluoropyrimidine analog S-1 has been studied primarily in Asia in patients with gastrointestinal malignancies. In patients with advanced PDAC, a phase 3 trial conducted in Japan and Taiwan compared gemcitabine monotherapy to either S-1 monotherapy or gemcitabine plus S-1. Monotherapy with S-1 was noninferior to gemcitabine, but the trial failed to demonstrate a significant improvement in OS with the gemcitabine plus S-1 combination compared with gemcitabine alone.
| Study | No. of Patients | Treatment Arms | Progression-Free Survival | Overall Survival | ||||
|---|---|---|---|---|---|---|---|---|
| Median (mo) | HR (95% CI) | Log-Rank P Value | Median (mo) | HR (95% CI) | Log-Rank P Value | |||
| Berlin et al, 2002 | 327 | Gemcitabine | 2.2 | 5.4 | ||||
| Gemcitabine + 5-fluorouracil | 3.4 | NA | .02 | 6.7 | NA | .09 | ||
| Rocha Lima et al, 2004 | 360 | Gemcitabine | 3.0 | 6.6 | ||||
| Gemcitabine + irinotecan | 3.5 | NA | .35 | 6.3 | NA | .79 | ||
| Louvet et al, 2005 | 313 | Gemcitabine | 3.7 | 7.1 | ||||
| Gemcitabine + oxaliplatin | 5.8 | 1.29 (1.01–1.69) | .04 | 9.0 | 1.20 (0.95–1.54) | .13 | ||
| Oettle et al, 2005 | 565 | Gemcitabine | 3.3 | 6.3 | ||||
| Gemcitabine + pemetrexed | 3.9 | NA | .11 | 6.2 | 0.98 (0.82–1.18) | .85 | ||
| Abou-Alfa et al, 2006 | 349 | Gemcitabine | 3.8 | 6.2 | ||||
| Gemcitabine + exatecan | 3.7 | NA | .22 | 6.7 | NA | .52 | ||
| Heinemann et al, 2006 | 195 | Gemcitabine | 3.1 | 6.0 | ||||
| Gemcitabine + cisplatin | 5.3 | 0.75 (NA) | .05 | 7.5 | 0.80 (NA) | .15 | ||
| Herrmann et al, 2007 | 319 | Gemcitabine | 3.9 | 7.2 | ||||
| Gemcitabine + capecitabine | 4.3 | NA | .10 | 8.4 | 0.87 (0.67–1.10) | .23 | ||
| Cunningham et al, 2009 | 533 | Gemcitabine | 3.8 | 6.2 | ||||
| Gemcitabine + capecitabine | 5.3 | 0.78 (0.66–0.93) | .004 | 7.1 | 0.86 (0.72–1.02) | .08 | ||
| Poplin et al, 2009 | 832 | Gemcitabine | 2.6 | 4.9 | ||||
| Gemcitabine FDR | 3.5 | NA | .04 a | 6.2 | 0.83 (0.69–1.00) | .04 a | ||
| Gemcitabine + oxaliplatin | 2.7 | NA | .10 | 5.7 | 0.88 (0.73–1.05) | .22 | ||
| Colucci et al, 2010 | 400 | Gemcitabine | 3.9 | 8.3 | ||||
| Gemcitabine + cisplatin | 3.8 | 0.97 (0.80–1.19) | .80 | 7.2 | 1.10 (0.89–1.35) | .38 | ||
| Ueno et al, 2013 | 554 | Gemcitabine | 4.1 | 8.8 | ||||
| Gemcitabine + S-1 | 5.7 | 0.66 (0.54–0.81) | <.001 | 10.1 | 0.88 (0.71–1.08) | .15 | ||
| Von Hoff et al, 2013 | 861 | Gemcitabine | 3.7 | 6.7 | ||||
| Gemcitabine + nab-paclitaxel | 5.5 | 0.69 (0.58–0.82) | <.001 | 8.5 | 0.72 (0.62–0.83) | <.001 | ||
a P values did not meet the study-defined thresholds for statistical significance.
Clinical trials assessing gemcitabine combined with other cytotoxic agents have been similarly disappointing (see Table 1 ). Phase 3 studies assessing combination therapy of gemcitabine with platinum compounds including cisplatin and oxaliplatin failed to recapitulate the suggested synergy observed in preclinical and phase 2 studies. In addition, phase 3 studies adding irinotecan, exatecan, or pemetrexed to gemcitabine were unable to demonstrate improved survival with combination treatment programs compared with gemcitabine alone.
In addition to cytotoxic doublets, phase 3 trials have also assessed several molecularly targeted agents in combination with gemcitabine ( Table 2 ). The dense tumor stroma and poor vascularity of PDAC suggested that inhibition of tumor-derived angiogenesis could normalize the vascular microenvironment of pancreatic tumors and permit improved chemotherapy delivery. Several trials assessed the addition to gemcitabine of antiangiogenic agents, including bevacizumab, ziv-aflibercept, and axitinib. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF)-A, while ziv-aflibercept binds to VEGF-A, VEGF-B, and placental growth factor and axitinib binds to VEGF receptors, inhibiting receptor signaling. No statistically significant survival benefit was seen for these agents in randomized phase 3 trials of gemcitabine plus placebo versus gemcitabine plus the antiangiogenic agent. A randomized phase 3 trial also failed to demonstrate benefit of adding sorafenib, an agent thought to inhibit downstream signaling from KRAS and with antiangiogenic activity, to gemcitabine. Agents targeting other molecular pathways have also been combined with gemcitabine in large randomized phase 3 trials with negative results, including ganitumab and cetuximab, monoclonal antibodies to the insulinlike growth factor 1 receptor and epidermal growth factor receptor (EGFR), respectively.
| Study | No. of Patients | Treatment Arms | Progression-Free Survival | Overall Survival | ||||
|---|---|---|---|---|---|---|---|---|
| Median (mo) | HR (95% CI) | Log-Rank P Value | Median (mo) | HR (95% CI) | Log-Rank P Value | |||
| Bramhall et al, 2002 | 239 | Gemcitabine | 3.2 | 5.4 | ||||
| Gemcitabine + marimastat | 3.0 | 0.95 (0.73–1.23) | .68 | 5.4 | 0.99 (0.76–1.30) | .95 | ||
| Van Cutsem et al, 2004 | 688 | Gemcitabine | 3.6 | 6.0 | ||||
| Gemcitabine + tipifarnib | 3.7 | 1.03 (0.87–1.22) | .72 | 6.3 | 1.03 (0.86–1.23) | .75 | ||
| Moore et al, 2007 | 569 | Gemcitabine | 3.6 | 5.9 | ||||
| Gemcitabine + erlotinib | 3.8 | 0.77 (0.64–0.92) | .004 | 6.2 | 0.82 (0.69–0.99) | .04 | ||
| Van Cutsem et al, 2009 | 301 | Gemcitabine + erlotinib | 3.6 | 6.0 | ||||
| Gem + erlotinib + bevacizumab | 4.6 | 0.73 (0.61–0.86) | .0002 | 7.1 | 0.89 (0.74–1.07) | .21 | ||
| Kindler et al, 2010 | 602 | Gemcitabine | 2.9 | 5.9 | ||||
| Gemcitabine + bevacizumab | 3.8 | NA | .08 | 5.8 | 1.04 (0.88–1.24) | .95 | ||
| Phillip et al, 2010 | 745 | Gemcitabine | 3.0 | 5.9 | ||||
| Gemcitabine + cetuximab | 3.4 | 1.07 (0.93–1.24) | .18 | 6.3 | 1.06 (0.91–1.23) | .23 | ||
| Kindler et al, 2011 | 632 | Gemcitabine | 4.4 | 8.3 | ||||
| Gemcitabine + axitinib | 4.4 | 1.01 (0.78–1.30) | .52 | 8.5 | 1.01 (0.79–1.31) | .54 | ||
| Goncalves et al, 2012 | 104 | Gemcitabine | 5.7 | 9.2 | ||||
| Gemcitabine + sorafenib | 3.8 | 1.04 (0.70–1.55) | .90 | 8.0 | 1.27 (0.84–1.93) | .23 | ||
| Rougier et al, 2013 | 546 | Gemcitabine | 3.7 | 7.8 | ||||
| Gemcitabine + ziv-aflibercept | 3.7 | 1.02 (0.83–1.25) | .86 | 6.5 | 1.17 (0.92–1.47) | .20 | ||
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