Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer in the United States. Surgical resection remains the only curative treatment, but fewer than 20% of patients qualify as candidates. The past two decades saw major changes in the treatment of advanced PDA, a shift of standard protocol from 5-fluorouracil to gemcitabine and gemcitabine-based combinations, the introduction of molecular target therapy and multi-agent regimens. However, even with advancements in medicine, PDA is still extremely resistant to currently available regimens, which results in poor prognosis, with only 5.2% of patients alive at three years. This provides a challenge to scientists as they seek to find the best active regimen with the least side-effects. In this article, we review the current recommended guidelines from the National Comprehensive Cancer Network. In addition, we highlight major clinical trials since 2011.
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related death in men and women in the US and the eighth leading cause of cancer death in men and ninth in women worldwide (1, 2). In the US, approximately 43,920 patients are diagnosed with pancreatic cancer involving the exocrine function, with the majority being adenocarcinoma arising from the ductal epithelium (3). Despite dismal survival rates, the incidence of pancreatic cancer and mortality rates in the U.S. have remained the same over the past two decades (4, 5). The peak incidence occurs during the seventh and eight decade of life and is rare before the age of 45 years (2). The incidence is greater in males than females and in blacks than whites (6). Although the overall prognosis of pancreatic cancer is poor (median survival=3.5 months, with 5.2% alive at three years), novel approaches have been explored to increase survival rates. In this article, we review the current standard chemotherapy treatment and highlight important studies since 2011, with specific emphasis on locally advanced and metastatic disease.
Current Treatment
Despite improved chemotherapy, survival rates for advanced pancreatic ductal adenocarcinoma (PDA) remain abysmal. 5-Fluorouracil (5-FU) was the accepted monotherapy until the late 1990s, when Burris and colleagues reported the result of a phase III clinical trial directly comparing gemcitabine and 5-FU (7). Gemcitabine was found to confer a significant median survival advantage over 5-FU; however, the clinical benefit was modest (5.65 months vs. 4.41 months, p=0.0025). Based on this important finding, gemcitabine has become the standard-of-care for first-line treatment of advanced disease and was used as a gold standard for subsequent trials. Scientists have made efforts to combine gemcitabine with other chemotherapies in the past decades. Many phase I/II trials showed promising progression-free survival (PFS)/overall survival (OS) rates; however, results for gemcitabine-based combination therapy in phase III trials have been unsatisfactory thus far. Better study designs and rigorous restrictions should be applied to future phase I/II trials in order to create more meaningful results for phase III trials. Table I adapted from Zafar SF et al. summarizes those trials (8).
Only two notable phase III trials in the past five years produced significant impact on median OS. Moore and colleagues introduced erlotinib, a human epidermal growth factor receptor (HER1/EGFR) inhibitor, to the gemcitabine monotherapy (21). OS for the erlotinib/gemcitabine arm was significantly prolonged (median 6.24 months vs. 5.91 months, p=0.038). However, in terms of clinical benefit, this was rather disappointing, given a modest improvement in survival advantage of 0.33 months. Based on the individual activity of each chemotherapy against PDA, Conroy and colleagues helped to establish a new combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as an acceptable alternative to gemcitabine-based therapy (22). The FOLFIRINOX arm was directly compared to the gemcitabine arm and showed significant improvements in median OS (11.1 months vs. 6.8 months, p<0.001), PFS (6.4 months vs. 3.3 months, p<0.001) and objective response rate (31.6% vs. 9.4%, p<0.001). However, the FOLFIRINOX arm was associated with more frequent side-effects, including grade 3 or 4 neutropenia, febrile neutropenia, thrombocytopenia, diarrhea and sensory neuropathy. At six months' follow-up, patients in the FOLFIRINOX group reported a definitive decrease in quality of life (QoL), but the time until definitive deterioration in QoL also increased. FOLFIRINOX was, therefore, recommended mainly for younger patients (<76 years) and hose with good performance status (Eastern Cooperative Oncology Group score of 0 or 1).
Gemcitabine-based combination chemotherapy in advanced pancreatic adenocarcinoma.
To better-understand the impact of FOLFIRINOX compared with gemcitabine on QoL in patients with metastatic PDA, Gourgou-Bourgade et al. enrolled 342 patients and randomized them to either regimen. QoL was assessed using the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every two weeks (23). The FOLFIRINOX group reported a significant improvement in global health status. Both groups had improvement in emotional functioning along with a decrease in pain, insomnia, anorexia, and constipation. The time until definitive deterioration analysis of 10 points or more was significantly longer for the FOLFIRINOX group for global health status, all five functional domains (physical, role, emotional, cognitive and social), and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation).
With explosive development of new regimens, physicians are left with many choices for locally advanced and metastatic PDA. This is reflected in the current National Comprehensive Cancer Network (NCCN) guidelines. Acceptable monotherapies include gemcitabine, fixed-dose rate (FDR) gemcitabine, and capecitabine. Acceptable chemotherapy combinations include gemcitabine/erlotinib, FOLFIRINOX, gemcitabine/capecitabine, gemcitabine/cisplatin, FDR gemcitabine/docetaxel/capecitabine, gemcitabine/nab-paclitaxel and fluoropyrimidine/oxaliplatin (24). In the end, choosing a regimen is at the physician's discretion and clinical judgment based on the patient's clinical condition, comorbidities, age and performance status.
New Developments Since 2011
Gemcitabine-based combinations involving molecular target agents. With the advancement of technology, molecular target therapy has become more readily available and acceptable for many different types of cancer, PDA included. The most common targets involve the inhibition of epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), or their combination. Successful results of the gemcitabine/erlotinib study prompted scientists to look for new combinations that could improve median OS. Among many phase I/II/III studies, a notable phase III trial involved axitinib (potent, selective inhibitor of VEGF receptors 1, 2 and 3) plus gemcitabine versus placebo plus gemcitabine in patients with advanced PDA (25). Even though axitinib was shown to increase the OS in a phase II trial, the result of this phase III trial was disappointing. The median OS was 8.5 months for gemictabine/axitinib and 8.3 months for gemcitabine/placebo. Although axitinib was well-tolerated, with the most common side-effects being anemia, lymphopenia, hypertension and fatigue, it did not improve OS.
Gemcitabine-based combination chemotherapy involving molecular target agents.
Gemcitabine-based combination chemotherapy not involving molecular target agent.
Chemotherapy for refractory advanced pancreatic adenocarcinoma.
As mentioned above, erlotinib/gemcitabine combination was one of the few phase-III trials that reported a statistical significant benefit for OS. Because of findings of synergistic effect of cisplatin with gemcitabine in several other studies, Hwang et al. added cisplatin to the regimen. The triple therapy was effective against advanced PDA, with a response rate of 26% and median OS of 6.8 months; however, the study was closed prematurely due to three unexpected treatment-related deaths (26). Further studies are needed to investigate the appropriate dosage for this triple therapy. Table II summarizes important trials involving molecular target therapy since 2011.
Gemcitabine-based combinations not involving molecular target agent. S-1 is an oral fluoropyrimidine derivative, widely used for a variety of malignancies. In previous phase-II trials, S-1 was found to have activity against metastatic PDA, with response rate of 21.1-37.5% and median OS of 5.6-9.2 months. Based on these findings, two randomized phase-II trials investigated the efficacy of gemcitabine/S-1 (GS) combination. Ueno and colleagues reported a high overall response rate and OS of 44.4% and 10.1 months respectively, among 55 patients enrolled in the study. Hematological toxicity was frequent (neutropenia 80%, leucopenia 59%, thrombocytopenia 22%), but these episodes were transient, with only one episode of febrile neutropenia greater than grade 3 (32). This survival benefit was confirmed in a multicenter phase-II study by Ozaka and colleagues (33): 117 patients were randomized into either the GS group or gemcitabine group. The overall response rates for the GS group and gemcitabine group were 28.3% and 6.8%, respectively. Moreover, the overall OS was also significantly longer in the GS group (13.7 months vs. 8.0 months, p=0.035). Besides GS, another combination worth mentioning is gemcitabine/docetaxel/capecitabine (GTX), which was shown in phase II trials to prolong survival. Jesus-Acosta and colleagues were able to replicate previous findings in their multicenter randomized study of 154 patients (117 with metastatic disease and 37 with locally advanced disease). The study recorded a response rate of 11% and OS of 11.6 months (11.3 months for metastatic disease and 25.0 months for locally advanced disease) (34). Table III summarizes other notable trials.
Other combinations not gemcitabine-based. FOLFIRINOX combination was tested in a phase III clinical trial and was shown to significantly increase median OS when compared to gemcitabine in a strict protocol setting (22). Despite this, FOLFIRINOX has not become widely popular due to concerns of toxicity. In multi-institutional experience, Peddi and colleagues tried to document the use of FOLFIRINOX and its efficacy and tolerance in a practical setting (39). Sixty one patients were included in this study. The majority of them had metastatic disease (62.3%) but good functional status (86.9% with ECOG of 0 or 1). Overall, the response rate was 25% and median OS was 13.5 months. Twenty-one patients (34.4%) were hospitalized as a result of therapy but there were no therapy-related deaths. The rate of therapy discontinuation as a result of adverse events was high (37.7%). These findings confirmed previous concerns of drug toxicity and adverse events of this regimen.
Epidermal growth factor receptor-2 (HER2) overexpression has been reported in up to 45% of cases of pancreatic cancer. In order to verify its clinical impact, Harder et al. studied a drug combination which included capecitabine and trastuzumab, a HER2 antibody (40). The study was closed prematurely due to low HER2 expression (17 out of 212 patients screened). Although the therapy was well-tolerated, the OS was not favorably altered compared to historical standard chemotherapy. The authors recommended no further evaluation of anti-HER2 treatments in patients with metastatic PDA.
Combinations for refractory advanced PDA. Patients who are refractory to first-line agents have dismal prognosis, with treatments mainly for palliative purposes. Even so, efforts have been made to find the best combinations to prolong life and improve QoL. The German CONKO study group helped establish the combination of oxaliplatin/folinic acid/5-FU (OFF) as one of the standard second-line treatments. In a randomized phase-III study, the group was able to recruit 46 patients (prior to premature termination due to lack of acceptance of best supportive care by patients and physicians) and randomize them into either OFF or best supportive care (BSC). There was a significant difference in median second-line survival between the OFF arm and BSC arm (4.82 months vs. 2.30 months, p=0.008). In another prospective open-label, single-arm study, Isayama et al. followed patients with advanced PDA refractory to gemcitabine and S-1; these patients were given a combination of gemcitabine and oxaliplatin. None of the 22 patients enrolled in the study had an objective response (41). The median OS and time-to-progression were 6.8 months and 2.6 months, respectively. The combination chemotherapy was tolerable (neutropenia 14%, anorexia 23% and no treatment-related death), but the authors concluded that it had limited activity against refractory disease. Currently acceptable second-line therapies based on NCCN recommendations include gemcitabine (for patients not previously treated with the drug), capecitabine, 5-FU/leucovorin/oxaliplatin, and capecitabine/oxaliplatin. To summarize, findings of recent trials on refractory PDA were discouraging, with most trials resulting in no response. Table IV reviews these findings.
Conclusion
Since 1997, gemcitabine has been the standard-of-care for advanced PDA. With the introduction of gemcitabine-based combination with capecitabine or platinum, molecular target therapy, and FOLFIRINOX, physicians are now equipped with more options. For patients with good functional status, FOLFIRINOX and gemcitabine-based combination can be used. Patients with poor functional status can be treated with gemcitabine and capecitabine monotherapy, or gemcitabine/erlotinib combination. Although statistically significant in clinical trials, these new regimens carry only modest impact on median OS in clinical practice, with improvement of several months over 5-FU. Scientists have relentlessly studied new combinations and molecular target pathways in order to overcome the resistance of PDA to chemotherapy. As we make progress within the next decades, one thing we should keep in mind is the purpose of the treatment. Is it for palliation or for cure? More drugs mean more toxicity and side-effects. Therefore, the patient's quality of life should be the top priority when considering a treatment for patients with advanced PDA.
- Received March 14, 2013.
- Revision received April 4, 2013.
- Accepted April 5, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
