Abstract
Introduction
Pancreatic cancer remains the tenth most common cancer diagnosis in the United States with approximately 48,960 new cases diagnosed in 2015 [American Cancer Society, 2015; SEER, 2015]. Unfortunately, pancreatic cancer remains a deadly diagnosis and is responsible for the fourth largest number of cancer-related deaths. With an estimated 40,560 deaths in 2015 it is second only to lung, prostate, and colorectal cancers. Unfortunately, most of patients with pancreatic cancer present with advanced disease and half of patients have distant metastatic disease at initial presentation [SEER, 2015]. Overall survival (OS) remains poor; only 7.2% of patients survive to 5 years following diagnosis. Unfortunately, the possibility of cure is limited unless the disease is detected early and completely resected. Recent studies have shown a benefit of a few chemotherapeutic regimens in the metastatic setting and investigators are currently exploring their role in earlier stages of pancreatic cancer. However, there remains a strong need for the development of novel agents, identification of biomarkers and improvement in the toxicity profile of current regimens.
Resectable or borderline resectable
Approximately only 20% of patients with pancreatic cancer are deemed resectable at the time of initial diagnosis. Despite improvements in chemotherapy, radiation and surgery, the median survival is still only 20 months for these patients. With regards to adjuvant therapy after an R0 resection, there is a dichotomy of ideas. Those in the United States often treat with adjuvant chemoradiation based on the GITSG 91–73 and RTOG 9704, while those in Europe often treat with chemotherapy alone based on the EORTC 40891 and ESPAC–1 trials [Kalser and Ellenberg, 1985; Neoptolemos et al. 2004; Smeenk et al. 2007; Regine et al. 2011]. For borderline-resectable patients, the current standard of care is neoadjuvant therapy such as chemoradiation, followed by surgical resection. Unfortunately, many neoadjuvant therapies exist such as 5-FU/RT, gem/RT, gem/nab-paclitaxel or FOLFIRINOX followed by 5-FU/RT, or gemcitabine/docetaxel/capecitabine (GTX) followed by 5-FU/RT, without clear evidence that one is superior over another [Breslin et al. 2001]. Recent studies have attempted to improve local and distant control with a focus on novel chemotherapeutic agents. Three abstracts presented at this year’s annual ASCO meeting, 2015, highlight some of the data gleaned from this research.
The AGITG GAP phase II study evaluated patients with resectable pancreatic cancer who underwent neoadjuvant chemotherapy consisting of nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 on days 1, 8 and 15 (28-day cycle) followed by resection and four cycles of postoperative chemotherapy [Barbour et al. 2015]. Drawing from impressive results in the metastatic setting, these authors hoped to evaluate the feasibility and improvement in R0 resection rate with this neoadjuvant chemotherapy regimen. They found that 36 (88%) of patients underwent surgery, while 5 (12%) did not, secondary to disease progression, refusal and cholangitis. Only 4 (10%) of resected patients had grade III to IV septic events and there were no treatment-related deaths. The R0 resection rate was 86% (25 patients) with a 0 mm margin, and 52% (15 patients) with a 1 mm margin. Overall, there was 95% compliance with neoadjuvant chemotherapy while only a 60% compliance with postoperative chemotherapy. Neoadjuvant chemotherapy was associated with a low toxicity profile and high R0 resection rate and deserves further study in a randomized setting.
Building on the impressive results from the CONKO–001 trial that showed a survival advantage for adjuvant gemcitabine versus observation for resected pancreatic cancer, the CONKO–005 was a randomized phase III trial that investigated the addition of erlotinib to gemcitabine in the adjuvant setting [Oettle et al. 2007]. A total of 436 patients were randomized to adjuvant gemcitabine plus erlotinib versus gemcitabine alone. Toxicity was slightly worse in the gemcitabine and erlotinib arm compared with the gemcitabine-alone arm with increased rash (7% versus 0.4%), diarrhea (5% versus 1%), fatigue (5% versus 2%), hypertension (3% versus 1%), and thrombocytopenia (5% versus 2%). There was no difference in disease-free survival or OS (median OS 24.6 months gemcitabine/erlotinib and 26.5 months gemcitabine alone), however, there was a trend towards improvement in the combined-drug arm after 2 years. Interestingly, there was no correlation between the grade of rash and improvement in disease-free survival in those who received erlotinib. At this time, the addition of erlotinib to gemcitabine in the adjuvant setting does not impact survival, however, further investigation and longer follow up may be helpful.
Following data in the metastatic setting, investigators evaluated the tolerability and efficacy of neoadjuvant FOLFIRINOX (infusional 5-FU, oxaliplatin, leucovorin and irinotecan) with standard of care chemoradiation (50.4 Gy and capecitabine 825 mg/m2 twice daily) and postoperative gemcitabine (100 mg/m2 on days 1, 8, and 15 × 2 cycles) in borderline resectable pancreatic cancer (Alliance Trial A021101) [Katz et al. 2015]. Compliance with neoadjuvant therapy was impressive; all 22 patients who started therapy completed FOLFIRINOX and 95% completed chemoradiation. Only 7 patients did not undergo planned resection because of progression (6) and refusal (1). The RECIST responses during preoperative therapy were: 2 complete response (CR); 4 partial response (PR); 15 stable disease; and 1 progressive disease (PD). For all comers, the R0/R1 resection rate was 68%, with 9% achieving a pathologic CR. Among the 15 (68%) patients who underwent resection, 14 (93%) were R0. Toxicity was moderate with 46% grade III and 5% grade IV events during neoadjuvant therapy, while no patients received any toxicity during chemoradiation. Despite limited RECIST response, neoadjuvant FOLFIRINOX and chemoradiation was well tolerated and provided impressive R0 resection and pathologic CR rates.
Unresectable or locally advanced
Approximately 30% of patients with pancreatic cancer present with locally advanced disease at the time of initial diagnosis. There are many treatment options, including definitive chemoradiation, induction chemotherapy followed by restaging and chemoradiation, or chemotherapy alone. Chemoradiotherapy regimens often include gemcitabine or 5-FU, with many oncologists turning to capecitabine for its tolerability and efficacy [Saif et al. 2007]. Chemotherapy without radiation often includes regimens such as gemcitabine with or without nab-paclitaxel or FOLFIRINOX. However, those who can undergo aggressive therapy achieve a median OS of approximately 12 months.
A Japanese team presented results from a randomized phase II study of S-1 (an oral fluoropyrimidine) with concurrent radiotherapy with or without induction gemcitabine before chemoradiation, at the annual meeting of ASCO 2015 [Fukutomi et al. 2015]. Importantly, those who received induction gemcitabine were restaged, and only those with controlled disease went on to receive chemoradiation. After chemoradiation, gemcitabine was continued until no longer tolerated or efficacious. With 100 appropriate patients, they found no difference in 1-year OS or progression-free survival (PFS). There was more anorexia (16% versus 4%), fatigue (8% versus 4%), and nausea (8% versus 2%) in the induction arm; all other toxicities were comparable. There were, however, two concerning treatment-related deaths in the induction arm (pneumonitis and duodenal hemorrhage). The authors point to the importance of a phase III trial comparing induction chemotherapy followed by chemoradiation, with chemoradiation only; however, based on the presented data, there are significant concerns about its efficacy and toxicity profile, as mentioned above.
Metastatic pancreatic adenocarcinoma
First-line chemotherapy for metastatic pancreatic cancer, per National Comprehensive Cancer Network (NCCN) guidelines, depends on performance status. For patients with a pretreatment performance status of 0 to1, first-line treatment remains a combination of leucovorin, 5-fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX), or gemcitabine in combination with an albumin-bound paclitaxel, capecitabine, erlotinib, or cisplatin [NCCN]. FOLFIRINOX is generally given to those with the highest pretreatment performance status and no liver dysfunction, as it is more toxic than gemcitabine-based combination regimens. Other less frequently used regimens include fixed-dose gemcitabine, docetaxel, and capecitabine (GTX) or a combination of capecitabine and oxaliplatin (Cape-Ox). For those with poor performance status, single-agent gemcitabine or palliative care with or without chemotherapy is recommended.
Second-line chemotherapy for those who progress following first-line treatment is not standardized, but includes fluoropyrimidine-based chemotherapy (if previously treated with gemcitabine) or gemcitabine-based therapy (if previously treated with a fluoropyrimidine).
Recent efforts have focused on improving treatment options for pancreatic cancer. A summary of the studies presented at the 2015 ASCO Annual Meeting is presented in Table 1.
Summary of the abstracts presented at the 2015 ASCO annual meeting.
OS, overall survival.
Rigosertib is a first-in-class Ras mimetic and small-molecular inhibitor of multiple signal pathways, including PLK-1 and PI3-K that has shown efficacy in preclinical pancreatic cancer models. One study presented at ASCO 2015 assessed the combination of rigosertib plus gemcitabine versus gemcitabine alone in treatment-naïve patients with metastatic pancreatic adenocarcinoma. A total of 160 patients were randomized 2 to 1 to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m2 via 2-hour continuous infusion given twice weekly for 3 weeks of a 4-week cycle (106 patients), versus gemcitabine 1000 mg/m2 weekly for 3 weeks in a 4-week cycle (54 patients) [O’Neil et al. 2015]. Median OS was 6.1 months for the rigosertib group versus 6.4 months for the gemcitabine group (with a hazard ratio 1.25, 95% confidence interval, 0.85–1.81). Median PFS was 3.4 months for both groups (hazard ratio 0.96, 95% confidence interval, 0.68–1.36). In addition, there was no correlation between KRAS and TP53 gene mutations and rigosertib efficacy. The most common grade III toxicities were neutropenia (8% versus 6%), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The combination of rigosertib plus gemcitabine failed to demonstrate an improvement in survival compared with gemcitabine alone.
Another study retrospectively analyzed the effectiveness and tolerability of early maintenance capecitabine administered to patients with metastatic pancreatic adenocarcinoma treated with first-line FOLFIRINOX [Reure et al. 2015]. A total of 103 patients treated between November 2009 and July 2014 were identified, 31 of who were treated with a minimum of 4 cycles of FOLFIRINOX and received maintenance capecitabine 2000 mg/m2 until progression of disease. At first progression, patients were then retreated with FOLFIRINOX until second progression. A total of 11 of 31 patients required dose reduction of maintenance capecitabine due to cutaneous and digestive toxicities. Median OS was 19 months. Survival rates were 74% at one year and 24% at two years. Median PFS was 11 months. A total of 30 patients relapsed during capecitabine maintenance. The role of maintenance capecitabine therapy will further be addressed in a French multicenter phase II/III study.
DocOx (AIO-PK0106), is a prospective single-arm, non-randomized, multicenter phase II trial that investigated the use of combination docetaxel plus oxaliplatin for second-line chemotherapy for advanced pancreatic adenocarcinoma [Ettrich et al. 2015]. A total of 44 patients were included between 2008 and 2012. The majority of patients received gemcitabine-based combination first-line chemotherapy. Docetaxel 75 mg/m2 on day 1 and oxaliplatin 80 mg/m2 on day 2 were administered in 21-day cycles for up to 8 cycles. The primary endpoint was tumor response according to RECIST 1.0; secondary endpoints were PFS, OS, safety or toxicity, quality of life and clinical benefit. Tumor response was achieved in 15.9% of patients, with 7 partial remissions and no complete remissions. Median PFS was 7 weeks (95% confidence interval, 6–15.9 weeks). Median OS was 40 weeks (95% confidence interval, 20.4–56.4 weeks). Adverse events included grade III or IV neutropenia (63.6%), febrile neutropenia (4.6%), grade III or IV mucositis (29.6%), and infection (18.2%).
An AGEO study prospectively analyzed the efficacy and tolerability of second-line gemcitabine plus nab-paclitaxel after FOLFIRINOX failure in patients with metastatic pancreatic adenocarcinoma [Portal et al. 2015]. From February 2013 to July 2014, 57 consecutive patients from 12 French centers were treated with nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after progression following FOLFIRINOX first-line chemotherapy. Nab-paclitaxel plus gemcitabine were administered on days 1, 8, and 15 every 4 weeks until disease progression, unacceptable toxicity, or patient preference to discontinue chemotherapy. Patients received a median of 4 cycles (range 1 to 12); disease control rate was 58% with an 18.5% objective response rate according to RECIST 1.0. Median OS was 8.8 months (95% confidence interval, 6.2–9.7). Median PFS was 5.1 months (95% confidence interval, 3.2–6.2). Grade III or IV toxicities were reported in 40% of patients, including neutropenia (12%), neurotoxicity (12%), asthenia (8%), and thrombocytopenia (8%). The authors are planning a phase III randomized trial as follow up.
Newer agents
Despite advances in treatment of pancreatic cancer over the preceding years, the most active regimens in the metastatic setting, FOLFIRINOX and gemcitabine/nab-paclitaxel, result in median OS of less than 12 months [Moore et al. 2007, Conroy et al. 2011, Von Hoff et al. 2013]. This fact underscores the need for novel therapeutics in the treatment of this disease [Saif, 2013].
At this year’s conference Hidalgo and colleagues presented a phase IB study of demcizumab and gemcitabine with or without nab-paclitaxel in the first-line treatment of patients with locally advanced or metastatic pancreatic cancer [Hidalgo et al. 2015]. Demcizumab is an IgG2 antibody that binds to delta-like ligand 4 (DLL4), a component of the intracellular Notch-signaling pathway which plays an important role in angiogenesis, cancer stem-cell viability and tumor growth [Yan and Plowman, 2007; Hoey et al. 2009]. In preclinical experimental models of pancreatic cancer, blockade of DLL4 has been shown to inhibit pancreatic tumor sphere formation in vitro and decrease cancer stem-cell frequency in mouse xenograft model of pancreatic cancer. Additionally, anti-DLL4 showed an additive effect on antitumor activity in combination with gemcitabine and demonstrated efficacy in tumors resistant to gemcitabine [Yen et al. 2012].
In the study presented by Hidalgo and colleagues, patients in cohorts 1 to 3 received either demcizumab 2.5 mg/kg every 2 weeks or every 4 weeks, or 5 mg/kg every 4 weeks along with gemcitabine 1000 mg/m2 given 7 of the first 8 weeks, and then 3 of every 4 weeks [Hidalgo et al. 2015]. Patients in cohorts 4 to 6 received demcizumab 2.5 mg/kg, 3.5 mg/kg or 5 mg/kg every 2 weeks with gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 0, 7 and 14 every 28 days. Adverse events of all grades included fatigue (36%), nausea (32%), vomiting (23%), hypertension (21%), diarrhea (20%), decreased appetite (18%), elevated B-natriuretic peptide [BNP (18%)] and peripheral edema (16%). Of note, grade II and III pulmonary hypertension occurred in 2 patients and grade II heart failure occurred in 1 patient receiving demcizumab for more than 100 days. During the study, the protocol was amended to include BNP and echocardiogram monitoring as well as the use of angiotensin-converting-enzyme inhibitor or carvedilol for rising BNP. Demcizumab use in further cohorts was truncated to 70 days of therapy. Of the patients evaluated, 69% (n = 11) in the demcizumab/gemcitabine group and 89% (n = 25) in the demcizumab/gemcitabine/nab-paclitaxel group achieved a partial response or stable disease. PFS was 9.0 months in demcizumab/gemcitabine/nab-paclitaxel group with an estimated OS of 10.1 months.
Dr Sunil Hingorani presented data from a phase II study of gemcitabine/nab-paclitaxel with or without PEGPH20 in patients with previously untreated metastatic pancreatic cancer [Hingorani et al. 2015]. PEGPH20 is a pegylated hyaluronidase, which degrades hyaluronan within the pancreatic cancer tumor microenvironment, thereby disrupting the integrity of the protective tumor extracellular matrix. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma [Feig et al. 2012; Provenzano et al. 2012]. In the oral presentation at the meeting, overall response rate, PFS and OS data was presented for each treatment arm. Additionally, subgroups of patients with high expression of hyaluronan (HA high) or low expression (HA low) were examined. In aggregate, there was no difference in either overall response rate or PFS for the total population of patients or those in the HA low group with the addition of PEGPH20. However, the key finding of this study was statistically significant improved overall response (52% versus 24%; p = 0.038) and PFS (9.2 months versus 4.3 months; p = 0.05) in the group receiving PEGPH20 versus placebo. OS was 12 months in the group receiving PEGPH20 plus gemcitabine/nab-paclitaxel, and 9 months in the group receiving gemcitabine/nab-paclitaxel alone, which was not statistically significant (p = 0.62). Of note, increased rates of thromboembolism in patients receiving PEGPH20 were identified in stage 1 of the study (42% in the PEGPH20 group versus 25% in the placebo arm), requiring the protocol to be amended with every patient receiving enoxaparin prophylaxis. The thromboembolic-event rate in the subsequent stage of the study was equivalent (28% in the PEGPH20 arm and 29% in the placebo group).
Another phase II study was presented by Chung and colleagues that compared selumetinib (MEK 1/2 inhibitor) 100 mg orally daily given with MK-2206 (Akt inhibitor) 135 mg orally weekly, compared with mFOLFOX in patients with metastatic pancreatic cancer previously treated with gemcitabine-containing chemotherapy [Chung et al. 2015]. A total of 115 patients were enrolled and the primary endpoint of OS was not statistically different in the two different treatment arms, with median survival of 4.0 months in the selumetinib and MK-2206 arm and 6.9 months in the mFOLFOX arm (p = 0.2). PFS was inferior in the experimental-treatment arm (1.9 months) versus the mFOLFOX arm (2.0 months) with a p value of 0.04. There was a higher proportion of patients who discontinued the experimental-treatment arm due to adverse effects (24%) compared with the mFOLFOX arm (10%). Grade III and IV adverse events that were increased in the selumetinib/MK-2206 arm compared with the mFOLFOX arm included elevated LFTs, 15% versus 0%, dehydration, 9% versus 2%, hyperglycemia, 13% versus 2%, mucositis, 7% versus 0%, acneiform rash, 9% versus 0%, erythema multiforme, 2% versus 0%, maculopapular rash, 13% versus 0%, and Stevens–Johnson syndrome, 2% versus 0%. Overall, the results of this study suggest that the combination treatment with selumetinib/MK-2206 is unlikely to be a viable or effective treatment in patients with metastatic pancreatic cancer.
Biomarkers or genomics
Despite extensive investments in targeted therapy trials for pancreatic cancer there has yet to be a meaningful impact on survival. Biomarkers that are both predictive and prognostic may play an important role in the treatment of pancreatic cancer. At present, serum CA19-9 (carbohydrate antigen 19-9) is the only FDA-approved biomarker for pancreatic ductal adenocarcinoma, however, its utility as prognostic predictive of disease recurrence is somewhat debatable [Berger et al. 2008; Pelzer et al. 2013; Shah and Saif, 2013]. There has been increasing enthusiasm in the pancreatic cancer biomarker field with more than 2000 biomarker studies implicating thousands of informative genes as candidate biomarkers [Fong and Winter, 2012; Joza and Saif, 2014]. There have been emerging data about many biomarkers of interest such as hENT1 (human equilibrative transporter 1), KRAS and SPARC (secreted protein, acidic, and rich in cysteine) presented in ASCO 2015.
hENT1 is a member of nucleoside-transporter proteins, which mediates cellular entry of cytotoxic chemotherapies such as gemcitabine [Farrell et al. 2009; Li et al. 2014]. hENT1 is the most abundant, and is the major route for gemcitabine transport. Therefore, hENT1 may potentially be a predictive marker for gemcitabine effectiveness [Kim et al. 2011]. At the annual meeting of ASCO 2015, two abstracts (e15295, e15216) further provided data to support the role of hENT1 as a predictive marker for gemcitabine effectiveness in pancreatic cancer with increased OS in patients with high epithelial hENT1 expression [Calegari et al. 2015; Renouf et al. 2015].
Overexpression of protein SPARC has been noted in pancreatic cancer and its peritumoral stroma. SPARC is involved in cell-matrix interaction; cell migration, proliferation and angiogenesis [Von Hoff et al. 2011]. Unfortunately, abstract e15264 demonstrated that SPARC expression level does not serve as a prognostic biomarker in advanced pancreatic cancer in patients in contrast to initial data [Von Hoff et al. 2011; Ormanns et al. 2015].
Abstract 4022 demonstrated that serial measurements of circulating tumor DNA KRAS mutation load alone or in combination with serum CA19-9 seems to be a prognostic biomarker in patients with unresectable pancreatic cancer undergoing palliative chemotherapy with either gemcitabine or FOLFIRINOX [Johansen et al. 2015]. Another abstract (4023) showed that pancreatic cancer with KRAS mutations at low-allelic ratios carry prognostic differences utilizing next-generation sequencing technologies [Lennerz and Stenzinger, 2015]. Further validation of these markers is needed in larger studies. Knowledge of how pharmacologic treatments are influenced by genetics may help improve the efficacy of therapy by providing more personalized medicine through guiding the choice of molecular and gene therapy for individual pancreatic-cancer patients based on their genomic information.
Discussion
Pancreatic adenocarcinoma remains a deadly malignancy with the only chance for cure occurring with early detection and complete surgical resection. All of the emerging data presented at the ASCO 2015 meeting indicate our desire and effort to improve outcomes while minimizing toxicity. Improvements in resectability and advances in local and distant control will likely lead to a survival benefit when tolerated. Locally advanced or unresectable pancreatic cancer carries a dismal prognosis, with the only real attempt of cure coming from aggressive neoadjuvant therapy aimed at downstaging of the tumor to resectable status. Despite aggressive local and distant control, failure with locally advanced pancreatic cancer remains a common scenario. Improved outcomes will be attained using prognostic and predictive factors to guide treatment while maintaining aggressive local control with dose-escalated radiation (such as SBRT, stereotactic-body-radiation therapy) and improved novel chemotherapeutic agents such as targeted therapies that will fight disease distantly. Given that 50% of patients have metastatic disease at time of diagnosis, most treatment approaches are palliative and focus solely on extending survival. First- and second-line chemotherapy regimens do prolong survival, but in a limited fashion and are not without significant toxicities. Patients with good performance status are typically offered combination-chemotherapy regimens, most commonly FOLFIRINOX or gemcitabine plus nab-paclitaxel. Patients with poor performance status are offered treatment with a single chemotherapeutic agent, typically gemcitabine or capecitabine. More randomized, controlled trials are needed in this vastly understudied topic.
Despite the disappointing results of the study with rigosertib, it exhibits the increasing need to develop further therapeutics that may act synergistically with conventional chemotherapeutic agents [O’Neil et al. 2015]. On the other hand, Reure and colleagues studied the efficacy and tolerability of maintenance capecitabine chemotherapy following first-line treatment with FOLFIRINOX. Median OS was 19 months, but data were limited given that only 31 patients were included. In addition, 30 of 31 patients relapsed while on capecitabine maintenance chemotherapy. Dose reductions did occur in 11 of 31 patients due to significant cutaneous and digestive toxicities [Reure et al. 2015]. The authors note that a phase II or III multicenter study is planned. Given the success of maintenance chemotherapy regimens in other malignancies, consideration of maintenance chemotherapy for pancreatic cancer is a growing trend as clinicians seek to extend PFS and OS [Conroy et al. 2011]. The authors of the DocOx study indicate that response and toxicity profiles are comparable to other commonly used second-line regimens, but did not directly compare this regimen with others [Ettrich et al. 2015]. The AGEO study showed that 40% of patients developed grade III and IV toxicities, which has been the downfall of many combination-chemotherapy regimens for pancreatic cancer [Portal et al. 2015].
Hidalgo’s study presents a novel first in class monoclonal antibody targeting the Notch-signaling pathway and stem-cell survival in pancreatic cancer [Hidalgo et al. 2015]. There are strong preclinical data for the efficacy of demcizumab alone and in combination with chemotherapy for pancreatic cancer, and further clinical studies will be necessary to determine if this novel agent offers PFS and OS benefit over current therapeutic options. The increased rates of hypertension and cardiac toxicities observed in this phase I study will need to be closely followed up in subsequent studies. There is currently a randomized, double-blind phase II study recruiting, that examines the efficacy and safety of demcizumab at a dose of 3.5 mg/kg every 2 weeks in combination with gemcitabine/nab-paclitaxel compared with gemcitabine/nab-paclitaxel alone [National Institue of Health, 2015a]. On the other hand, PEGPH20 appears to show activity with improved overall response rate and PFS in the subset of patients with high tumor hyaluronan expression [Hingorani et al. 2015]. The increased risk of thromboembolic events in the PEGPH20 groups appears to be mitigated by use of enoxaparin prophylaxis in patients. PEGPH20 is a promising novel therapeutic which merits further investigation in phase III studies, as well as in combination with other regimens active in pancreatic cancer such as FOLFIRINOX in the SWOG 1313 study [Southwest Oncology Group, 2015].
Table 2 summarizes ongoing studies of first-line therapies for metastatic pancreatic adenocarcinoma [National Institue of Health, 2015b].
Summary of ongoing studies of first-line therapy for metastatic pancreatic adenocarcinoma [http://www.clinicaltrials.gov].
mFOLFIRINOX, modified FOLFIRINOX; FOLFIRINOX, leucovorin, 5-fluorouracil, irinotecan, oxaliplatin; FOLFOX, 5-fluorouracil, leucovorin, oxaliplatin; RECIST, response evaluation criteria in solid tumors; OS, overall survival; PFS, progression-free survival.
First- and second-line chemotherapy regimens for metastatic pancreatic adenocarcinoma remain limited by toxicities and disease progression. However, ongoing efforts to prolong survival through combination-chemotherapy regimens are focused on novel small-molecule signal-pathway inhibitors, monoclonal antibodies, and maintenance therapies that may provide a synergistic effect to the current standards of care and extend both PFS and OS [Saif et al. 2014]. In addition, there remains a need for standardization of second-line therapies, all of which remain limited in their effectiveness [Kang and Saif, 2008].
In ASCO 2015, we had further insights on hENT1, KRAS and SPARC as biomarkers for pancreatic cancer. Understanding the molecular biology of pancreatic carcinogenesis will provide an avenue for the clinician to use different molecular biomarkers in prognosticating cancer patients. None of these markers are currently validated for use in routine clinical practice, while we await more results from biomarker-based clinical trials in pancreatic cancer. Such prospective studies will hopefully be able to elucidate personalized pancreatic cancer care, a growing trend in many cancer sites.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare that there is no conflict of interest.