Developments in metastatic pancreatic cancer: Is gemcitabine still the standard?

Abstract

In the past 15 years, we have seen few therapeutic advances for patients with pancreatic cancer, which is the fourth leading cause of cancer-related death in the United States. Currently, only about 6% of patients with advanced disease respond to standard gemcitabine therapy, and median survival is only about 6 mo. Moreover, phase III trials have shown that adding various cytotoxic and targeted chemotherapeutic agents to gemcitabine has failed to improve overall survival, except in cases in which gemcitabine combined with erlotinib show minimal survival benefit. Several meta-analyses have shown that the combination of gemcitabine with either a platinum analog or capecitabine may lead to clinically relevant survival prolongation, especially for patients with good performance status. Meanwhile, many studies have focused on the pharmacokinetic modulation of gemcitabine by fixed-dose administration, and metabolic or transport enzymes related to the response and toxicity of gemcitabine. Strikingly, a phase III trial in 2010 showed that, in comparison to gemcitabine alone, the FOLFIRINOX regimen in patients with advanced disease and good performance status, produced better median overall survival, median progression-free survival, and objective response rates. This regimen also resulted in greater, albeit manageable toxicity.

Key Words: Chemotherapy, Palliative therapy, Metastasis, Biomarkers, Pancreatic neoplasms

INTRODUCTION

In 2010, there were an estimated 43 140 new cases and 36 800 deaths from pancreatic cancer in the United States[1]. This represents the 10th most common new cause of cancer and the fourth most common cause of cancer-related death in 2010, highlighting the disproportionate mortality associated with this disease. Additionally, unlike most of the more frequent causes of cancer mortality (lung, colon, prostate, and breast), whose death rates are declining, the death rate for pancreatic cancer has remained relatively stable, which also indicates the limited progress in this field.

Data from the 2000-2007 Surveillance, Epidemiology and End Results registry indicate that at diagnosis, the majority of pancreatic cancer is advanced (50.5% metastatic, 8% localized, 25.9% regional spread, and 15.5% unstaged)[2]. Only 15%-20% of patients are eligible for surgery at diagnosis[3]. Standard surgical procedures include pancreaticoduodenectomy (stomach-or pylorus-preserving) for tumors of the pancreatic head, and distal pancreatectomy with splenectomy for tumors arising in the body or tail of the pancreas[4]. Although radical resection alone, or in combination with other therapy, is the only way to eradicate the disease, only 10%-20% of patients who have radical resection survive beyond 5 years, underscoring the need for better preoperative staging and more effective systemic therapy.

This article reviews a variety of clinical trials for locally advanced or metastatic pancreatic cancer, including those using cytotoxic drugs and targeted agents, to evaluate if gemcitabine (Gem) should still remain the standard chemotherapy for advanced or metastatic pancreatic cancer after 15 years of developments in this field. We also briefly discuss the pharmacokinetic modulation by fixed-dose administration and metabolic or transport enzymes, related to the response and toxicity of Gem.

PALLIATIVE CHEMOTHERAPY IN PANCREATIC THERAPY

5-Fluorouracil

5-Fluorouracil (5-FU) was considered the only chemotherapeutic option for about 20 years until the development of Gem. A systematic review and meta-analysis of nine trials from the American Society of Clinical Oncology (ASCO) 2003, which compared 5-FU-based combination to best support care, showed positive results in overall survival (OS) (6.38 mo vs 3.87 mo, P < 0.0001)[5].

Gem

Single agent Gem: Gem became the standard regimen for advanced pancreatic cancer after a randomized trial in 1997 that presented significant improvements in median OS compared to 5-FU (5.6 mo vs 4.4 mo, P = 0.002). One hundred and twenty-six untreated pancreatic cancer patients randomly received either 5-FU (600 mg/m² once weekly) or Gem (1000 mg/m² weekly × 7 with 1 wk off, followed by weekly × 3 wk every 4 wk). The clinical benefit response (CBR) also significantly improved in Gem-treated patients (23.8% vs 4.8%, P = 0.0022)[6].

Fixed-dose Gem: There has been some evidence suggesting that maintaining a constant dose rate of Gem with a fixed dose rate regimen (FDR) may improve outcomes[7-9]. An initial trial was done by Tempero and colleagues to test this hypothesis. Patients were administered either 2200 mg/m² Gem over 30 min (standard arm) or 1500 mg/m² Gem over 150 min (FDR arm) on days 1, 8 and 15 of every 4-wk cycle. Patients treated with FDR had a trend towards improved survival (8 mo vs 5 mo, P = 0.013) but more severe adverse events, namely hematological toxicity[10]. However, a subsequent phase III Eastern Cooperative Oncology Group (ECOG) trial failed to demonstrate a statistically significant improvement in OS of Gem FDR regimen over the standard administration (6.2 mo vs 4.9 mo)[11].

Biomarkers of Gem: Gem is a specific analog of the pyrimidine nucleotide deoxycytidine, and a prodrug that requires cellular uptake and intracellular phosphorylation[12]. Gem intracellular uptake is mainly mediated by the human equilibrative nucleoside transporter (hENT1) and to a lesser extent, by human concentrative nucleoside transporters (hCNTs), hCNT1 and hCNT3. Gem is phosphorylated to its monophosphate form by deoxycytidine kinase (dCK), and this step is essential for further phosphorylation to its active triphosphate form. The active diphosphate metabolite of Gem is also active and inhibits DNA synthesis indirectly by inhibiting ribonucleotide reductase (RRM1). Gem is inactivated by deoxycytidine deaminase (CDA) and deoxycytidylate deaminase into 2’,2’-difluorodeoxyuridine[13]. Many studies have demonstrated the relationship between Gem metabolic or transport enzymes and clinical outcome.

In clinical studies of pancreatic cancer, the high expression of hENT1 in tumors has been associated with improved survival in patients treated with Gem[14-16]. In the RTOG 9704 trial, 538 patients were randomly assigned to groups that were given either Gem or 5-FU after surgical resection. Immunohistochemistry analysis showed that hENT1 expression was associated with OS and disease-free survival (DFS) in the group given Gem (P = 0.004 and P = 0.003, respectively), whereas hENT1 expression was not associated with survival in the group given 5-FU.

The relationship between the expression of dCK, RRM1, and efficacy of Gem is inconsistent[17-24]. A study reported in ASCO 2011 evaluated the association of hENT1, dCK and RRM1 with efficacy of Gem in 434 patients with resected pancreatic cancer. In multivariate models, Gem was associated with better OS in hENT1 high tumors [n = 163; hazard ratio (HR): 0.44, 95% CI: 0.28-0.69, P < 0.001] and in dCK high tumors (n = 302; HR: 0.57, 95% CI: 0.41-0.78, P = 0.001). In contrast, in dCK low tumors (n = 114, P = 0.73) and in hENT1 low tumors (n = 249, P = 0.66), patients derived no benefit from Gem[25]. Fujita et al[17] also showed high dCK expression groups had a significantly longer DFS in the Gem-treated group (P = 0.0067).

Several reports have demonstrated that the genotype of degradation enzymes such as CDA, is related to Gem-mediated severe adverse reactions[26-30]. Major contributing factors for Gem clearance are genetic polymorphisms of CDA. The CDA 208AA homozygote allele and its related haplotype, is associated with severe drug toxicity in Japanese cancer patients after Gem-based chemotherapy. However, Tanaka et al[30] from MD Anderson Cancer Center have shown that the CDA A-76C genotypes were significantly associated with grade 3/4 neutropenia (P = 0.020).

S-1

S-1 is an oral fluorinated pyrimidine, which contains tegafur, gimeracil, and oteracil in a molar ratio of 1:0.4:1[31-32]. Tegafur, a prodrug of 5-FU, is gradually converted to 5-FU by hepatic microsomal enzymes. Gimeracil inhibits the degradation of 5-FU by inhibiting dihydropyrimidine dehydrogenase; oteracil is a competitive inhibitor of orotate phosphoribosyltransferase that inhibits phosphorylation of 5-FU in the gastrointestinal tract to reduce the gastrointestinal toxicity associated with 5-FU.

Two phase II trials of S-1 in untreated patients with metastatic pancreatic cancer have shown that this appears to be an active and well-tolerated drug[33,34]. A randomized, open-label, three-arm, phase III study (GEST) was reported in ASCO 2011, in which 834 chemotherapy-naive unresectable advanced pancreatic cancer patients with an ECOG performance status (PS) of 0-1 were randomly assigned to receive Gem (1000 mg/m², days 1-8 and 15, q4w), S-1 (80/100/120 mg/d based on BSA, days 1-28, q6w), or GS (Gem 1000 mg/m², days 1 and 8 plus S-1 60/80/100 mg/d based on BSA, days 1-14, q3w)[35]. S-1 was confirmed to be non-inferior to Gem with respect to OS (9.7 mo vs 8.8 mo, P < 0.001). Response rate (RR) was 13.3% and 21.0%, respectively. Grade 3/4 hematological toxicities were more common in the Gem arm (neutropenia 41.0% vs 8.8%, thrombocytopenia 11.0% vs 1.5%), while digestive toxicities were more common in the S-1 arm (anorexia 7.3% vs 11.4%, diarrhea 1.1% vs 5.5%). This is the first trial demonstrating that oral S-1 has similar efficacy and tolerable toxicity to Gem. Therefore, its potential as a first-line treatment for pancreatic cancer warrants further study.

Gem-based combination chemotherapy

Due to the dissatisfactory results of single-agent Gem for advanced pancreatic cancer, a variety of phase III trials have been initiated to investigate the efficacy and toxicity of Gem-based combination therapy (Table 1).

Table 1 Gem combined chemotherapy regimens.

Phase III trial	Combination	No. of patient	OS (mo)	P value	PFS (mo)	P value	RR (%)	P value
Berlin et al[36]	GemFU vs Gem	322	6.7 vs 5.4	0.09	3.4 vs 2.2	0.022	6.9 vs 5.6	NR
Riess et al[37]	GemFU vs Gem	473	6.2 vs 5.85	0.68	NR	0.44	NR	NR
Cunningham et al[43]	GemCap vs Gem	533	7.1 vs 6 .2	0.08	5.3 vs 3.8	0.004	19.1 vs 12.4	0.034
Herrmann et al[41]	GemCap vs Gem	319	8.4 vs 7.2	0.234	4.3 vs 3.9	0.103	10 vs 7.8	NS
Colucci et al[48]	GemCIS vs Gem	107	7.5 vs 5	0.43	4.6 vs 1.8	0.048	26.4 vs 9.2	0.02
Heinemann et al[50]	GemCIS vs Gem	195	7.5 vs 6	0.15	5.3 vs 3.1	0.053	10.2 vs 8.2	NS
Colucci et al[49]	GemCIS vs Gem	400	8.3 vs 7.2	0.38	3.9 vs 3.8	0.8	10.1 vs 12.9	0.37
Louvet et al[52]	GemOX vs Gem	313	9.0 vs 7.1	0.13	5.8 vs 3.7	0.04	26.8 vs 17.3	0.04
Poplin et al[11]	GemOX vs Gem	832	5.7 vs 4.9	0.09	2.7 vs 2.6	0.1	6 vs 9	0.11
Stathopoulos et al[59]	GemIRI vs Gem	145	6.4 vs 6.5	0.97	2.8 vs 2.9	0.795	15 vs 10	0.387
O’Reilly et al[61]	Gem-EXE vs Gem	349	6.7 vs 6.2	0.52	3.7 vs 3.8	0.22	6.3 vs 4.6	NR
Oettle et al[55]	Gem-PEM vs Gem	565	6.2 vs 6.3	0.85	3.9 vs 3.3	0.11	14.8 vs 7.1	0.004
Ioka et al[35]	GS vs Gem	454	10.1 vs 8.8	0.15	5.7 vs 4.1	0.0001	29.3 vs 13.3	NR

OS: Overall survival; PFS: Progression-free survival; RR: Response rate; Gem: Gemcitabine; NR: Not reported; NS: Not significant.

Gem and FU: Two phase III trials which compared Gem plus FU with single-agent Gem in patients with advanced disease did not show any benefit in terms of survival[36,37]. In a phase III ECOG trial, 322 patients with advanced pancreatic cancer were randomized into groups treated with Gem alone or Gem combined with 5-FU. OS was 5.4 mo for Gem and 6.7 mo for Gem plus FU (P = 0.09). Progression-free survival (PFS) was 2.2 mo vs 3.4 mo (P = 0.022).

Gem and capecitabine: Capecitabine is an orally administered fluorouracil pro-drug, which is activated by a three-step targeted process (carboxylesterases, cytidine deaminase, and thymidine phosphorylase). This drug mimics the continuous infusion of 5-FU, and its intratumoral activation improves the therapeutic index and reduces toxicity in normal tissue[38-40].

A phase III trial conducted by Herrmann and colleagues randomized 319 patients into a Gem (1000 mg/m² on days 1 and 8) plus capecitabine (1300 mg/m² on days 1-14 every 21 d) (GemCap) arm, or a standard Gem arm. OS was not statistically significant different between the two arms (8.4 mo vs 7.2 mo, P = 0.23). Only subgroup analysis of patients with good PS (Karnofsky performance status 90-100) showed significant prolongation of median OS in the GemCap arm compared to the Gem arm (10.1 mo vs 7.4 mo, respectively, P = 0.014)[41]. In addition, a more recent analysis of the CBR and quality of life (QOL) did not disclose differences between the two treatment arms[42]. In the more recently reported United Kingdom Phase III trial, a higher dose intensity of Gem (12% higher) and capecitabine (44% higher) was used in 533 patients. GemCap significantly improved objective response rate (ORR) (19.1% vs 12.4%; P = 0.034) and PFS (5.3 mo vs 3.8 mo, P = 0.004), and was associated with a trend towards improved OS (7.1 mo vs 6.2 mo, P = 0.08) compared with Gem alone[43]. A meta-analysis of these two studies revealed a survival benefit for GemCap combination (HR: 0.86; 95% CI: 0.75-0.98).

Gem and S-1: In the GEST trial, 454 patients were enrolled in the Gem arm or GS arm[35]. There was no significant difference in OS between these two treatment groups (8.8 mo vs 10.1 mo, P = 0.15), but PFS differed significantly (4.1 mo vs 5.7 mo, P < 0.0001). RR was 13.3% and 29.3% for the Gem and GS arms, respectively. The EQ-5D QOL score in the GS arm was significantly better than that in the Gem arm (P = 0.003). This trial suggests that GS contributes to a better QOL. Further clinical investigations are needed to ensure its efficacy.

Gem and platinum derivatives: Platinum derivatives are frequently used in combination schedules to treat pancreatic cancer[44-47]. Encouraging results have been obtained in several phase II trials using Gem combined with cisplatin, with a RR ranging from 11.5% to 26.0%, and median OS ranging from 7.1 mo to 8.2 mo[44-46]. The following phase III trial conducted by Colucci and colleagues did not present a benefit in survival for combination treatment (7.5 mo vs 6.0 mo, P = 0.43), despite a marked improvement in RR (26.4% vs 9.2%, P = 0.02) and time to progression (TTP) (4.6 mo vs 1.8 mo, P = 0.048)[48]. Recently, Colucci and colleagues reported another phase III trial with the same regimen. There, the improvement in PFS and RR disappeared when the number of patients increased from 107 to 400[49]. Another randomized phase III trial conducted by Heinemann et al[50] also did not demonstrate statistically significant differences in OS (7.5 mo vs 6.0 mo , P = 0.15), PFS (5.3 mo vs 3.1 mo , P = 0.053) and RR (10.2% vs 8.2%).

The French Multidisciplinary Clinical Research Group in Oncology (GERCOR) conducted a phase II study of Gem and oxaliplatin (GemOx) in 64 patients with advanced or metastatic pancreatic cancer[51]. The encouraging results (PFS 5.3 mo, OS 9.2 mo) in this study prompted the initiation of a phase III trial, conducted by both GERCOR and the Italian Group for the Study of Gastrointestinal Tract Cancer. In this phase III study, GemOx was superior in terms of PFS (5.8 mo vs 3.7 mo, P = 0.04), RR (26.8% vs 17.3%, P = 0.04), and clinical benefit (38.2% vs 26.9%, P = 0.03) in both the metastatic and locally advanced population[52]. However, median OS did not significantly improved (9.0 mo vs 7.1 mo, P = 0.13). The largest trial, the ECOG 6201 trial which was mentioned earlier, showed that the median OS was 4.9 mo for the standard Gem arm, and 5.7 mo for the GemOx arm. These differences were not statistically significant, and GemOx caused higher rates of neuropathy, nausea and vomiting[11].

Gem and pemetrexed: Pemetrexed is a multi-targeted antifolate that has synergistic activity with Gem[53]. Miller et al[54] reported an OS of 6.5 mo, and a median time to treatment failure (TTF) of 4 mo in a phase II trial of pemetrexed as a single agent therapy for advanced pancreatic cancer. A phase III trial was carried out in 565 advanced pancreatic patients who were randomly assigned to either Gem plus pemetrexed (PG) or Gem alone. No significant differences between the two treatment arms were observed in terms of OS (6.2 mo vs 6.3 mo, P = 0.85) and PFS (3.9 mo vs 3.3 mo, P = 0.11), although RR was significantly better in the PG arm (14.8% vs 7.1%, P = 0.004), although hematologic toxicity was significantly more common in this arm as well[55].

Gem and topoisomerase inhibitors: Irinotecan (CPT-11) and exatecan are the most widely used topoisomerase inhibitors[56,57]. The first phase II trial to evaluate the combination regimen of irinotecan with Gem showed a median survival of 5.7 mo and a median TTP of 2.8 mo[58]. A subsequent phase III study failed to improve OS (6.4 mo vs 6.5 mo, P = 0.970), TTP (2.8 mo vs 2.9 mo, P = 0.795) and tumor RR (15% vs 10%, P = 0.387). The incidence of grade 3 diarrhea was higher in the combination group, but grade 3/4 hematologic toxicity and QOL were similar[59]. Another topoisomerase inhibitor, exatecan (DX-8951f), was studied in a randomized phase III trial and was shown to be inferior to Gem in respect to RR and improvement in QOL[60]. Furthermore, the combination of exatecan and Gem failed to show any significant survival benefit over Gem alone in a phase III study (6.7 mo vs 6.2 mo, P = 0.52)[61]. Patients in the combination treatment arm experienced significantly more grade 3/4 toxicity, in particular neutropenia (30% vs 15%, P = 0.001), thrombocytopenia (17% vs 5%, P = 0.004), and vomiting (11% vs 5%, P = 0.04).

Meta-analysis

To overcome the statistical limitation of the individual trials, a meta-analysis was performed to investigate the treatment effects of combination regimens.

In 2007, Sultana and colleagues reported a systematic review and meta-analysis of 4060 patients, comparing Gem-based combination chemotherapy with Gem alone in patients with locally advanced and metastatic pancreatic cancer[62]. OS was significantly better for combination chemotherapy (HR: 0.91; 95% CI: 0.85-0.97), and results from subgroup analysis suggested a survival advantage for Gem combined with either a platinum agent (HR: 0.85; 95% CI: 0.74-0.96) or capecitabine (HR: 0.83; 95% CI: 0.72-0.96), although there was insufficient evidence to support combinations of Gem with either 5-FU (HR: 0.98; 95% CI: 0.86-1.11) or irinotecan (HR: 1.01; 95% CI: 0.84-1.22). Another meta-analysis conducted by Banu and colleagues, which included 5886 patients with advanced pancreatic cancer, showed a small but significant improvement in OS for patients receiving Gem-based doublets compared to Gem alone[63]. In addition, a meta-analysis conducted by Heinemann and colleagues, which included 4465 patients, also revealed a significant survival benefit for Gem combination chemotherapy, with a pooled HR of 0.91 (P = 0.004)[64]. The analysis of platinum-based combinations indicated a HR of 0.85 (P = 0.010), whereas for fluoropyrimidine-based combinations, the HR was 0.90 (P = 0.030). No risk reduction was observed when combining Gem with irinotecan, exatecan or pemetrexed. For the 1682 patients with adequate information on baseline PS, analysis indicated that patients with a good PS had a marked survival benefit when receiving combination chemotherapy (HR: 0.76, P < 0.0001). In contrast, application of combination chemotherapy to patients with an initially poor PS appeared to be ineffective (HR: 1.08, P = 0.40). However, a meta-analysis conducted by Bria and colleagues, involving 6296 patients, did not show significant differences in the primary endpoint OS, although a significant advantage was evident with regard to both PFS and the ORR, especially in platinum combination therapy[65].

Taken together, it appears that patients taking Gem in combination with either a platinum analog or capecitabine, may have a clinically relevant survival prolongation, especially if they have good PS.

Targeted therapy

Several pathways have been targeted in an attempt to treat pancreatic cancer, but the results from most of these have been disappointing [66-68] (Table 2).

Table 2 Gem in combination with targeted therapy.

Phase III trial	Combination	No. of patient	OS (mo)	P value	PFS	P value	ORR (%)	P value
Moore et al[76]	Gem ± Erlotinib	569	6.24 vs 5.91	0.038	3.75 vs 3.55	0.004	8.6 vs 8.0	NS
Philip et al[79]	Gem ± Cetuximab	745	6.3 vs 5.9	0.23	3.4 vs 3.0	0.18	12 vs 14	0.59
Kindler et al[83]	Gem ± BEV	602	5.8 vs 5.9	0.95	3.8 vs 2.9	0.07	13 vs 10	NS
Van Cutsem et al[84]	Gem + Erlotinib ± BEV	607	7.1 vs 6.0	0.2087	4.6 vs 3.6	0.0002	13.5 vs 8.6	0.057
Goncalves et al[87]	Gem ± Sorafenib	104	8.5 vs 9.2	0.146	3.8 vs 5.6	0.601	NR	NR

OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate rate; Gem: Gemcitabine; BEV: Bevacizumab; NR: Not reported; NS: Not significant.

Epidermal growth factor receptor inhibitors

The overexpression of epidermal growth factor receptor inhibitors (EGFR) has been reported in pancreatic cancer, thus EGFR inhibitors has emerged as a new therapeutic approach for this disease. EGFR can be inhibited by small molecular tyrosine kinase inhibitors that block the intrinsic tyrosine kinase activity pathway and monoclonal antibodies directed against the extracellular ligand binding domain[69-75].

Gem and erlotinib: The original approval of erlotinib to be used in the treatment of pancreatic cancer was obtained in 2005 after a double-blind international Phase III trial in which a total of 569 patients were randomly assigned to receive standard Gem plus erlotinib at 100 mg or 150 mg daily, or Gem alone plus placebo[76]. The study showed statistically significant improvements in OS (6.24 mo in the erlotinib arm and 5.91 mo in the control arm, P = 0.038) and PFS (3.75 mo vs 3.55 mo , P = 0.004). However, ORR were not significantly different (8.6% vs 8.0%), and most patients had disease stabilization. Although this study was statistically significant, major concerns still remained about using erlotinib in light of the minimal median survival duration benefit and high costs. In addition, patients receiving erlotinib had higher frequencies of rash, diarrhea, infection and stomatitis, although they were generally well-tolerated and were notably of grade 1 or 2[77]. As in studies of anti-EGFR agents in colorectal cancer, the presence of rash was associated with a higher likelihood of achieving disease control (P = 0.05).

Gem and cetuximab: A phase II trial of cetuximab combined with Gem in pathologically confirmed EGFR-expressing pancreatic cancer patients showed moderate activity (TTP 3.8 mo, OS 7.1 mo)[78]. However, a phase III study (SWOG S0205) that assigned 745 patients to Gem plus cetuximab or Gem alone did not have any survival benefits[79]. There were also no significant differences in terms of OS (6.3 mo vs 5.9 mo, P = 0.23), PFS (3.4 mo vs 3.0 mo, P = 0.18) and RR (12% vs 14%, P = 0.59).

Antiangiogenesis

Vascular endothelial growth factor receptor (VEGF) is known to stimulate cell growth, survival, and proliferation. VEGF inhibitors effectively reduce neovascularization. They inhibit new and recurrent tumor vessel growth and improve the capacity of the tumor vasculature for effective delivery of antitumor growth compounds[80,81].

Gem and bevacizumab: A phase II study evaluated the combination of bevacizumab plus Gem in 52 advanced pancreatic patients; the median OS and PFS were 8.8 and 5.4 mo, respectively[82]. These interesting results led to a phase III study that failed to confirm the previous findings. It showed median OS was 5.8 mo vs 5.9 mo (P = 0.95), and PFS was 3.8 mo vs 2.9 mo (P = 0.07) in the bevacizumab arm and the control arm, respectively[83]. Subgroup analysis demonstrated statistically significant differences in survival by PS. Patients with a PS of 0 survived a median of 7.9 mo compared to 4.8 mo, and 2.4 mo for PS 1 and PS 2 patients, respectively (P = 0.001). Another Roche sponsored trial, in which 607 patients with metastatic pancreatic cancer were randomized to Gem and erlotinib with or without bevacizumab, showed no significant prolongation of survival with the addition of bevacizumab (7.1 mo vs 6.0 mo, P = 0.20), although the PFS was statistically significantly improved (4.6 mo vs 3.6 mo, P = 0.0002)[84]. Bevacizumab was reported to be safe in this combination, despite an increase in the incidence of epistaxis, hypertension, and proteinuria.

Gem and sorafenib: With its inhibitory effects against Raf-1 kinase and VEGF-2, sorafenib is an oral anticancer agent that targets Ras-dependent signal transduction as well as angiogenic pathways[85]. A phase I trial demonstrated that Gem in combination with sorafenib was well tolerated and had activity in advanced pancreatic cancer patients[86]. A multicenter, randomized, double-blind, placebo-controlled phase III trial (BAYPAN study), which was reported in ASCO 2011, compared Gem combined with sorafenib to Gem combined with placebo in 104 untreated patients with locally advanced or metastatic pancreatic adenocarcinoma[87]. There was no significant differences in median PFS between the two groups (5.6 mo vs 3.8 mo, P = 0.601). Median OS were also similar (9.2 mo vs 8.5 mo, P = 0.146).

Other targeted agents: Recently there have been many phase I or II trials assessing the efficacy and safety of other novel targeted agents, including the hypoxia-activated prodrug (TH-302), the PARP inhibitor (ABT-888), the anti-IGF-1R antibody (MK-0646, GAN), and the fully human monoclonal antibody directed against prostate stem cell antigen. Some of these have shown promising results[88-93].

Non-Gem containing regimen

In 2005, Conroy et al[94] evaluated the RR and toxicity of FOLFIRINOX in 46 chemotherapy-naive advanced pancreatic adenocarcinoma patients. The FOLFIRINOX regimen comprised oxaliplatin 85 mg/m² and irinotecan 180 mg/m² plus leucovorin 400 mg/m² followed by bolus FU 400 mg/m² on day 1, then FU 2400 mg/m² as a 46-h continuous infusion. This report showed promising results with an RR of 26%, a TTP 8.2 mo, and an OS of 10.2 mo. Despite the fact that grade 3/4 neutropenia occurred in 52% of patients, patients had improvement in all functional scales of the EORTC QLQ-C30. Based on these data, Conroy and colleagues conducted a phase III trial comparing FOLFIRINOX with Gem as first-line treatment for metastatic pancreatic adenocarcinoma in 342 patients with good PS (0-1)[95]. The median OS was 11.1 mo in the FOLFIRINOX group compared to 6.8 mo in the Gem group (HR: 0.57; 95% CI: 0.45-0.73; P < 0.001). Median PFS was 6.4 mo vs 3.3 mo (HR: 0.47; 95% CI: 0.37-0.59, P < 0.001). The ORR was 31.6% vs 9.4% ( P < 0.001). At 6 mo, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the QOL, vs 66% in the Gem group (HR: 0.47; 95% CI: 0.30-0.70; P < 0.001). Grade 3/4 toxicities were more common in the FOLFIRINOX, diarrhea 12.7% vs 1.8%, nausea 15.6% vs 6.3%, vomiting 14.5% vs 8.3%, fatigue 23.6% vs 17.8%, neutropenia 45.7% vs 21%, and febrile neutropenia 5.4% vs 1.2%. In the FOLFIRINOX arm, 42% of patients received support with granulocyte colony-stimulating factor. Two patients died from treatment-related causes: one from febrile neutropenia in the FOLFIRINOX group and one from cardiac decompensation in the Gem group. This trial was highly selective: only 39% of patients had a primary tumor in the head of the pancreas; whereas in clinical practice, about two-thirds of patients present with a primary tumor in the pancreas, possibly requiring biliary stents. Therefore, for patients with a good PS, normal bilirubin, and a good supportive care system, FOLFIRINOX could be a viable option.

CONCLUSION

As a first-line therapy, Gem has been the standard treatment for pancreatic cancer since 1997, despite its low RR and short OS. Trials for Gem-based combination regimens have failed to improve survival. Striking, FOLFIRINOX regimen increased median OS from 6.8 mo to 11.1 mo (P < 0.0001), and RR was 31.6% for patients with a good PS. Thus the question that arises is whether FOLFIRINOX should be considered standard therapy for advanced pancreatic cancer instead of Gem. Does this trial represent the start of a change for the management of advanced pancreatic cancer? The FOLFIRINOX regimen was quite toxic because nearly half of the patients suffered grade 3/4 toxicity. Considering the efficacy and toxicity, FOLFIRINOX could be a viable option in selected patients (good PS, normal bilirubin, and a good supportive care system). This trial provided more evidence that Gem does not have to be the backbone of chemotherapy in pancreatic cancer[96-98]. The GEST trial was the first to show that oral S-1 had similar efficacy and tolerable toxicity to Gem in pancreatic cancer patients with good PS. Considering the convenience of oral S-1, it may be worthwhile to initiate further studies. Based on its high RR, further studies are needed to explore the value of a FOLFIRINOX regimen in borderline or unresectable pancreatic tumors, together with radiation for a possible downstaging effect. FOLFIRINOX should also be studied in adjuvant settings where patients can potentially accept more toxic effects. In the future, better tolerated doublet regimens such as FOLFOX and FOLFIRI should be compared to Gem. It will also be necessary to screen the dominant group based on the expression and genotype of metabolic or transport enzymes of Gem.