Study/authorpublication year
Launched date
Study design
N
LAPDAC (%)
Gem DI (%)
Median (95% CI) survival, months
ORR (%)
PFS
OS
I. Gemcitabine vs. non-gemcitabine-containing regimens in advanced pancreatic cancer
Burris et al. [3]
1992.07
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
63
28
–
5
2.2
5.6
(JCO 1997)
5-FU 600 mg/m2 × 3/4 weeks
63
24
–
0
1.0
4.4
ACCORD 11 study [4]
2005.12
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
171
0
9
3.3 (2.2–3.6)
6.8 (5.5–7.6)
(NEJM 2011)
Oxo/CPT-11/5-FU 85/180/400/2,400 mg/m2, q 2 weeks
171
0
32
6.4 (5.5–7.2)
11.1 (9.0–13.1)
II. Gemcitabine vs. gemcitabine-based combinations in advanced pancreatic cancer
II-1. Combined with cytotoxic agents
Platinums
Heinemann et al. [5]
1997.12
Gem 1 g/m2 × 3/4 weeks
98
21
95
8
4.7
6.0
(JCO 2006)
Gem 1 g/m2 + cisplatin 50 mg/m2, q 2 weeks
97
20
95
10
7.2
7.5
GIP-1 [6]
2002.04
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
199
17
95
10
3.9
8.3
(JCO 2010)
Gem 1 g/m2 + cisplatin 25 mg/m2, × 3/4 weeks
201
15
83
13
3.8
7.2
GERCOR/GISCAD [7]
2001.03
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
156
30
81
17
6.7
7.1
(JCO 2005)
Gem 1 g/m2 + oxaliplatin 100 mg/m2, q 2 weeks
157
32
91
27
8.5
9.0
ECOG E6201 [8]
2003.03
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
275
10
–
6
2.6
4.9 (4.5–5.6)
(JCO 2009)
Gem 1.5 g/m2, 10 m/m2/min × 3/4 weeks
277
11
–
10
3.5
6.2 (5.4–6.9)
Gem 1 g/m2 + oxaliplatin 100 mg/m2, q 2 weeks
272
11
–
9
2.7
5.7 (4.9–6.5)
Fluoropyrimidines and antifolate
ECOG E2297 [9]
1998.04
Gem 1 g/m2 × 3/4 weeks
162
10
–
6
2.2
5.4
(JCO 2002)
Gem 1.25 g/m2 + 5-FU 600 mg/m2 × 3/4 weeks
160
11
–
7
3.4
6.7
Swiss/Austria [10]
2001.06
Gem 1 g/m2 × 3/4 weeks
156
21
95
8
3.9 (3.6–5.3)
7.2 (6.5–8.3)
(JCO 2007)
Gem 1 g/m2 + cap 650 mg/m2 bid, × 2/3 weeks
159
20
97
10
4.3 (3.7–5.3)
8.4 (6.3–9.8)
Cunningham et al. [11]
2002.05
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
266
29
–
12
3.8 (2.9–4.8)
6.2 (5.5–7.2)
(JCO 2009)
Gem 1 g/m2 + cap 830 mg/m2 bid, × 3/4 weeks
267
30
–
19
5.3 (4.5–5.7)
7.1 (6.2–7.8)
Oettle et al. [12]
2001.10
Gem 1 g/m2 × 3/4 weeks
273
9
95
7
3.4 (2.5–3.6)
6.3 (5.4–6.9)
(Ann Oncol 2005)
Gem 1.25 g/m2 × 2/3 weeks + PTX 500 mg/m2 D8
273
10
97
15
3.9 (3.3–4.7)
6.2 (5.4–6.9)
GEST study [13]
2007.07
Gem 1 g/m2 × 3/4 weeks
277
24
83
13
4.1 (3.0–4.4)
8.8 (8.0–9.7)
(JCO 2013)
S-1 alone 80 mg/m2 qd, × 4/6 weeks
280
24
–
21
3.8 (2.9–4.2)
9.7 (7.6–10.8)
Gem 1 g/m2 + S-1 80 mg/m2 qd, × 2/3 weeks
275
25
83
29
5.7 (5.4–6.7)
10.1 (9.0–11.2)
Topoisomerase I inhibitors
Rocha Lima et al. [14]
2000.02
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
180
13
76
4
5.9
6.6
(JCO 2004)
Gem 1 g/m2 + CPT-11 100 mg/m2, × 2/3 weeks
180
15
82
16
5.4
6.3
Alou-Alfa et al. [15]
2001.08
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
174
22
92
5
3.8 (3.0–4.3)
6.2 (5.2–7.5)
(JCO 2006)
Gem 1 g/m2 + exatecan 2 mg/m2, × 2/3 weeks
175
21
91
7
3.7 (2.7–4.7)
6.7 (5.4–7.9)
Anti-microtubular agent
MPACT study [16]
2009.05
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
430
0
85
7
3.7 (3.6–4.0)
6.7 (6.0–7.2)
(NEJM 2013)
Gem 1 g/m2 + nab-paclitaxel 125 mg/m2, × 3/4 weeks
431
0
71
23
5.5 (4.5–5.9)
8.5 (7.9–9.5)
Hypoxia-driven cytotoxic agent
MAESTRO study [17]
2012.12
Gem 1 g/m2 × 3/4 weeks
347
21
–
9
3.7 (3.6–3.8)
7.6 (6.7–8.3)
(ASCO GI 2016)
Gem 1 g/m2 + evofosfamide 340 mg × 3/4 weeks
346
22
–
15
5.5 (4.8–5.6)
8.7 (7.6–9.9)
II-2. Combined with targeted agents, including biologic agents
RAS signaling pathway inhibitors: farnesyltransferase inhibitors and RAS mimic
Van Cutsem et al. [18]
1999.11
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
347
23
~90
8
109 days
182 (155–202) days
(JCO 2004)
Gem + tipifarnib (200 mg BID)
341
~80
6
112 days
193 (176–218) days
ONTRAC study [19]
2011.05
Gem 1 g/m2 × 3/4 weeks
54
0
–
13
3.4
6.4
(Ann Oncol 2015)
Gem + rigosertib 1,800 mg/m2 BIW × 3/4 weeks
106
0
–
19
3.4
6.1
Anti-epidermal growth factor receptor agents
NCIC CTG PA.3 [20]
2001.10
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
284
25
–
8
3.6
5.9
(JCO 2007)
Gem + Erlotinib (100 mg/day)
285
24
–
9
3.8
6.2
Van Cutsem et al. [21]
2005.07
Gem 1 g/m2 × 7/8 weeks →3/4 weeks + erlotinib 100 mg/day
301
0
–
9
3.6
6.0
(JCO 2009)
Gem + erlotinib + bev (5 mg/kg q 2 weeks)
306
0
–
14
4.6
7.1
SWOG S0205 [22]
2004.01
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
371
22
–
7
3.0
5.9
(JCO 2010)
Gem + cetuximab (250 mg/m2 q weeks)
372
21
–
8
3.4
6.3
Anti-angiogenic agents
CALGB 80303 [23]
2004.06
Gem 1 g/m2 × 3/4 weeks
300
15
–
10
3.8 (3.4–4.0)
5.9 (5.1–6.9)
(JC0 2010)
Gem + Bev (10 mg/kg q 2 weeks)
302
16
–
13
2.9 (2.4–3.7)
5.8 (4.9–6.6)
Rougier et al. [24]
2007.12
Gem 1 g/m2 × 7/8 weeks → 3/4 weeks
275
10
82
–
3.7 (3.5–4.6)
7.8 (6.8–8.6)
(EJC 2013)
Gem + aflibercept (4 mg/kg q 2 weeks)
271
11
77
–
3.7 (3.5–4.5)
6.5 (5.6–7.9)
Kindler et al. [25]
2007.07
Gem 1 g/m2 × 3/4 weeks
316
23
77
2
6.9 (3.7–5.2)
8.3 (6.9–10.3)
(Lancet Oncol 2011)
Gem + axitinib (5 mg p.o. BID)
314
25
79
5
7.0 (3.0–5.6)
8.5 (6.9–9.5)
Deplanque et al. [26]
2008
Gem (standard clinical practice)
175
14
–
–
7.6a
7.0 (8.2a)
(Ann Oncol 2015)
Gem + masitinib (4.5 mg/kg BID)
173
13
–
–
–
7.7
GAMMA study [27]
2011.04
Gem 1,000 mg/m2 × 3/4 weeks
322
0
84
10
3.7 (3.6–4.4)
7.2 (6.3–8.2)
(Ann Oncol 2015)
Gem + ganitumab (12 mg/kg q 2 weeks)
318
0
81
16
3.6 (3.4–3.8)
7.0 (6.2–8.5)
Gem + ganitumab (20 mg/kg q 2 weeks)
160
0
82
15
3.7 (3.2–5.0)
7.1 (6.4–8.5)
37.1.2 Erlotinib Plus Gemcitabine: Approved Combination with Limited Activity
Based on the findings of prognostic significance of EGFR overexpression in pancreatic cancer and the growth inhibition activity of EGFR blockage either alone or in combination with gemcitabine on pancreatic cancer cells [30–33], a phase III trial comparing the effect of gemcitabine with and without erlotinib as frontline therapy in patients with advanced pancreatic cancer was launched in October 2001. A total of 569 patients were enrolled into PA.3 trial, which was co-sponsored by both industry and the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) [20]. Survival analysis showed gemcitabine plus erlotinib at a dose of 100 or 150 mg daily could achieve a statistically significant survival benefit over gemcitabine alone, with a median overall survival of 6.24 months vs. 5.91 months (estimated HR = 0.82 [95% CI, 0.69–0.99]; P = 0.038) and median progression-free survival of 3.75 months vs. 3.55 months (estimated HR = 0.77 [95% CI, 0.64–0.92]; P = 0.004). Of the 282 patients with erlotinib treatment, the median overall survival of the 101 patients (36%) with grade 2 or more skin rash was 10.5 months vs. 5.3–5.8 months in those with less severe skin rash, P < 0.001 [20]. Erlotinib became the first FDA-approved drug in combination with gemcitabine for the treatment of advanced pancreatic cancer in November 2005. Gemcitabine/erlotinib combination became a new standard treatment option for patients with advanced pancreatic cancer. It served as the control arm in a July 2005-launched randomized phase III trial to evaluate the effect of add-on bevacizumab in patients with metastatic pancreatic cancer [21]. The new trial completed 607 patients recruited within 14 months. Despite such enthusiasm for the effectiveness of the control and experimental arm, add-on bevacizumab did not provide significant survival benefit as compared to gemcitabine/erlotinib alone in patients with metastatic pancreatic cancer. Of note, the median progression-free survival and overall survival of patients receiving gemcitabine/erlotinib alone were 3.6 months and 6.0 months, respectively [21]. In addition, gemcitabine/erlotinib combination also served as the experimental arm vs. standard gemcitabine control in LAP07 trial for locally advanced pancreatic cancer [34] and in CONKO-005 and RTOG 8048 adjuvant trials for post-resection pancreatic cancer [35, 36]. All three trials were lunched in 2008–2009. In the former two trials, the LAP07 and CONKO-005 trial, gemcitabine/erlotinib combination therapy was associated with nonsignificant inferior survival as compared to their gemcitabine comparator [34, 35]. Owing to the emergence of more active multi-agent combinations, such as FOLFIRINOX and nab-paclitaxel, the role gemcitabine plus erlotinib in pancreatic cancer management will be vanished.
37.1.3 FOLFIRINOX: The First Active Gemcitabine-Free Regimen for Advanced Pancreatic Cancer
Based on the known efficacies of bolus and infusion 5-FU and high-dose leucovorin plus either irinotecan (FOLFIRI) [37] or oxaliplatin (FOLFOX) in metastatic colorectal cancer [38], and the different action mechanisms and non-overlapping toxicity among the three agents [39], French investigators initiated a phase I trial to investigate the feasibility of combining oxaliplatin, CPT-11, and simplified LV5FU (leucovorin 400 mg/m2 followed by bolus FU 400 mg/m2 on day 1, then 5-FU 2,400 mg/m2 as a 46-h continuous infusion) in patients with refractory solid tumor in April 1998 [40]. In that study, they not only determined the recommended dose of oxaliplatin and CPT-11 as 85 mg/m2 and 180 mg/m2, respectively, but also surprisingly noted that two of five patients with advanced pancreatic cancer responded to the triplet regimen. The exciting finding led to a single-arm phase II study to investigate the effect of FOLFIRINOX in advanced pancreatic cancer [41]. A total of 47 patients were enrolled from June 2000 to June 2002, with 26% response rate, 8.2 (95% CI, 5.3–11.6) months of time to progression, and 10.2 (95% CI, 8.1–14.4) months of overall survival. The response rate and median survival of patients with metastatic diseases were 26% and 9.5 months, respectively. So that despite associated with 52% of grade 3–4 neutropenia, a phase II/III trial comparing FOLFIRINOX with gemcitabine monotherapy in patients with chemo-naïve metastatic pancreatic cancer was launched in December 2005, the PRODIGE (Partenariat de Recherche en Oncologie Digestive)/ACCORD (Actions Concertées dans les Cancers Colo-Rectaux et Digestifs) phase III trial [4]. The study completed patient enrollment in October 2009 with data lock in April 2010, which was first presented at the 2010 American Society of Clinical Oncology annual meeting. In a highly selected patient population, median age of 61 years old, ECOG performance status of 0–1 in all but one patient, 38% with pancreatic head cancer, and 14% with biliary stenting, the clinical outcomes of patients receiving FOLFIRINOX were significantly superior to those receiving gemcitabine only, with response rate of 31% versus 9.4% (p < 0.001), median overall survival of 11.1 (95% CI, 9.0–13.1) months versus 6.8 (95% CI, 5.5–7.6) months (hazard ratio = 0.57; 95% CI, 0.45–0.73; P < 0.001), and median progression-free survival of 6.4 (95% CI, 5.5–7.2) months versus 3.3 (95% CI, 2.2–3.6) months (hazard ratio = 0.47; 95% CI, 0.37–0.59; P < 0.001). Not surprisingly, FOLFIRINOX was associated with a significant higher incidence of grade 3 or 4 adverse events, neutropenia (45.7% versus 21.0%, p < 0.001), thrombocytopenia (9.1% versus 3.6%, p = 0.04), febrile neutropenia (5.4% versus 1.2%, p = 0.03), diarrhea (12.7% versus 1.8%, p < 0.001), and sensory neuropathy (9.0% versus 0%, p < 0.001), but less elevation of alanine aminotransferase (7.3% versus 20.8%, p < 0.001). In a follow-up study, the investigators showed that in addition to higher incidence of significant adverse events, FOLFIRINOX treatment was associated with significant reduction of quality of life (QoL) impairment compared with gemcitabine in patients with metastatic pancreatic cancer [42].
The full-dose FOLFIRINOX regimen has also been evaluated in Asian population with metastatic pancreatic cancer. In a Japanese phase II study with more stringent patient selection criteria, which included neutrophil count ≥2,000⁄mm3, a normal total bilirubin level, but excluded patients with UGT1A1*6/*6,*28/*28,*6/*28 genotypes, full-dose FLOFIRINOX could achieve 38.9% (95% CI, 23.1–56.5%) response rate, 10.7 (95% CI, 6.9–13.2) months of median overall survival, and 5.6 (95% CI, 3.0–7.8) months of median progression-free survival. The incidence of grade 3 or 4 toxicities was higher than those observed in the original PRODIGE 4/ACCORD 11 study, including 77.8% neutropenia, 22.2% febrile neutropenia, and 8.3% diarrhea [43]. Based on the results, Japan’s Ministry of Health, Labour and Welfare (MHLW) approved FOLFIRINOX as a standard regimen for Japanese patients in December 2013. To reduce the toxicities, Ueno et al. conducted a multicenter phase II study to evaluate the effect and safety profile of a modified FOLFIRINOX regimen consisting of intravenous oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, and 5-FU infusion 2,400 mg/m2 over 46 h and omitted bolus 5-FU [44]. Of 69 accruals, the response rate, median overall survival, and median progression-free survival were 37.7% (95% CI, 26.3–50.2%), 11.2 (95% CI, 9.0 to) months, and 5.5 (95% CI, 4.1–6.7) months, respectively. The grade 3 or 4 neutropenia (47.8%) and febrile neutropenia (8.7%) were significantly reduced but not diarrhea (10.1%). It suggested the approach is feasible in the Asian population and should be further validated in a larger study.
37.1.4 Nab-Paclitaxel Plus Gemcitabine: The First Active Gemcitabine-Containing Chemotherapy Doublet for Advanced Pancreatic Cancer
Based on an earlier molecular profiling study by immunohistochemistry and DNA microarray showing a high expression level of secreted protein acidic and rich in cysteine (SPARC), a known albumin-binding protein, in pancreatic cancer tissue [45], Van Hoff et al. initiated a phase I/II study with a companion translational research program to evaluate the potential application of gemcitabine and nab-paclitaxel combination in patients with advanced pancreatic cancer [46]. With a weekly intravenous administration of nab-paclitaxel following gemcitabine 1,000 mg/m2 for 3 weeks every 4 weeks, the maximum tolerated dose (MTD) of nab-paclitaxel was determined to be 125 mg/m2. Of the 44 patients at MTD level, the nab-paclitaxel/gemcitabine combination could achieve 48% response rate, 7.9 (95% CI, 5.8–11.0) months median progression-free survival, and 12.2 (95% CI, 8.9–17.9) months of median overall survival that was associated with significant grade 3–4 neutropenia (71%) and thrombocytopenia (28%) [46]. In vivo patient-derived xenograft model study demonstrated the nab-paclitaxel/gemcitabine combination regimen could result in higher tumor regression rate as compared to either agent treatment alone. In addition, nab-paclitaxel treatment was associated with the reduction of tumor stroma and the increase of tumor vascularization [46]. With such exciting findings, a global phase III trial comparing gemcitabine with and without nab-paclitaxel, the MPACT study, was launched [16]. Between May 2009 and April 2012, a total of 861 patients were included aiming to have a 90% power to detect a 23% reduction in risk of death at a two-sided alpha level of 0.049. Patients received nab-paclitaxel/gemcitabine had significant better median overall survival (8.5 [95% CI, 7.9–9.5] months versus 6.7 [6.0–7.2] months, hazard ratio = 0.72; 95% CI, 0.62–0.83; P < 0.001), median progression-free survival (5.5 [4.5–5.9] months versus 3.7 [95% CI, 3.6–4.0] months, hazard ratio = 0.69; 95% CI, 0.58–0.82; P < 0.001), and response rate (23% [95% CI, 19–27%] vs. 7% [95% CI, 5–10%]; P < 0.001) than those with gemcitabine treatment. As expected, nab-paclitaxel plus gemcitabine treatment was associated with higher incidence of grade 3–4 adverse events than gemcitabine alone, notably neutropenia (38% versus 27%) and sensory neuropathy (17% versus 1%) [16]; however, the results led to rapid approval of the nab-paclitaxel plus gemcitabine for advanced pancreatic cancer by US FDA in September 2013 and EMEA in December 2013. One of the most surprising translational research findings from MPACT study was that neither tumor epithelial SPARC expression level nor plasma SPARC level served as a predictive factor for overall survival [47]. However, recent preclinical studies seemed to support the synergism between nab-paclitaxel and gemcitabine through the modulation of intracellular level of cytidine deaminase, a catabolic enzyme of gemcitabine, rather than the interaction between nab-paclitaxel and the stroma or SPARC within tumor microenvironment [48–50].
Since the MPACT study only included patients from Europe, America, and Australia, a prospective phase I/II study to evaluate the efficacies and safety profile of the nab-paclitaxel plus gemcitabine combination in Japanese population was performed. With an identical dosing schedule, the nab-paclitaxel plus gemcitabine combination achieved 58.8% (95% CI, 40.7–75.4%) of tumor response rate, 6.5 (95% CI, 5.1–8.3) months of median progression-free survival, and 13.5 (95% CI, 10.6 to not reached) months of median overall survival in 34 Japanese patients with metastatic diseases [51]. Despite no obvious pharmacokinetic variation as compared with monotherapy data, the treatment was associated with grade 3–4 neutropenia and sensory neuropathy in 71% and 12% of patients, respectively. Based on the results of the bridging study, the Japan’s MHLW approved the regimen for advanced pancreatic cancer in December 2014.
37.1.5 S-1: The Only Approved Fluoropyrimidine with Documented Activity
In Asia, S-1 is a designed third-generation oral fluoropyrimidine composed of tegafur (pro-drug of 5-FU) and two modulators of 5-FU metabolism-related enzymes, 5-chloro-2,4-dihydroxypyridine (CDHP, a competitive antagonist of dihydropyrimidine dehydrogenase) and potassium oxonate (Oxo, a modulator of pyrimidine phosphoribosyl transferase), in a 1:0.4:1 molar ratio. In an international randomized phase III trial, investigators from Japan and Taiwan compared the first-line activity of gemcitabine and S-1 or in combination in patients with advanced pancreatic cancer, the GEST study [13]. This three-arm study was launched in July 2007, and patients were randomly assigned to have gemcitabine monotherapy (1,000 mg/m2, weekly for 3 weeks, every 4 weeks), S-1 (fixed twice daily dose of 40/50/60 mg based on body surface, day 1–14 every 3 weeks), and gemcitabine/S-1 combination (weekly gemcitabine 1,000 mg/m2, plus S-1 30/40/50 mg twice daily, for 2 weeks every 3 weeks). The study aimed to demonstrate the non-inferiority of S-1 to gemcitabine monotherapy and the superiority of gemcitabine/S-1 combination over gemcitabine alone. A total of 832 patients were included, 277 in the gemcitabine alone arm, 280 in S-1 arm, and 275 in combination arm. After a median follow-up of 18.4 months for all survivors, the median overall survival in the gemcitabine, S-1, and combination arms was 8.8 (95% CI, 8.0–9.7) months, 9.7 (95% CI, 7.6–10.8) months, and 10.1 (95% CI, 9.0–11.2) months, respectively; while the median progression-free survivals were 4.1 (95% CI, 3.0–4.4) months, 3.8 (95% CI, 2.9–4.2) months, and 5.7 (95% CI, 5.4–6.7) months, respectively. The objective response rate in corresponding group was 13.3% (95% CI, 9.3–18.2), 21.0% (95% CI, 16.1–26.6), and 29.3% (95% CI, 23.7–35.5), respectively. In summary, S-1 was shown to have a significant better objective response rate and non-inferior overall survival and progression-free survival as compared to gemcitabine alone in patients with chemo-naïve advanced pancreatic cancer. On the other hand, gemcitabine/S-1 combination had a significant better tumor response rate and median progression-free than gemcitabine alone, but not overall survival [13]. Of note, since both gemcitabine and S-1 were approved agents for advanced pancreatic cancer in Japan, crossover after disease progression was allowed in current study. In addition, S-1 had significant better safety profile as compared to gemcitabine and combination arm. The incidence of grade 3–4 neutropenia was 8.8% in the S-1 arm, 41.0% in gemcitabine arm, and 62,2% in the combination arm. Based on this study, Taiwan regulatory authority approved the use of S-1 in advanced pancreatic cancer in September 2013.
37.1.6 Summary
After two decades of intensive investigation and struggle, the introduction and approval of new agents and multi-agent regimens have led to an increase of overall survival time from 6 months with gemcitabine monotherapy up to 9–12 months with nab-paclitaxel plus gemcitabine or FOLFIRINOX or Asia-restricted S-1 in patients with advanced pancreatic cancer, notably for those with metastatic diseases. Metastatic pancreatic cancer should be recognized as a treatable disease nowadays. On the other hand, facing so much failure on trials involving in developing molecular targeted agents for pancreatic cancer, it should be strongly urged to request more comprehensive and dedicated preclinical research before scientists push any new compound into clinical investigation.
37.2 Chemotherapy in Locally Advanced Pancreatic Cancer
Pancreatic cancer is an aggressive malignancy with 15–20% or less of patients presenting with localized tumors that are amenable for curative-intent surgery [1]. Among the other 80–85% of patients who presented with incurable advanced diseases, 40% of them exhibit locally advanced diseases with one or more of the following radiological findings, the aorta encasement, the superior mesenteric vein obliteration, or more than 180° of the superior mesenteric artery or celiac vessels involvement, to preclude a grossly negative tumor margins resection. In such circumstance, surgical resection is not considered to serve as the primary therapy due to its morbidities and unlikely to be curative even after extensive surgical procedure [2]. An optimal therapy for patients with locally advanced pancreatic cancer remains controversial [2].
37.2.1 5-FU and Gemcitabine-Based Concurrent Chemoradiation Therapy
Based on the results of three randomized trials before the 1980s, 5-fluorouracil (5-FU)-based concurrent chemoradiotherapy (5-FU-CCRT) has been a favorable approach for patients with locally advanced pancreatic cancer [52–55]. However, the median overall survival of patients who received frontline 5-FU-CCRT was limited between 8.0 and 11.4 months [52–54]. The result has recently been confirmed by three randomized studies conducted in the early 2000s comparing 5-FU-CCRT with either gemcitabine alone [56], gemcitabine/cisplatin-based CCRT (GC-CCRT), or 5-FU-CCRT plus TNFerade biologic (GenVec, Gaithersburg, MD), a novel means of selectively delivering TNF-α to tumor cells by gene transfer through intratumoral vector injection [57, 58]. In the former two studies, the median overall survival of patients with frontline 5-FU-CCRT was 8.6 and 9.6 months, respectively [56, 57]. The large-scale randomized trial of 5-FU-CCRT with or without TNFerade with a total 304 enrolled patients showed that the median overall survival were 10 months in both two study arms [58].
With the introduction of gemcitabine as a standard of care for advanced pancreatic cancer and a well-known potent radiosensitizer [59, 60], gemcitabine-based concurrent chemoradiation therapy has been evaluated as a frontline therapy in patient with LAPDAC comparing to either 5-FU-based CCRT or gemcitabine monotherapy alone. In a three-arm randomized study, Wilkowski et al. compared conventionally fractionated 50 cGy radiotherapy in combination with concurrent 5-FU (350 mg/m2/day on each day of radiotherapy, 5-FU-CCRT), concurrent gemcitabine and cisplatin (300 mg/m2 and 30 mg/m2, respectively, on days 1, 8, 22, and 29, GC-CCRT), or the latter followed by sequential gemcitabine 1,000 mg/m2 and cisplatin 50 mg/m2 every 2 weeks (GC-CCRT+GC) [57]. The 9-month survival rates in patients of the 5-FU-based CCRT, GC-CCRT and GC-CCRT+GC arms were 52%, 58%, and 45%, respectively. The outcomes from these three arms all failed to meet the 60% of assumption of a 9-month survival rate which was originally designed for the control arm with 5-FU-CCRT. The median overall survival in corresponding study arm was 9.3 months, 9.6 months, and 7.3 months, respectively [57]. In a small Eastern Cooperative Oncology Group trial, Loehrer Sr. et al. compared gemcitabine alone versus gemcitabine (600 mg/m2/week for weeks 1–5)-based CCRT followed by maintenance gemcitabine (G-CCRT+G) [61]. The trial was early terminated after a total 74 patients were randomized due to poor accrual. However, the median overall survival in locally advanced pancreatic cancer patients with frontline G-CCRT+G was significantly longer than those with gemcitabine treatment alone, 11.1 months versus 9.2 months, p = 0.017. The results indicated the median overall survival that could be achieved with frontline concurrent 5-FU or gemcitabine with conventional radiation technology for locally advanced pancreatic cancer would be limited below 12 months.
37.2.2 Primary, Palliative Chemotherapy in Locally Advanced Pancreatic Cancer
In the era of gemcitabine, patients with unresectable, locally advanced pancreatic cancer are frequently included into clinical trials to evaluate the efficacies of primary chemotherapy for advanced pancreatic cancer, as did patients with metastatic diseases. Available subgroup analyses from phase II or III trials evaluating new drugs or new combinations for patients with advanced pancreatic cancers showed that the median survival of patients with locally advanced pancreatic cancer receiving gemcitabine monotherapy ranged from 9.2 to 13.8 months versus the 5.4–8.3 months of patients with metastatic diseases, Table 37.2 [5, 7, 13, 14, 18, 23, 26, 56, 61]. Of note, the median overall survival of the locally advanced disease subgroups was comparable between the controlled arm with gemcitabine alone and the gemcitabine-doublet combination arm, as what was observed in the analysis of intent-to-treat population. The approximate range from 9 to 14 months of overall survival in gemcitabine monotherapy-treated patients with locally advanced pancreatic cancer has recently been confirmed by two small randomization studies, which compared gemcitabine monotherapy with frontline gemcitabine- or 5-FU/cisplatin-based concurrent chemoradiation therapy. The median overall survival after gemcitabine monotherapy was 9.2 months for the 37 patients in the Eastern Cooperative Oncology Group (ECOG 4201) study [61], and 13.0 months for the 60 patients in the Federation Francophone de Cancerologie Digestive (FFCD) and the Societe Francophone de Radiotherapie Oncologique (SFRO) study [56]. The results of large-scale, prospective randomization studies evaluating the effect of modern multi-agent chemotherapy regimens, such as nab-paclitaxel plus gemcitabine and FOLFIRINOX, in patients with locally advanced pancreatic cancer are still pending [62].
Table 37.2
Overall survival of locally advanced pancreatic cancer patients in multicenter randomized trials with gemcitabine-based therapy for advanced pancreatic cancer
Study/author publication year | Launched date | Study design | N | % LAPDAC | Objective response rate | Median overall survival (months) | ||||
|---|---|---|---|---|---|---|---|---|---|---|
IIT | mPDAC | LAPDAC | IIT | mPDAC | LAPDAC | |||||
I. Gemcitabine vs. gemcitabine-based doublet therapy for advanced PDAC | ||||||||||
Van Cutsem et al. [18] | 1999.11 | Gem | 347 | 23% | 8% | – | – | 182 days | 170 days | 264 days |
(JCO 2004) | Gem + tipifarnib | 341 | 6% | – | – | 193 days | 318 days | |||
Rocha Lima et al. [14] | 2000.02 | Gem | 180 | 13% | 4% | 4% | 4% | 6.6 | 5.9 | 11.7 |
(JCO 2004) | Gem + irinotecan | 180 | 15% | 16% | 15% | 26% | 6.3 | 5.4 | 9.8 | |
GERCOR/GISCAD [7] | 2001.03 | Gem | 156 | 30% | 17% | 18% | 15% | 7.1 | 6.7 | 10.3 |
(JCO 2005) | Gem + oxaliplatin | 157 | 32% | 27% | 26% | 27% | 9.0 | 8.5 | 10.3 | |
Heinemann et al. [5] | 1997.12 | Gem | 98 | 21% | 8% | – | – | 6.0 | 4.7 | 10.4 |
(JCO 2006) | Gem + cisplatin | 97 | 20% | 10% | – | – | 7.5 | 7.2 | 10.3 | |
CALGB 80303 [23] | 2004.06 | Gem | 300 | 15% | 10% | – | – | 5.9 | 5.7 | 9.9 |
(JC0 2010) | Gem + bevacizumab | 302 | 16% | 13% | – | – | 5.8 | |||
GEST study [13] | 2007.07 | Gem S-1 alone | 277 | 24% | 1 | – | – | 8.8 | 8.3 | 12.7 |
(JCO 2013) | Gem + S-1 | 280 | 24% | 3% | – | – | 9.7 | 7.4 | 13.8 | |
275 | 5% | 21% | – | – | 10.1 | 9.4 | 15.9 | |||
29% | ||||||||||
Kindler et al. [25] | 2007.07 | Gem | 316 | 23% | 2% | – | – | 8.3 | 6.9 | 10.6 |
(Lancet Oncol 2011) | Gem + axitinib | 314 | 25% | 5% | – | – | 8.5 | 7.0 | 9.5 | |
Deplanque et al. [26] | 2008 | Gem | 175 | 14% | – | – | – | 7.0 (8.2a) | 7.6a | 13.8a |
(Ann Oncol 2015) | Gem + masitinib | 173 | 13% | – | – | – | 7.7 | – | – | |
II. Gemcitabine vs. frontline CCRT for LAPDAC | ||||||||||
ECOG 4201 [61] | 2003.04 | Gem | 37 | 100% | – | – | 3% | – | – | 9.2 |
(JCO 2011) | Gem-CCRT + Gem | 34 | 100% | – | – | 6% | – | – | 11.1 | |
FFCD/SFRO [56] | 2000.03 | Gem | 60 | 100% | – | – | – | – | – | 13.0 |
(Ann Oncol 2008) | 5-FU/Cis-CCRT + Gem | 59 | 100% | – | – | – | – | – | 8.6 | |
37.2.3 Induction Chemotherapy Followed by Consolidation Concurrent Chemoradiotherapy
In 2007, two retrospective studies from MD Anderson Comprehensive Cancer Center and GERCOR showed that induction chemotherapy followed by consolidation CCRT could achieve significant longer survival than those with either CCRT alone or continuous gemcitabine-based chemotherapy in patients with locally advanced pancreatic cancer, respectively [63, 64]. In the former study, 323 consecutive patients with locally advanced pancreatic cancer who had gemcitabine- or fluoropyrimidine-based CCRT in MD Anderson hospital between December 1999 and July 2005 were included. Among them, 247 patients had frontline CCRT; while 76 patients had a median of 2.5 months of induction gemcitabine-based chemotherapy before CCRT. The median overall survival of patient with and without induction chemotherapy was 11.9 and 8.5 months, respectively, P < 0.001 [63]. In the latter study, Huguet et al. retrospectively analyzed the outcome of 181 patients with locally advanced pancreatic cancer who participated onto prospective phase II and III GERCOR gemcitabine-based chemotherapy studies for advanced or metastatic pancreatic cancer. Excluding the 53 (29.3%) patients who had systemic dissemination during the first 3 months of assigned chemotherapy, of the rest 128 non-progressed patients, 72 (56%) received consolidation CCRT, while 56 (44%) continued their chemotherapy. The median overall survival of patients with and without consolidation CCRT was 15.0 and 11.7 months, respectively, P = 0.0009 [64]. This novel, multidisciplinary approach is attractive because of the unsatisfactory therapeutic effect of frontline chemoradiation therapy and the recognition of locally advanced pancreatic cancer as a systemic disease with frequent occult metastases. Induction chemotherapy can not only provide systemic control for micrometastases but also help to identify patients who are likely to benefit from aggressive local therapy so as to avoid unnecessary radiotherapy for those with rapid systemic progression even during chemotherapy. It soon became a favorable investigational treatment option for patients with locally advanced pancreatic cancer. In the past decade, several single-arm phase II studies prospectively evaluated the therapeutic effect of this multidisciplinary approach in patients with unresectable locally advanced diseases with various induction chemotherapy regimens and duration of treatment and also different radiosensitizing agents and the administration of maintenance chemotherapy [65–72]. In general, the multidisciplinary approach could achieve encouraging 12.2–18.3 months of overall survival in per protocol patients who were progression-free after induction chemotherapy and received consolidation CCRT. However, in those studies, only 50–85% of intent-to-treat patients would receive the assigned consolidation CCRT, and median overall survival of intent-to-treat population including those who failed induction chemotherapy were 12–14.5 months (Table 37.3). The results seem not so different from that of the 13.0 months in the gemcitabine alone control arm in the FFCD/SFRO randomization study [56]. The therapeutic efficacies and potential superiority of incorporating CCRT after induction chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer can only be defined by large-scale prospective randomization trials. In 2 × 2 designed, LAP07 randomized phase III trials, the largest prospective study for locally advanced pancreatic cancer investigated the effect of chemoradiotherapy versus chemotherapy on survival of patients with locally advanced pancreatic cancer following gemcitabine-based induction chemotherapy [34]. The primary endpoint of the trial was overall survival with an assumption that chemoradiotherapy could improve median overall survival from 9 to 12 months. A total of 442 patients were included between February 2008 and December 2011, with 223 randomized to receive 4 months of weekly gemcitabine 1,000 mg/m2 for 3 weeks every 4 weeks alone and 219 to have the same gemcitabine dose schedule plus erlotinib 100 mg daily. Tumor assessments were performed every 8 weeks by spiral computed tomography scan or magnetic resonance imaging. After the second tumor assessment, 269 (61%) without disease progression, unacceptable toxicity, or consent withdraw underwent the second randomization with 136 to continue the assigned chemotherapy for 2 months and 133 to have capecitabine (800 mg/m2 twice daily on the days of radiotherapy)-based CCRT. Maintenance erlotinib 150 mg daily was given only to patients who were initially allocated to the gemcitabine plus erlotinib arm. After a median follow-up of 34.3 (95% CI, 27.6–43.8) months with 379 deaths, the median survival was 13.6 (95% CI, 12.3–15.3) months and 11.9 (95% CI, 10.4–13.5) months for patients who were initially assigned to gemcitabine alone and gemcitabine plus erlotinib arms, respectively (hazard ratio, 1.19 [95% CI, 0.97–1.45], P = 0.09); while the median survival of a patient who underwent second randomization was 15.2 (95% CI, 13.9–17.3) months and 16.5 (95% CI, 14.5–18.5) months in the chemoradiotherapy and chemotherapy arms, respectively (hazard ratio, 1.03 [95% CI, 0.79–1.34], P = 0.83). The median overall survival of the 173 patients who failed to the induction chemotherapy was 7.7 (95% CI, 6.6–8.7) months.
Table 37.3
Clinical outcomes of patients with locally advanced pancreatic cancer received induction chemotherapy (ICT) followed by CCRT
Organization/ author | Launched date | Study design ICT regimen | ICT duration (months) | N | Intent-to-treat population | Per-protocol cohort | ||||
|---|---|---|---|---|---|---|---|---|---|---|
ORR (%) | Median PFS (months) | Median OS (months) | N | Median PFS (months) | Median OS (months) | |||||
I. Single-arm phase II studies | ||||||||||
Marti et al. [65] | 1997.11 | Gem/cisplatin + GC-CCRT | 2 | 26 | – | 7.0 | 13.0 | 18 | – | – |
GERCOR [66] | 2001.03 | GEMOX + ciFOxal-CCRT | 2 | 59 | 15.2% | 7.6 | 12.2 | 50 | 9.4 | 12.6 |
Ko et al. [67] | 2002.05 | Gem/Cisplatin + Cap-CCRT | 6 | 25 | – | 10.5 | 13.5 | 12 | 12.5 | 17.0 |
Nakachi et al. [68] | – | Gem + S-1 | 4 | 20 | – | 8.1 | 14.4 | 16 | – | – |
TCOG [69] | 2004.12 | Gem + FOLFOX + Gem-CCRT | 3 | 50 | 28% | 9.3 | 14.5 | 30 | 14.7 | 18.3 |
AGITG [70] | 2005.07 | GEMOX + 5-FU CCRT | 1 | 47 | 35% | 11.0 | 15.7 | 45 | – | – |
Crane et al. [71] | 2005.10 | C-GEMOX | 2 | 69 | 18% | 12.5 | 19.2 | 60 | – | – |
Esnaola et al. [72] | 2006.03 | C-GEMOX + Cap-CCRT | 3 | 37 | 18% | 10.4 | 11.8 | 26 | – | – |
II. Randomized phase II/III studies | ||||||||||
LAP07 [34] (IIT) | 2008.02 | Gem ± Cap-CCRT | 4 | 233 | – | 7.8 | 13.6 | 135 | – | 17.1 |
Gem/erlotinib ± Cap-CCRT
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