Chemotherapy for Advanced Pancreatic Cancer: Past, Present, and Future Gregory Friberg, MD and Hedy Lee Kindler, MD

Address Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637-1470, USA. E-mail: [email protected] Current Oncology Reports 2005, 7:186–195 Current Science Inc. ISSN 1523-3790 Copyright © 2005 by Current Science Inc.

Advanced pancreatic cancer is a devastating illness characterized by significant morbidity and a brief median survival. Although standard chemotherapy with gemcitabine achieves only modest improvements in survival and quality of life, classic cytotoxic agents, such as 5-fluorouracil, pemetrexed, irinotecan, exatecan, cisplatin, or oxaliplatin, given alone or in combination with gemcitabine, have not proved superior. Thus, more recent trials have focused on targeting the biologic characteristics of pancreatic cancer. Although phase III trials of farnesyl transferase and matrix metalloproteinase inhibitors have not improved survival, encouraging preliminary results have been observed in phase II studies of inhibitors of the vascular endothelial growth factor and the epidermal growth factor receptor.

Introduction In 2004, an estimated 31,860 people were diagnosed with pancreatic cancer in the United States, and 31,270 died of their disease [1]. Diagnosis unfortunately occurs too late for a majority of patients, at which time surgical or radiotherapeutic interventions are of limited value. Although cytotoxic chemotherapies have been extensively studied in advanced pancreatic cancer, historically they have provided only modest benefits. We review these data and explore several new classes of biologic therapies that have shown promise in early clinical trials.

Cytotoxic Chemotherapy 5-Fluorouracil 5-Fluorouracil (5-FU) is a fluorinated pyrimidine that interferes with DNA synthesis by blocking the enzyme thymidylate synthase (TS). Until the 1990s, 5-FU–based chemotherapy was the standard of care for pancreatic cancer, though there was little evidence that it improved survival or quality of life. A pooled analysis of 5-FU regimens from the 1970s reported response rates of 28%, but

many of these trials lacked the standardized CT-based evaluation criteria used today [2]. More recent trials have reported response rates ranging from 0% with bolus 5-FU to 9% with weekly 24-hour infusional 5-FU [3,4]. A metaanalysis of 43 randomized trials found that survival was i m pr ov e d in tr i a l s o f 5 -F U – b a s e d c h e m o t he r a py compared with best supportive care (6.4 vs 3.9 months, hazard ratio [HR] 0.53, P<0.0001), but with a more modest 4- to 6-month survival time for other pooled 5FU–based trials [5].

Gemcitabine Gemcitabine hydrochloride is a nucleoside analogue of deoxycytidine that inhibits ribonucleotide reductase and incorporates directly into DNA. Gemcitabine is a prodrug that requires intracellular phosphorylation into phosphorylated metabolites. Casper et al. [6] reported that gemcitabine produced an 11% obje ctive r esponse rate in previously untreated pancreatic cancer patients, whereas Rothenberg et al. [7] reported a 26% clinical benefit rate (reduced pain or improved performance status) in previously treated patients. Burris et al. [8•] conducted a randomized trial of gemcitabine (1000 mg/m 2 intravenously [IV] over 30 minutes weekly × 4, and on days 1, 8, and 15 every 28 days thereafter) versus bolus 5-FU (600 mg/m 2 IV over 30 minutes weekly) in 126 symptomatic pancreatic cancer patients. Gemcitabine improved 1-year survival (18% vs 2%) and median survival (5.7 vs 4.4 months, P=0.0025) compared with 5-FU. In addition, 24% of patients administered with gemcitabine improved in clinical symptoms (pain, weight loss, and performance status) compared with only 5% with 5-FU (P=0.0022). A subsequent analysis of over 3000 patients treated with gemcitabine reported a response rate of 12% and a median survival of 4.8 months [9]. Multiple randomized trials have continued to report similar efficacy with single-agent gemcitabine (Table 1). As the control arm in randomized phase III trials, gemcitabine consistently achieves response rates of 5% to 15% and median survival of 5 to 6 months. One strategy to improve upon the efficacy of gemcitabine has been through pharmacokinetic modulation. Delivery of gemcitabine at a fixed dose rate (FDR) infusion of 10 mg/m 2 /min maximizes the kinetics of deoxycytidine kinase, the enzyme that catalyzes the rate-limiting step in gemcitabine activation [10•]. Tempero et al. [10•] reported that patients treated with FDR gemcitabine (1500 mg/m 2

63 103 162 119 100 139 170 180 156 174 47 282 344

Patients, n LA, 28; Met, 72 LA, 32; Met, 68 LA, 10; Met, 90 LA, 27; Met, 73 LA, 21; Met, 79 LA, 35; Met, 65 LA, 29; Met, 71 LA, 13; Met, 81 LA, 30; Met, 70 LA, 22; Met, 78 LA, 30; Met, 70 LA, 9; Met, 91 LA, 23; Met, 77

Stage, % 5 26 6 16 8 5 8 4 17 7 9 7 8

ORR, % 2.1* 3.8* 2.2 3.2 2.5* 3.5 4.3* 2.8 3.7 3.8* 3.3* 3.3 3.6

Median PFS, mo 5.7 5.6 5.4 5.4 6.0 6.6 6.5 6.6 7.1 6.2 NS 6.3 6.0

Median survival, mo 18 19 17 17 25 25 22 22 28 21 22 20 17

1-Year survival, % 26 7 5 9 NS 54 20 32 27 15 19 13 30

10 5 11 NS 10 12 9 14 3 4 2 6 12

Grade 3/4 Grade 3/4 neutropenia, % thrombocytopenia, %

*Time to progression. LA—locally advanced (stage II/III); Met—metastatic (stage IV); mo—months; NS—result not stated; ORR—overall response rate; PFS—progression-free survival.

Burris et al. [8•] Bramhall et al. [43] Berlin et al. [13] Bramhall et al. [42] Heinemann et al. [22] Moore et al. [41] Cheverton et al. [28] Rocha Lima et al. [26] Louvet et al. [25] O’Reilly et al. [29] Reni et al. [24] Richards et al. [15] Van Cutsem et al. [38]

Study

Table 1. Outcomes with single-agent gemcitabine in randomized phase III trials

Chemotherapy for Advanced Pancreatic Cancer: Past, Present, and Future • Friberg and Kindler 187

188

Gastrointestinal Cancers

at 10 mg/m 2 /min on days 1, 8, and 15 every 28 days) achieved a median survival of 8.0 months and a 29% 1-year survival rate. These results were statistically superior to a high-dose gemcitabine arm in this randomized phase II study, though hematologic toxicities were consistently higher with FDR delivery. These data require confirmation in a larger study, such as the ongoing European Cooperative Oncology Group (ECOG) 6201, a randomized phase III trial of gemcitabine given over 30 minutes, FDR gemcitabine, and FDR gemcitabine with oxaliplatin. Because the efficacy of gemcitabine in improving survival and relieving symptoms is well established, it has been used as the foundation for numerous cytotoxic combinations (Table 2). Although many phase II trials of such combinations have shown promising response and progression-free survival rates, subsequent phase III trials have not demonstrated a survival improvement for any of these combinations over gemcitabine alone.

have reported response rates of 7% with single-agent capecitabine and 27% when capecitabine is combined with gemcitabine [16,17]. A randomized phase II study of high-dose gemcitabine (2200 mg/m 2 on day 1 every 14 days) given with and without capecitabine (1250 mg/m 2 twice daily on days 1–7 every 14 days) found similar response rates (17% vs 14%) and overall survival times (9.5 vs 8.2 months) on both arms [18]. Two large European phase III trials of gemcitabine with or without capecitabine are ongoing. S-1, an oral TS inhibitor containing the prodrug tegafur with the dihydropyrimidine dehydrogenase inhibitor gimestat and the toxicity modulator otastat, have also recently shown phase II activity. S-1 produced a single-agent response rate of 21% in previously untreated patients and a response rate of 47% when combined with gemcitabine [19,20].

Pemetrexed Pemetrexed, a multitargeted antifolate that inhibits TS, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase, is synergistic with gemcitabine in vitro [14]. Kindler et al. [14] reported that patients treated in a phase II trial of gemcitabine and pemetrexed had a 15% response rate and median survival of 6.5 months. An international phase III trial of gemcitabine (1250 mg/m 2 on days 1 and 8 every 21 days) with pemetrexed (500 mg/m2 on day 8 every 21 days) versus standard gemcitabine (1000 mg/m 2 on days 1, 8, and 15 every 28 days) was recently reported [15]. Although the response rate was improved with gemcitabine and pemetrexed (15% vs 7%, P=0.004), progression-free (3.9 and 3.3 months, P=0.11) and overall survival (6.2 and 6.3 months, P=0.718) were no better than with single-agent gemcitabine. The combination also had more grade 3/4 hematologic toxicity.

The platinums Cisplatin Cisplatin is synergistic with gemcitabine in preclinical models [21]. A phase II study of the combination reported a response rate of 26% and a median survival of 7.1 months [21]. Heinemann et al. [22] conducted a multicenter phase III trial that randomly assigned 198 patients to gemcitabine (1000 mg/m 2 on days 1 and 15 every 28 days) with cisplatin (50 mg/m 2 , same schedule) or gemcitabine alone (1000 mg/m 2 on days 1, 8, and 15 every 28 days). Despite an improved progression-free survival with the combination (5.8 vs 2.8 months, P<0.01), overall survival in the gemcitabine–cisplatin arm was statistically no better than with gemcitabine alone (7.6 and 6.0 months, P=0.12). The combination also produced increased rates of grade 3/4 nausea (21% vs 6%). It is possible that this study was underpowered to detect a potential survival difference in the arms, because it was designed with 80% power to detect a 60% survival increase from 5 to 8 months. In a phase II study the PEFG regimen (cisplatin, epirubicin, 5-FU, and gemcitabine) was reported to provide a 51% response rate and a median survival of 11 months [23]. A phase III study by Reni et al. [24] subsequently randomized 99 patients to either the PEFG regimen or single-agent gemcitabine. The study was designed to detect a one-sided improvement in 4-month progression-free survival from 35% to 65%. Whereas PEFG produced a superior response rate (40% vs 9%) and TTP (5.3 vs 3.3 months, P=0.003), the median survival times for each arm were not reported, and the Kaplan-Meier survival curves appeared to be similar at the median survival points. Patients who received PEGF had significantly more grade 3/4 neutropenia (43% vs 19%, P<0.01) and thrombocytopenia (29% vs 2%, P<0.01) than did those who received single-agent gemcitabine.

Oral thymidylate synthase inhibitors Several of the oral TS inhibitors have been studied alone and in combination with gemcitabine. Phase II studies

Oxaliplatin A phase II study of the GemOx regimen, FDR gemcitabine (1000 mg/m2 at 10 mg/m2/minute on day 1 every 14 days)

Thymidylate synthase 5-Fluorouracil Numerous phase II trials have combined gemcitabine with infusional or bolus 5-FU, with response rates ranging from 5% to 25% and survival times up to 10 months [11,12]. ECOG conducted a large phase III trial comparing the combination of gemcitabine (1000 mg/m 2 on days 1, 8, and 15 every 28 days) and bolus 5-FU (600 mg/m2, same schedule) with single-agent gemcitabine [13]. Despite an improvement in time to progression (TTP, 3.4 vs 2.2 months; P=0.022), overall survival in the combination arm was statistically equivalent to gemcitabine alone (6.7 vs 5.4 months, P=0.09). It is not known whether gemcitabine combined with infusional 5-FU would improve survival as compared with gemcitabine alone.

3.4 2.2 3.9 3.3 5.8 2.8 5.3* 3.3* 5.5 3.7 3.5* 3.0* 3.7 3.8 3.7 3.6 2.9 3.2

7 6 15 7 10 8 40 9 29 17 16 4 8 7 6 8 11 16

ORR, %

Median PFS, mo

0.70

0.72

0.22

0.35

0.02

0.003

<0.01

0.11

0.02

P-value vs gemcitabine (log-rank)

6.3 6.0 5.4 5.4

6.7 5.4 6.2 6.3 7.6 6.0 NS NS 9.0 7.1 6.3 6.6 6.7 6.2

Median survival, mo

0.95

0.75

0.52

0.79

0.13

NS

0.12

0.85

0.09

P-value vs gemcitabine (log-rank)

40 30 3 9

7 5 45 18 NS NS 43 19 20 27 38 32 30 15

15 12 NS NS

19 11 13 6 4 10 29 2 14 3 20 14 17 4

Grade 3/4 Grade 3/4 neutropenia, % thrombocytopenia, %

*Time to progression. Cis—cisplatin; Epi—epirubicin; FDR—fixed drug rate; 5-FU—5-fluorouracil; Gem—gemcitabine; NS—result not stated; ORR—overall response rate; PFS—progression-free survival.

Phase III trials: gemcitabine + cytotoxic chemotherapy Gem/5-FU [13] 160 Gem 162 Gem + pemetrexed [15] 283 Gem 282 Gem + cisplatin [22] 98 Gem 100 Cis/Epi/5-FU/Gem (PEFG) [24] 52 Gem 47 FDR gem + oxaliplatin [25] 157 Gem 156 Gem + irinotecan [26] 180 Gem 180 Gem + exatecan [29] 175 Gem 174 Phase III trials: gemcitabine + novel biologics Gem + R115777 [38] 341 Gem 347 Gem + marimastat [42] 120 Gem 119

Combination

Patients, in arm, n

Table 2. Phase III trials of gemcitabine combinations for advanced pancreatic cancer

Chemotherapy for Advanced Pancreatic Cancer: Past, Present, and Future • Friberg and Kindler 189

190

Gastrointestinal Cancers

and oxaliplatin (100 mg/m 2, over 2 hours on day 2 every 14 days), achieved a response rate of 31% and a median survival of 9.1 months. Louvet et al. [25] recently reported the results of a phase III trial of GemOx versus single-agent gemcitabine (1000 mg/m2 weekly for 4 weeks, then days 1, 8, and 15 every 28 days thereafter). Again, despite an improvement in progression-free survival with the combination (5.5 vs 3.7 months, P=0.02), overall survival in the GemOx arm was statistically no better than with gemcitabine alone (9.0 and 7.1 months, P=0.13). GemOx also produced increased rates of grade 3/4 neuropathy (19% vs 0%). The authors hypothesized that crossover from the single-agent gemcitabine arm might have obscured any potential benefit in the GemOx arm.

Topoisomerase inhibitors Irinotecan The topoisomerase I inhibitor irinotecan was noted to have a single-agent response rate of 9% in a phase II trial; in combination with gemcitabine a 24% objective response rate was achieved [26]. Rocha Lima et al. [26] conducted a 360-patient phase III trial that compared irinotecan/gemcitabine (gemcitabine, 1000 mg/m 2 on days 1 and 8 every 21 days and irinotecan, 100 mg/m 2 , same schedule) with standard gemcitabine (1000 mg/m2 weekly × 4, then on days 1, 8, and 15 every 28 days thereafter). The combination was no better than single-agent gemcitabine with respect to TTP (3.5 vs 3.0 months, respectively, P=0.35) and overall survival (6.3 vs 6.6 months, P=0.79) and resulted in greate r grade 3/4 gastrointestinal toxicity. Irinotecan combinations not containing gemcitabine have also demonstrated activity in the phase II setting. A phase II study of irinotecan (50 mg/m 2 on days 1, 8, 15, and 21 every 35 days) with docetaxel (35 mg/m 2, same schedule) was reported to provide a 24% response rate with a median survival of 8.7 months [27]. An ECOG randomized phase II study of irinotecan/docetaxel with and without the anti–epidermal growth factor receptor (EGFR) antibody cetuximab is ongoing. Exatecan Exatecan is another topoisomerase 1 inhibitor that has been tested as a single agent as well as in combination with gemcitabine. In a large phase III trial reported by Cheverton et al. [28], the median survival with singleagent exatecan was less than with single-agent gemcitabine (5.0 vs 6.5 months, respectively, P=0.09), though the differences were not significant. O’Reilly et al. [29] recently reported the results of a phase III trial of gemcitabine and exatecan in combination versus single-agent gemcitabine. Both arms had a similar TTP (3.7 vs 3.8 months, P=0.22) and overall survival (6.7 vs 6.2 months, P=0.52), and there was greater hematologic toxicity in the combination arm.

Microtubule inhibitors Several phase II studies have suggested that microtubule inhibitors may have a role in the treatment of pancreatic cancer. Whereas docetaxel has little single-agent activity, a phase II study of gemcitabine (750 mg/m 2 on days 1, 8, and 15 every 28 days) and docetaxel (35 mg/m 2 , same schedule) was reported to produce a 27% response rate and 7.0-month overall survival [30]. Although the efficacy of the gemcitabine/docetaxel combination has not been formally tested in a phase III trial, a Cancer and Leukemia Group B (CALGB) randomized phase II study compared this combination with FDR gemcitabine, gemcitabine/cisplatin, and gemcitabine/irinotecan. All four treatments had similar response rates and 6-month survival rates (between 45% and 53%) [31]. A Southwest Oncology Group (SWOG) phase II study of the epothilone B analogue BMS-247550 in previously untreated pancreatic cancer patients reported five confirmed partial responses (9%) and a median survival of 6.9 months [32]. Second-line chemotherapy Second-line chemotherapy for advanced pancreatic cancer is difficult to study due to the short survival and poor performance status of most patients after first-line therapy. TS inhibitors such as capecitabine and infusional 5-FU are often used as second-line therapies because of their favorable toxicity profiles, though no randomized data exist to support this practice. Second-line 5-FU (200 mg/m 2/d by continuous infusion) with celecoxib (400 mg twice daily) was well tolerated in a pilot study of 17 patients, with a reported 12% response rate and a 3.4-month median survival [33]. GemOx also has second-line activity, with seven partial responses (23%) and a median survival of 4 months reported in a study of 30 gemcitabine-refractory patients [34]. The second-line combination of oxaliplatin, 5-FU, and leucovorin (oxaliplatin, 85 mg/m 2 on days 8 and 22, and leucovorin, 500 mg/m 2 over 30 minutes followed by 5-FU, 2600 mg/m2 over 24 hours on days 1, 8, 15, and 22) was reported to produce a median survival of 12.5 months from the time of primary diagnosis [35]. A second-line trial of irinotecan and the TS inhibitor raltitrexed achieved a response rate of 16% and a median survival of 6.5 months [36]. An ongoing randomized phase II trial is studying the combination of bevacizumab and docetaxel compared with bevacizumab alone in previously treated patients. Rubitecan The oral topoisomerase 1 inhibitor rubitecan has been tested in chemotherapy-refractory patients. In a phase III study reported by Jacobs et al. [37], pretreated patients (70% of whom had received two or more prior therapies) were randomly assigned to rubitecan or “best choice” chemotherapy, with crossover allowed at progression. Median survival was similar in the rubitecan and “best choice” arms (3.5 vs 3.1 months, respectively, P=0.63),

Chemotherapy for Advanced Pancreatic Cancer: Past, Present, and Future • Friberg and Kindler

though the tumor control rate (response rate plus stable disease rate) was greater with rubitecan (28% vs 13%), and crossover may have confounded the survival data.

191

harmful to some patients, potentially through inhibition of endogenous antiangiogenic cytokines that are stored within the extracellular matrix that require proteinases for activation. No large trials of matrix metalloproteinase inhibitors are currently enrolling patients.

Targeted Therapy Given the historic lack of success in treating pancreatic cancers with cytotoxic chemotherapies beyond gemcitabine, investigators have looked to novel approaches with the hope that targeting the underlying biology of the disease might ultimately improve patient survival. Included in these targeted approaches are a diverse group of endocrine and growth factor pathways that are believed to contribute to the pathogenesis of pancreatic cancer (Table 3).

The ras oncogene Activating mutations in the K-ras oncogene are found in up to 90% of human pancreatic cancers and are believed to play a role in the initiation of carcinogenesis [38]. As a result, several strategies have been tried to target this pathway. Farnesylation is an essential post-translational modification of Ras proteins that anchors them to the extracellular membrane. Inhibitors of farnesyl protein transferase block this process and display antiproliferative effects on pancreatic cancer cells in vivo [38]. The oral farnesyl transferase inhibitor SCH 66336 achieved a 7% singleagent response rate in a randomized phase II study, but survival appeared to be inferior to that of gemcitabine (3.3 vs 4.4 months, respectively) [39]. Van Cutsem et al. [38] reported that the oral farnesyl transferase inhibitor R115777, given in combination with gemcitabine, did not improve survival compared with single-agent gemcitabine in a 688-patient phase III trial (6.3 vs 6.0 months respectively, P=0.75). The North Central Cancer Treatment Group conducted a phase II study of the H-ras antis e n se co m p ou n d I S I S -2 503 i n co m bi na t io n w i th gemcitabine [40]. They observed a response rate of 15%, a 6-month survival rate of 58%, and a median survival of 6.6 months. Matrix metalloproteinase inhibitors The matrix metalloproteinase inhibitors are a family of proteolytic enzymes that degrade the extracellular matrix, and high serum levels have been correlated with poor clinical outcomes in pancreatic cancer [41]. A 277-patient phase III study fr om the Na tiona l C anc er Institute of Canada (NCIC) of the oral matrix metalloproteinase inhibitor BAY 12-9566, reported by Moore et al. [41], noted that survival with BAY 12-9566 was inferior to survival with single-agent gemcitabine (3.7 vs 6.6 months, P<0.001). Marimastat, another oral matrix metalloproteinase inhibitor, failed to improve survival, compared with single-agent gemcitabine when administered alone or in combination with gemcitabine in two separate randomized trials [42,43]. The lack of benefit in these trials has led some investigators to postulate that matrix metalloproteinase inhibition may be

Gastrin immunogens Gastrin stimulates proliferation of pancreatic cancer cells in vivo and is abnormally expressed in human pancreatic tumors [44]. Brett et al. [44] first reported that the immunogen G17DT was capable of stimulating gastrin-specific antibodies in 20 of the 30 pancreatic cancer patients tested, and that survival in these immune responders was superior to that of non-responders (7.1 vs 4.0 months respectively, P=0.002). A subsequent randomized, double-blind, phase II study in pancreatic cancer patients unsuitable for or unwilling to take chemotherapy (n=154) found that G17DT provided a significant survival advantage (5.0 vs 2.5 months, P=0.03) and time to performance status decline (4.5 vs 2.6 months, P=0.04) as compared with placebo [45]. Targeting angiogenesis Angiogenesis describes the ability of a tumor to develop new blood vessels in response to hypoxia and nutrient depletion. Among the endogenous angiogenic growth factors that have been identified, the most potent is the vascular endothelial growth factor, or VEGF. Both VEGF and its receptor are overexpressed in pancreatic cancers, where they are associated with a poor prognosis [46]. Several strategies have been used to target angiogenesis for the treatment of pancreatic cancer. Vascular endothelial growth factor inhibitors In addition to serving as a paracrine cytokine, VEGF may also be an autocrine growth factor in pancreatic cancer, making it a potentially important regulator of its pathogenesis [47]. The University of Chicago conducted a phase II trial of the humanized monoclonal anti-VEGF antibody bevacizumab (10 mg/kg on days 1 and 15 every 28 days) with gemcitabine (1000 mg/m 2 on days 1, 8, and 15 every 28 days) in previously untreated metastatic pancreatic cancer patients [48•]. Preliminary reports from the first 42 patients showed this combination to be well tolerated and potentially active, achieving a response rate of 21%, TTP of 5.8 months, and median survival of 9.1 months. The 6month survival rate was 74%, and the 1-year survival rate was 30%. Based on these data, a randomized, placebo controlled, phase III trial comparing gemcitabine and bevacizumab versus gemcitabine and placebo (CALGB 80303) is currently accruing patients. Companion studies evaluate the role of serum and urine biomarkers, serum proteomics, and pharmacogenomics in an attempt to discover potential predictive markers for clinical outcomes. Another companion study will evaluate the clinical-economic consequences of adding bevacizumab to gemcitabine.

Ras VEGF Antiangiogenic COX-2 HER-2 EGFR EGFR

Class 48 52 27 32 21 14 41

Patients, n Met (100) Met (100) LA (11), Met (89) LA (31), Met (69) Met (100) NS LA (15), Met (85)

Stage (%) 15 21 14 NS 22 7 12

ORR, % NS 5.8 3.7 NS NS 4.0 (PFS) 3.8

Median TTP, mo 6.6 9 6 9.1 NS NS 7.1

Median survival, mo 58 74 33 NS NS NS NS

6-Month survival, % NS 30 15 36 NS NS 32

1-Year survival, %

COX—cyclooxygenase; EGFR—epidermal growth factor receptor; Gem—gemcitabine; LA—locally advanced (stage II/III); Met—metastatic (stage IV); mo—months; NS—result not stated; ORR—overall response rate; PFS—progression-free survival; TTP—time to progression; VEGF—vascular endothelial growth factor.

Phase II trials Gem + ISIS-2503 [40] Gem+ bevacizumab [48•] Gem + thalidomide [49] Gem + celecoxib [50] Gem + trastuzumab [53] Gem + erlotinib [54] Gem + cetuximab [52•]

Agent(s)

Table 3. Outcomes with novel biologic agents in phase II trials

192 Gastrointestinal Cancers

Chemotherapy for Advanced Pancreatic Cancer: Past, Present, and Future • Friberg and Kindler

Thalidomide Thalidomide is an oral immunomodulator with antiangiogenic properties. Maples et al. [49] reported the results from a phase II trial of gemcitabine (1000 mg/m 2 on days 1, 8, and 15 every 28 days) with dose-escalating thalidomide (50–700 mg orally each day) in 27 patients with untr eate d pancre atic cance r. O f 21 e valua ble patients, there were three partial responses (14%) and 13 (62%) with stable disease after two cycles, with a median survival of 6.0 months. Grade 3 to 5 toxicities occurred in 23 patients (85%), with 11 cases of grade 3/ 4 neutropenia (41%) and four deaths during treatment. Although the response rate with this combination was encouraging, toxicities at these doses likely preclude its further development. Cyclooxygenase-2 inhibitors The cyclooxygenase (COX)-2 system appears to modulate the growth of some carcinomas, and preclinical knockout models suggest that this effect is through upregulation of angiogenic cytokines such as VEGF [50]. Marini et al. [51] reported preliminary results from a phase II trial of the COX-2 inhibitor celecoxib (400 mg orally twice a day) and gemcitabine (1000 mg/m 2 on days 1 and 8 every 21 days). They reported a median overall survival of 9.1 months, with a 36% 1-year survival and 46% clinical benefit response rate. There was no significant gastric or renal toxicity. Accrual to this trial is ongoing.

Human epithelial receptors (HER-2 and EGFR) Aberrations in expression of the human epithelial receptors, including the EGFR and HER-2, play an important role in the malignant potential of many tumors. In pancreatic cancer, overexpression of the EGFR occurs in up to 95% of cases and predicts advanced disease [52•]. Overexpression of HER-2/neu has also been found in 21% of pancreatic cancers, though its clinical significance is not well established [53]. HER-2 antibodies Safran et al. [53] reported results from a phase II study of gemcitabine and the anti-HER-2 antibody trastuzumab in patients with metastatic pancreatic cancer who overexpressed HER-2/neu (≥2+ expression by immunohistochemistry). Of 18 evaluable patients, there were four partial responses (22%). Although these findings are provocative, HER-2 overexpression was found in only 31 (21%) of the 151 patients screened for the study. The significance of this overexpression remains unknown, and the utility of this approach is limited by the small fraction of patients who overexpress HER-2. Epidermal growth factor receptor tyrosine kinase inhibitors A phase I/II trial has shown the combination of OSI-774 (erlotinib) and gemcitabine to be well tolerated [54]. Fourteen pancreatic cancer patients were treated in an expanded

193

cohort, with a reported response rate of 7% and TTP of 4 months. Preliminary reports from an NCIC phase III trial comparing gemcitabine with and without OSI-774 have indicated that the gemcitabine/OSI-774 arm showed a statistically significant improvement in survival (HR 0.81, P=0.025), though the magnitude of this advantage was only 2 weeks [55]. Epidermal growth factor receptor antibodies Xiong et al. [52•] conducted a phase II trial of gemcitabine and the humanized anti-EGFR antibody cetuximab in previously untreated patients with documented EGFR expression (by immunohistochemistry). Fifty-eight (95%) of the 61 patients screened for the study were 1+ or greater for EGFR. Of the 41 treated patients, there were five partial responses (12%) and 26 with stable disease (63%). The median progression-free survival duration was 3.8 months, the median survival was 7.1 months, and the 1-year survival rate was 32%. Acneiform rash was note d in 68% of patients, and there appeared to be a correlation between rash severity and overall survival (log-rank P=0.0007). In addition to the ECOG randomized phase II trial of docetaxel, irinotecan, and cetuximab mentioned previously, a 704-patient randomized phase III trial of gemcitabine and cetuximab versus gemcitabine alone (SWOG S0205) is now accruing patients.

Platelet-derived growth factor Platelet-derived growth factor (PDGF) receptors are expressed on endothelial cells, stromal cells, and pancreatic cancer cells, where they may play a role in regulating angiogenesis. Imatinib mesylate is a tyrosine kinase inhibitor for a variety of growth factor receptors, including PDGF, and has shown activity in pancreatic cancer xenograft models [56]. A small randomized phase II trial of imatinib versus gemcitabine in 24 patients with locally advanced and metastatic pancreatic cancer noted similarly high median survival times in both groups (11.2 and 12.0 months, respectively) [57].

Future Directions Several other biologically targeted treatments for pancreatic cancer are currently being evaluated in phase II trials, including CCI779 (an inhibitor of mammalian target of rapamycin [mTOR]) and LY29311 (a leukotriene B4 inhibitor). Although discovery of new biologic targets is important, signaling redundancies and pathway resistance will likely limit the effectiveness of single-targeted approaches. In preclinical models, multitargeted strategies can overcome such resistance and can result in greater suppression of proliferation than can be achieved by either agent alone [58]. For this reason, there is great interest in combining biologically targeted agents for the treatment of pancreatic cancer.

194

Gastrointestinal Cancers

The University of Chicago is currently leading two trials of multitargeted therapy for pancreatic cancer. The first is a randomized phase II study of combined VEGF and EGFR inhibition in untreated pancreatic cancer patients. This trial, sponsored by the National Cancer Institute (NCI) is randomly assigning 126 patients between gemcitabine, bevacizumab, and cetuximab or gemcitabine, bevacizumab, and erlotinib arms. An NCI-sponsored phase II study of gemcitabine and the oral tyrosine kinase inhibitor BAY-439006 (which inhibits VEGFR2, raf, PDGF, and c-kit) is also underway. A phase I trial has determined the combination to be safe, and efficacy has been demonstrated in other solid tumors, including renal cell cancers and sarcomas [59].

Conclusions Despite many attempts to improve upon its efficacy, singleagent gemcitabine remains the standard of care for the treatment of advanced pancreatic cancer. Additional cytotoxic agents have not improved survival over gemcitabine alone, and researchers have begun to explore novel biologically targeted therapies as alternate additions. The gastrin immunogens, anti-EGFR agents, and anti-VEGF agents are farthest along in their development for this disease. As we learn more about the biology of pancreatic cancer, we hope that novel agents and classes of drugs will become available that might ultimately improve the survival and quality of life for those with this devastating illness.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2.

3.

4.

5.

6.

7.

Jemal A, Tiwari RC, Murray T, et al.: Cancer statistics, 2004. CA Cancer J Clin 2004, 54:8–29. Carter SK, Comis RL: The integration of chemotherapy into a combined modality approach for cancer treatment. VI. Pancreatic adenocarcinoma. Cancer Treat Rev 1975, 2:193–214. Van Rijswijk RE, Jeziorski K, Wagener DJ, et al.: Weekly high-dose 5-fluorouracil and folinic acid in metastatic pancreatic carcinoma: a phase II study of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Eur J Cancer 2004, 40:2077–2081. Rubin J, Gallagher JG, Schroeder G, et al.: Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma. Cancer 1996, 78:1888–1891. Fung MC, Takayama S, Ishiguro H, et al.: [Chemotherapy for advanced or metastatic pancreatic cancer: analysis of 43 randomized trials in 3 decades (1974–2002)]. Gan To Kagaku Ryoho 2003, 30:1101–1111. Casper ES, Green MR, Kelsen DP, et al.: Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 1994, 12:29–34. Rothenberg ML, Moore MJ, Cripps MC, et al.: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 1996, 7:347–353.

8.• Burris HA 3rd, Moore MJ, Andersen J, et al.: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997, 15:2403–2413. This classic phase III study of gemcitabine versus 5-FU was the first of many to support gemcitabine as the standard of care for advanced pancreatic cancer. 9. Storniolo AM, Enas NH, Brown CA, et al.: An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer 1999, 85:1261–1268. 10.• Tempero M, Plunkett W, Ruiz Van Haperen V, et al.: Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 2003, 21:3402–3408. A phase II trial of fixed dose rate gemcitabine modulation. This gemcitabine modulation strategy is currently being evaluated in an ECOG randomized phase III study versus 30-minute gemcitabine and GemOx. 11. Oliani C, Padovani M, Manno P, et al.: Gemcitabine and continuous infusion of 5-fluorouracil in locally advanced and metastatic pancreatic cancer: a phase I-II study. Anticancer Res 2004, 24:2107–2112. 12. Correale P, Messinese S, Marsili S, et al.: A novel biweekly pancreatic cancer treatment schedule with gemcitabine, 5-fluorouracil and folinic acid. Br J Cancer 2003, 89:239–242. 13. Berlin JD, Catalano P, Thomas JP, et al.: Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 2002, 20:3270–3275. 14. Kindler HL, William D, Hochster H, et al.: Clinical outcome in patients (pts) with advanced pancreatic cancer treated with pemetrexed/gemcitabine [abstract]. Proc ASCO 2002, 21:499. 15. Richards DA, Kindler HL, Oettle H, et al.: A randomized phase III study comparing gemcitabine + pemetrexed versus gemcitabine in patients with locally advanced and metastatic pancreas cancer [abstract]. Proc ASCO 2004, 23:4007. 16. Cartwright TH, Cohn A, Varkey JA, et al.: Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 2002, 20:160–164. 17. Hess V, Salzberg M, Borner M, et al.: Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: a phase I/II trial. J Clin Oncol 2003, 21:66–68. 18. Scheithauer W, Schull B, Ulrich-Pur H, et al.: Biweekly highdose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol 2003, 14:97–104. 19. Okada S, Okusaka T, Ueno H, et al.: A phase II and pharmacokinetic trial of S-1 in patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 2002, 21:682. 20. Nakamura K, Yamaguchi T, Ishihara T, et al.: A phase I/II study of gemcitabine (GEM) with oral S-1 in metastatic pancreatic carcinoma [abstract]. Proc ASCO 2004, 23:4134. 21. Philip PA, Zalupski MM, Vaitkevicius VK, et al.: Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma. Cancer 2001, 92:569–577. 22. Heinemann V, Quietzsch D, Gieseler F, et al.: A phase III trial comparing gemcitabine plus cisplatin vs. gemcitabine alone in advanced pancreatic carcinoma [abstract]. Proc ASCO 2003, 22:1003. 23. Reni M, Passoni P, Panucci MG, et al.: Definitive results of a phase II trial of cisplatin, epirubicin, continuous-infusion fluorouracil, and gemcitabine in stage IV pancreatic adenocarcinoma. J Clin Oncol 2001, 19:2679–2686. 24. Reni M, Cordio S, Passardi A, et al.: Final results of a phase III trial of gemcitabine (G) versus PEFG regimen in stage IVA or metastatic pancreatic adenocarcinoma (PA) [abstract]. Proc ASCO 2004, 23:4010.

Chemotherapy for Advanced Pancreatic Cancer: Past, Present, and Future • Friberg and Kindler

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

Louvet C, Labianca R, Hammel P, et al.: GemOx (gemcitabine + oxaliplatin) versus Gem (gemcitabine) in non-resectable pancreatic adenocarcinoma: final results of the GERCOR / GISCAD Intergroup Phase III [abstract]. Proc ASCO 2004, 23:4008. Rocha Lima CM, Green MR, Rotche R, et al.: Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004, 22:3776–3783. Burtness B, Sipples R, Mirto G, et al.: Phase II trial of irinotecan/docetaxel combination for advanced pancreatic cancer [abstract]. Proc ASCO 2004, 23:4116. Cheverton P, Friess H, Andras C, et al.: Phase III results of exatecan (DX-8951f) versus gemcitabine (Gem) in chemotherapy-naïve patients with advanced pancreatic cancer (APC) [abstract]. Proc ASCO 2004, 23:4005. O Reilly EM, Abou-Alfa GK, Letourneau R, et al.: A randomized phase III trial of DX-8951f (exatecan mesylate, DX) and gemcitabine (GEM) vs. gemcitabine alone in advanced pancreatic cancer (APC) [abstract]. Proc ASCO 2004, 23:4006. Schneider BP, Ganjoo KN, Seitz DE, et al.: Phase II study of gemcitabine plus docetaxel in advanced pancreatic cancer: a Hoosier Oncology Group study. Oncology 2003, 65:218–223. Kulke M, Niedzwiecki D, Tempero M, et al.: A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/docetaxel, or gemcitabine/ irinotecan in patients with metastatic pancreatic cancer (CALGB 89904) [abstract]. Proc ASCO 2004, 23:4011. Whitehead R, McCoy S, Rivkin S, et al.: A phase II trial of epothilone B analogue BMS-247550 (NSC #710428) in patients with advanced pancreas cancer: a Southwest Oncology Group Study [abstract]. Proc ASCO 2004, 23:4012. Milella M, Gelibter A, Di Cosimo S, et al.: Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma. Cancer 2004, 101:133–138. Van Laethem J, Polus M, Marechal R, et al.: Gemcitabine and oxaliplatine (GEMOX) in gemcitabine-refractory advanced pancreatic cancer: a phase II study. Proc ASCO 2004, 23:4119. Pelzer U, Hempel C, Stieler J, et al.: Oxaliplatin (OXA) in combination with high dose 5-FU (24h)/folinic acid (FA) as salvage therapy in patients with gemzar-refractory advanced pancreatic cancer [abstract]. Proc ASCO 2002, 21:684. Ulrich-Pur H, Raderer M, Verena Kornek G, et al.: Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br J Cancer 2003, 88:1180–1184. Jacobs A, Burris HA 3rd, Rivkin S, et al.: A randomized phase III study of rubitecan (ORA) vs best choice (BC) in 409 patients with refractory pancreatic cancer report from a North-American multi-center study [abstract]. Proc ASCO 2004, 23:4013. Van Cutsem E, van de Velde H, Karasek P, et al.: Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004, 22:1430–1438. Lersch C, Van Cutsem E, Amado R, et al.: Randomized phase II study of SCH 66336 and gemcitabine in the treatment of metastatic adenocarcinoma of the pancreas [abstract]. Proc ASCO 2001, 20:608. Burch PA, Alberts SR, Schroeder MT, et al.: Gemcitabine and ISIS-2503 for patients with pancreatic adenocarcinoma (ACA): A North Central Cancer Treatment Group (NCCTG) phase II study [abstract]. Proc ASCO 2003, 22:1038. Moore MJ, Hamm J, Dancey J, et al.: Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 129566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003, 21:3296–3302.

42.

195

Bramhall SR, Schulz J, Nemunaitis J, et al.: A double-blind placebo-controlled, randomized study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002, 87:161–167. 43. Bramhall SR, Rosemurgy A, Brown PD, et al.: Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001, 19:3447–3455. 44. Brett BT, Smith SC, Bouvier CV, et al.: Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer. J Clin Oncol 2002, 20:4225–4231. 45. Gilliam AD, Topuzov EG, Garin AM, et al.: Randomized, double blind, placebo-controlled, multi-center, groupsequential trial of G17DT for patients with advanced pancreatic cancer unsuitable or unwilling to take chemotherapy [abstract]. Proc ASCO 2004, 23:2511. 46. Seo Y, Baba H, Fukuda T, et al.: High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000, 88:2239–2245. 47. Itakura J, Ishiwata T, Shen B, et al.: Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer 2000, 85:27–34. 48.• Kindler HL, Friberg G, Stadler WM, et al.: Bevacizumab (B) plus gemcitabine (G) in patient (pts) with advanced pancreatic cancer (PC): Updated results of a multi-center phase II trial [abstract]. Proc ASCO 2004, 23:4009. A phase II trial of the anti-VEGF antibody bevacizumab in combination with gemcitabine. This combination is currently being evaluated in a CALGB randomized phase III study. 49. Maples WJ, Stevenson J, Sumrall SV, et al.: Advanced pancreatic cancer: a multi-institutional trial with gemcitabine and thalidomide [abstract]. Proc ASCO 2004, 23:4082. 50. Williams CS, Tsujii M, Reese J, et al.: Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 2000, 105:1589–1594. 51. Marini G, Simoncini E, Valcamonico F, et al.: Gemcitabine (Gem) plus celecoxib in advanced pancreatic carcinoma: a phase II study [abstract]. Proc ASCO 2004, 23:4103. 52.• Xiong HQ, Rosenberg A, LoBuglio A, et al.: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol 2004, 22:2610–616. A phase II trial of the anti-EGFR antibody cetuximab in combination with gemcitabine. This combination is currently being evaluated in a SWOG randomized phase III study. 53. Safran H, Ramanathan R, Schwartz J, et al.: Herceptin and gemcitabine for metastatic pancreatic cancers that over-express HER-2/neu [abstract]. Proc ASCO 2001, 20:517. 54. Porterfield B, Dragovich T, Patnaik A, et al.: Erlotinib + gemcitabine in patients with unresectable pancreatic carcinoma: results from a phase IB trial [abstract]. Proc ASCO 2004, 23:4110. 55. OSI Pharmaceuticals I: Tarceva plus gemcitabine improves survival compared to gemcitabine alone in first-line pancreatic cancer patients. Press release. September 20, 2004. 56. Hwang RF, Yokoi K, Bucana CD, et al.: Inhibition of plateletderived growth factor receptor phosphorylation by STI571 (Gleevec) reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model. Clin Cancer Res 2003, 9:6534–6544. 57. Ebert M, Nitsche B, Roecken C, et al.: A prospective and randomized clinical trial of the tyrosine kinase inhibitor imatinib mesylate as an initial therapy of advanced pancreatic cancer [abstract]. Proc ASCO 2004, 23:4151. 58. Abdollahi A, Lipson KE, Sckell A, et al.: Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects. Cancer Res 2003, 63:8890–8898. 59. Siu L, Takimoto C, Awada A, et al.: A phase I/II trial of BAY 43-9006 and gemcitabine in advanced solid tumors and in advanced pancreatic cancer [abstract]. Proc ASCO 2004, 23:3059.