Combination chemotherapy

Although the benefit of chemotherapy in patients with advanced pancreatic cancer is well established, the magnitude of the effect is rather small, with an absolute improvement of survival at 5 years of 3% to 6% (survival rates from 1975-77 to 1999-2005) (Oberstein & Saif, 2011). Over the past decade, multiple randomized trials have been performed to assess a number of gemcitabine-combination chemotherapy regimens in an effort to improve these modest results. These have included combinations with 5-FU (Berlin et al, 2002; Riess et al, 2005), capecitabine (Herrmann et al, 2007; Bernhard et al, 2008; Cunningham et al, 2009), cisplatin (Heinemann et al, 2006; Colucci et al, 2002, 2009), oxaliplatin (Louvet et al, 2005; Poplin et al, 2009), irinotecan (Rocha et al, 2004; Stathopoulos et al, 2006), exatecan (Abou Alfa et al, 2006) and pemetrexed (Oettle et al, 2005a). Individually, although many of these studies observed some improvement in terms of response rate and progression free survival favoring combination therapy, the great majority failed to demonstrate a survival benefit (Table 1).

The largest and most recent meta-analysis, however, confirm a modest although significant benefit in survival for gemcitabine combinations over gemcitabine alone (HR 0.91; 95% CI: 0.85 to 0.97; p=0.004) in patients with locally advanced or metastatic pancreatic cancer (Sultana et al, 2007; Heinemann et al, 2008b). The magnitude of this benefit was remarkably greater (HR 0.76; 95%CI: 0.67 to 0.87; p<0.0001) in patients with good performance status (representing 38% of all patients included in the meta-analysis). In subgroup analysis, platinum compounds (3 trials, 1077 patients; HR 0.85; 95%CI 0.74-0.96) and capecitabine (3 trials, 935 patients; HR 0.83; 95%CI 0.72-0.96) in combination with gemcitabine consistently showed improved survival over single-agent gemcitabine. Insufficient evidence was observed, nevertheless, to support combination of gemcitabine with 5FU or irinotecan.

The rationale for the combined use of gemcitabine and cisplatin is based on the preclinical evidence that gemcitabine not only increases cisplatin-induced DNA cross links, but also effectively inhibits their repair, and cisplatin, on the other hand, enhances the incorporation of gemcitabine triphosphate into DNA. In vitro studies show synergistic cytotoxicity and several non-controlled clinical studies suggested improved efficacy. Some early randomized studies observed increased response rates and progression free survival for patients treated with the cisplatin-gemcitabine combination as compared to those treated with gemcitabine alone (Colucci et al, 2002; Heinemann et al, 2006), with a non-significant trend towards a longer survival. However, more recent and larger trials have failed to confirm a significant

Reference

Treatment

Number

Response Rate

PFS

OS

of patients

(%)

(months)

(months)

Berlin et al

GEM vs

327

5.6 vs 6.9

2.2 vs 3.4

5.4 vs 6.7

(2002)

GEM+5FU

(p=0.022)

(p=0.09)

Herrmann

GEM vs

319

7.8 vs 10

3.9 vs 4.3

7.2 vs 8.4

et al (2007)

GEM+ CAP

(p=0.103)

(p=0.234)

Cunningh

GEM vs

533

12 vs 19

3.8 vs 5.3

6.2 vs 7.1

am et al

GEM+

(p=0.034)

(p=0.004)

(p=0.08)

(2009)

CAP

Colucci et

GEM vs

107

9.2 vs 26.4

1.8 vs 4.6

5 vs 7.5

al (2002)

GEM+CIS

(p=0.02)

(p=0.048)

(p=0.43)

Colucci et

GEM vs

400

10.1 vs 12.9

3.9 vs 3.8

8.3 vs 7.2

al (2010)

GEM+CIS

(p=0.37)

(p=0.80)

(p=0.38)

Heineman

GEM vs

195

8.2 vs 10.2

3.1 vs 5.3

6 vs 7.6

n et al

GEM+CIS

(p=0.053)

(p=0.15)

(2006)

Louvet et

GEM vs

313

17.3 vs 26.8

3.7 vs 5.8

7.1 vs 9

al (2005)

GEM+OX

(p=0.04)

(p=0.04)

(p=0.13)

Poplin et al

GEM vs

832

6 vs 10 vs 9

2.6 vs 3.5

4.9 vs 6.2

(2009)

GEM FDR GEM+OX

(p=0.11)

(p=0.04) vs 2.7 (p=0.1)

(p=0.04) vs 5.7 (p=0.22)

Stathopoul

GEM vs

145

10 vs 15

2.8 vs 2.9

6.4 vs 6.5

os et al

GEM+IRI

(p=0.39)

(p=0.79)

(p=0.97)

(2006)

Rocha

GEM vs

360

4.4 vs 16.1

3 vs 3.5

6.6 vs 6.3

Lima et al (2004)

GEM+IRI

(p<0.001)

(p=0.352)

(p=0.789)

Oettle et al

GEM vs

565

7.1 vs 14.8

3.3 vs 3.9

6.3 vs 6.2

(2005a)

GEM+ PEM

(p=0.004)

(p=0.11)

(p=0.847)

Abou Alfa

GEM vs

349

4.6 vs 6.3

3.8 vs 3.7

6.2 vs 6.7

et al (2006)

GEM+EXA

(p=0.22)

(p=0.52)

5FU, 5-fluomracil; GEM, gemcitabine; CAPE, capecitabine; CIS, cisplatin; OX, oxaliplatin; IRI, irinotecan; EXE, exatecan; PEM, pemetrexed; RR, response rate; PFS, progression free survival; OS, overall survival.

5FU, 5-fluomracil; GEM, gemcitabine; CAPE, capecitabine; CIS, cisplatin; OX, oxaliplatin; IRI, irinotecan; EXE, exatecan; PEM, pemetrexed; RR, response rate; PFS, progression free survival; OS, overall survival.

Table 1. Selected phase III trials of gemcitabine-based chemotherapy in advanced pancreatic cancer impact on overall survival, whereas combination therapy was associated with greater hematological toxicity (Colucci et al, 2010). Similar findings have been observed with the combination of gemcitabine with oxaliplatin (GEMOX). GEMOX was superior to gemcitabine in terms of response rate (26.8% v 17.3%; p=0.04), progression-free survival (5.8 v 3.7 months; p=0.04), and clinical benefit (38.2% v 26.9%; p=0.03), with a trend for an improved survival (9.0 v 7.1 months, p=0.13) (Louvet et al, 2005). Severe toxicities were however more commonly induced by the combination, particularly thrombocytopenia, emesis and neurotoxicity. More recently published trials, again, did not confirm these benefits for the GEMOX regimen (Poplin et al, 2009).

Combination of gemcitabine plus capecitabine is the other cytotoxic chemotherapy doublet that has shown some advantage over gemcitabine alone. Two recent phase III studies consistently demonstrated a gain in terms of progression free survival (PFS) for the combination, although the benefit in overall survival (OS) only achieved statistical significance in the meta-analysis of these trials (Cunningham et al, 2009; Herrmann et al, 2007). Cunningham et al randomized 533 patients to receive gemcitabine (1000 mg/m2 in 30-min infusion weekly x 3 every 4 weeks) plus capecitabine (830 mg/m2/12 hours day 1-21 every 28 days) versus gemcitabine alone. Combination therapy obtained higher response rates (19.1% vs 12.4%, p=0.034) and PFS (5.3 vs 3.8 months; HR 0.78, 95% CI 0.66-0.93, p=0.004) and a trend toward better OS of borderline significance (7.1 vs 6.2 months; HR 0.86, 95% CI 0.72-1.02, p=0.08). Herrmann and colleagues randomized 319 patients to receive either gemcitabine (1000 mg/m2 days 1 and 8 every 21 days) plus capecitabine (650 mg/m2/12 hours days 1-14 every 21 days) or gemcitabine alone (1000 mg/m2 weekly for 7 weeks and one week off, and then weekly x 3 every 4 weeks). No significant differences were observed among study arms in terms of response rate, clinical benefit or quality of life (Bernhard et al, 2008), and the primary endpoint of the study, OS, was not reached (8.4 vs 7.2 months, p=0.234). However, post hoc analysis did show a significant survival advantage for the gemcitabine-capecitabine combination in patients with good performance status (10.1 vs 7.4 months, p=0.004). In both studies toxicity in the combination arm was tolerable, with a low incidence of grade 3-4 adverse events, being neutropenia and diarrhea the most commonly encountered toxicities. In light of these results, treatment with gemcitabine plus capecitabine may be considered in fit patients with advanced pancreatic cancer.

Other multidrug combinations have also been investigated over the past years in several phase II-III trials, including PEFG (cisplatin, epirubicin, gemcitabine and 5-FU) (Reni et al, 2005), G-FLIP (irinotecan, gemcitabine, 5-FU, leucovorin and cisplatin) (Goel et al, 2007), and active schedules in other gastrointestinal cancers such as FOLFOX-6 (oxaliplatin, 5-FU and folinic acid) (Ghosn et al, 2007) or FOLFIRI.3 (irinotecan, 5-FU and folinic acid) (Tai'eb et al, 2007). Increased tumor responses and progression free survival have been reported for some of these regimens (Reni et al, 2005), although at the expense of a worse toxicity profile with no impact on survival. However, the combination of Gemcitabine and nab-paclitaxel, an albumin-bound formulation of paclitaxel particles (Celgene, Summit, NJ), deserves special mention (Von Hoff et al, 2011). nab-Paclitaxel has shown antitumor activity in various advanced cancer types that overexpress the albumin-binding protein SPARC (secreted protein acidic and rich in cysteine), including breast, lung, and melanoma. Results of the phase I/II trial of this combination, with an overall response rate of 48%, a median survival of 12.2 months, and a 1-year survival rate of 48% at the MTD are among the highest ever reported for a phase II study in patients with advanced pancreatic cancer. Interestingly, SPARC expression in the stroma, but not in the tumor, was correlated with improved survival (median survival of 17.8 v 8.1 months for high- vs low- SPARC tumors, respectively; P= .0431), suggesting SPARC could be a potential new predictive biomarker of nab-paclitaxel activity. This promising results have prompted the conduction of a large international phase III study that is close to complete accrual. Also recently reported, results of the PRODIGE 4/ACCORD 11 trial comparing gemcitabine alone (1000 mg/m2 weekly x 7 every 8 weeks and then weekly x 3 every 4 weeks) to FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, 5-FU 400 mg/m2 given as a bolus followed by 2400 mg/m2 given as a 46-hour continuous infusion; and leucovorin 400 mg/m2; every 2 weeks) demonstrated remarkable and significant improvements in response, progression free and overall survival rates favoring patients treated with FOLFIRINOX (31% vs. 9%, 6.4 months vs. 3.3 months, and 11.1 months vs. 6.8 months, respectively) (Conroy, 2011). These results are somewhat surprising, given the known modest activity of each of the individual drugs included in the regimen, and shall be confirmed. In addition, the higher toxicity profile of this combination limits its widespread use as standard of care in patients with metastatic disease, often frail. However, it may be an excellent option for carefully selected patients, particularly those with locally advanced borderline resectable disease. Anyhow, this is the first phase III randomized trial that has demonstrated a benefit in overall survival of unquestionable clinical relevance for patients with advanced pancreatic cancer, and it may change the classical paradigm of gemcitabine as the keystone in the management of advanced pancreatic cancer.

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