Background
In contrast to the steady increase in survival observed for most cancer types, advances have been slow for pancreatic cancers. More than one-half of cases are diagnosed at a distant stage, for which the 5-year survival rates is 3% [
1]. Only a small percentage of patients, approximately 10–15%, have a chance of surgical resection [
2‐
4]. However, the postoperative recurrence rate is high, with approximately 75–92% of patients relapsed [
5,
6]. Masato et al. [
7] reported that 80% local retroperitoneal recurrence, 66% hepatic metastasis, 53% peritoneal dissemination, 47% lymph node recurrence was discovered in postmortem examinations and 87% recurrence, 53% hepatic metastases in antemortem studies. The median survival after resection of pancreatic cancer remains in the range of 11–20 months and is associated with a 5-year survival rate of 7–25% [
8,
9]. More radical resection procedures or extensive lymphadenectomy have not improved the course of disease [
8]. Accordingly, adjuvant therapy appears to be very important in order to reduce recurrence and prolong survival after surgery.
The main adjuvant therapy after resection of pancreatic adenocarcinoma included chemotherapy and chemoradiation. Chemoradiation (moderate dose radiation with fluorouracil) has been the standard practice in the U.S. since the study (GITSG 9173) was conducted by the Gastrointestinal Tumor Study Group [
10]. The results of some studies also support the survival benefit of chemoradiotherapy for patients with resected pancreatic cancer [
11,
12]. But other researches have reached the opposite conclusion [
13,
14]. The European Study Group for Pancreatic Cancer (ESPAC-1) took on a head-to-head comparison trial and found a lower median survival for chemoradiation,(15.9 months versus 17.9 months for patients who did not receive chemoradiation) and the median time to recurrence was 10.7 months among patients who received chemoradiotherapy and 15.2 months among those who did not receive chemoradiotherapy [
15]. This resulted in far less use of adjuvant chemoradiation in Europe [
16]. Chemotherapy mainly includes gemcitabine, fluorouracil, FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin), and gemcitabine in combination with other drugs. At present, most pancreatologists believe that FOLFIRINOX is superior to gemcitabine. But gemcitabine is still an important chemotherapy drug. Previous clinical trials have demonstrated that postoperative chemotherapy with gemcitabine may prolong survival time and significantly delay the development of recurrent disease after complete resection of pancreatic cancer [
5,
17]. Furthermore, some control studies have also been performed between certain drugs and gemcitabine monotherapy after pancreatic cancer surgery, but the outcomes were uncertain. Here, we performed a systematic review and quantitative meta-analysis to assess the role of adjuvant treatments compared with gemcitabine alone after macroscopically complete resection of pancreatic cancer.
Discussion
For pancreatic cancer treatment, surgery is preferred for best survival [
4,
29]. However, the prognosis of the patient remains poor even after curative surgery owing to the high recurrence rate. Since 1996, gemcitabine has become the cornerstone for the treatment of pancreatic cancer. Burris et al. [
30] further demonstrated that gemcitabine had a modest survival advantage over treatment with 5-FU in patients with advanced pancreatic cancer. The median survival duration of patients treated with gemcitabine was 5.65 months, compared with 4.41 months for patients treated with 5-FU. The CONKO-001 trial [
31] also showed that the median DFS was 13.4 months in the gemcitabine-treated group and 6.7 months in the observation group after radical pancreatic cancer resection (HR, 0.55; 95%CI, 0.44–0.69;
P < 0.001). Patients randomized to adjuvant gemcitabine therapy had longer OS than those randomized to observation alone (HR, 0.76; 95%CI, 0.61–0.95;
P = 0.01), with 5-year OS of 20.7% vs 10.4%, respectively, and 10-year OS of 12.2% vs 7.7%. Furthermore, some clinical trials have aimed at assessing the potential superiority of adjuvant chemotherapy over single-agent gemcitabine in resected pancreatic cancer, but the results were not determinate.
In this study, we evaluated six randomized controlled trials comparing adjuvant treatments with gemcitabine monotherapy in first-line treatment of patients undergoing pancreatectomy. Our pooled analysis revealed the overall clinical efficacy of adjuvant chemotherapy was not superior to that of gemcitabine monotherapy in OS (HR, 0.87; 95% CI, 0.70–1.07; P = 0.19) and DFS (HR, 0.85; 95% CI, 0.71–1.02; P = 0.08). The incidence of adverse events in adjuvant treatments group were increased in grade 3/4 diarrhea and decreased in grade 3/4 leucopenia, thrombocytopenia compared with gemcitabine alone. Although our analysis did not show that adjuvant therapy was superior to gemcitabine monotherapy for resected pancreatic cancer, further stratification analysis was needed given the large heterogeneity of the pooled results.
We next analyzed the clinical efficacy of FU + FA regimen, S-1 regimen and Gem combined regimen respectively, and found that only patients receiving S-1 treatment had a benefit compared with patients receiving gemcitabine alone.
Toxicity of subgroup in S-1 regimen showed the lower incidence of leucopenia, thrombocytopenia, neutropenia and higher diarrhea. Pooled analysis of subgroup analysis showed that S-1 chemotherapy had a significant OS benefit (HR, 0.59; 95% CI, 0.46–0.74;
P < 0.0001) and DFS benefit (HR, 0.63; 95% CI, 0.52–0.75;
P < 0.00001). But it should be pointed out that this was only included the results of two trials (
n = 434). Most patients in the JASPAC 01 [
27] study had stage II disease, whereas the majority in another study had stages III and IV [
23]. The JASPAC 01 study was only enrolled with patients of Asians. At the same dose, Asians had lower toxic reaction to S-1 than Europeans due to different metabolism. Furthermore, the CAP-002 study [
22] also reported that S-1and Gem+S-1(GS) provided similar efficacy to Gem as the adjuvant chemotherapy for resected pancreatic cancer. Two year DFS rate was 24.2%, 28.1% and 34.4% in Gem, S-1 and GS, respectively and the median OS was 21 m in Gem, 26 m in S-1 and 27.9 m in GS.
The ESPAC-1 trial reported that fluorouracil plus folinic acid regimen could improve OS after pancreatic cancer resection, increasing the estimated 2 year and 5 year survival to 40% and 21% compared with 30% and 8.0% for surgery alone [
15]. However, the ESPAC-3 [
28] trial showed no difference in OS and PFS between the study groups (median OS and 2-year survival rate, 23.0 months and 48.1% in the FU + FA group vs 23.6 months and 49.1% in the Gem group, respectively;
P = 0.39. median PFS and 2-year survival rate, 14.1 months and 30.7% in the FU + FA group vs 14.3 months and 29.6% in the Gem group, respectively;
P = 0.53). The outcome of univariate analysis of the ESPAC-3 trial revealed that tumor grade, tumor size, nodal status, resection margin, postoperative CA19–9 levels, performance status, and smoking were independent prognostic factors of OS. But resection margin status was not significant on multivariate analysis, confirming the results of the ESPAC-1 trial that increasingly differentiated tumors, tumor size, and lymph-node status were associated with prognosis. Toxicity analysis of the ESPAC-3 trial showed the lower incidence of leucopenia, thrombocytopenia and higher diarrhea in FU + FA group.
Our subgroup analysis showed that Gem combined therapy did not had a significant OS benefit (HR, 0.89; 95% CI, 0.78–1.02;
P = 0.09) and DFS benefit (HR, 0.92; 95% CI, 0.82–1.05;
P = 0.21). It had higher incidence of diarrhea in gemcitabine-based combination therapy group, but leucopenia, thrombocytopenia and neutropenia were no difference between the three groups. In the ESPAC-3 trial [
28], the outcome demonstrated that gemcitabine was not superior to fluorouracil plus folinic acid in overall survival for patients with completely resected pancreatic cancer and suggested further comparison of the effects between gemcitabine combined with fluorouracil and folinic acid and gemcitabine monotherapy. Afterward, gemcitabine plus capecitabine (ESPAC-4) [
26] trial showed a increase in overall survival, with an estimated 5 year OS of 28.8% (22.9–35.2) compared with 16.3% (10.2–23.7) with Gem and found that prognosis was relationship with postoperative CA19–9 concentrations and pathological margin. However, gemcitabine plus uracil/tegafur had no benefit compared with GEM alone for patients with resected pancreatic cancer. 1-year DFS rate was 50.0% in GU group and 49.0% in the Gem group. Median survival time was 21.2 months and 29.8 months, respectively [
24]. Moreover, there were no significant differences in DFS and OS rates between N1, N2 and R0, R1 patients. Although gemcitabine plus erlotinib (GemErlo) had demonstrated a mild survival advantage for advanced pancreatic cancer [
32,
33], it did not improve median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months) in patients with R0 resections in CONKO-005 trial [
25]. Similarly, the combination therapy of Gem with sorafenib for 12 months can not improve DFS or OS for R1 resected pancreatic cancer patients in the CONKO-006 trial [
21].
At present, some trials demonstrated that the oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and the combination chemotherapy of gemcitabine and nab-paclitaxel regimens had effect on metastatic pancreatic ductal adenocarcinoma (PDAC) [
34‐
36]. Compared with gemcitabine, FOLFIRINOX and nab-paclitaxel plus gemcitabine showed survival advantage [
34,
36]. Now, gemcitabine and nab-paclitaxel regimen is being investigated in ongoing phaseIII trial for its efficacy in the adjuvant setting (APACT [NCT01964430: Nab-Paclitaxel and Gemcitabine vs Gemcitabine Alone as Adjuvant Therapy for Patients With Resected Pancreatic Cancer]) [
20].
The limitations of this study was the fact that the medicines tested in the trials were different, including chemotherapy drug and molecular targeted drug, which was used alone or in combination. Another limitation was the small number of trials that be included in the study because there were not many of these researches. The third limitation was relatively small number patients of some trials, although the total number of patients included in the meta- analysis was conspicuous.