Gemcitabine combination regimens may be superior to single agents (a) A meta-analysis of a two-drug combination regimen of gemcitabine A meta-analysis of 4465 patients with advanced pancreatic cancer from 15 randomized studies supported the gemcitabine combination regimen (GEM+X) for the treatment of advanced pancreatic cancer. In this meta-analysis, the drugs in combination with gemcitabine were 5-FU, FDR, capecitabine, irinotecan, topotecan, pemetrexed, cisplatin, and oxaliplatin. The results showed that the GEM+X regimen had a significant survival benefit, with a 9% reduction in the risk of death (HR=0.91; P=0.004); in combination with platinum, a 15% reduction in the risk of death (HR=0.85; P=0.01); in combination with fluorouracil, a 10% reduction in the risk of death (HR=0.9; P=0.03); and in combination with irinotecan, topotecan, and pemetrexed, there was no reduction in risk of death (HR=0.99); further analysis revealed that patients in good physical condition (high KPS score) treated with the combination regimen significantly reduced the risk of death (HR=0.76; P<0.0001). The authors concluded that gemcitabine-based combination chemotherapy regimens resulted in a survival benefit for patients in good physical condition and no survival benefit for patients in poor physical condition. (ii) A phase III randomized clinical study of gemcitabine in combination with oxaliplatin GERCOR /GISCAD, 313 patients with locally advanced or metastatic pancreatic cancer were randomized into 2 groups; GemOx group (157 patients): gemcitabine 1000 mg/m2 d1 + oxaliplatin 100 mg/m2 d2, repeated every 2 weeks; Gem group (156 patients): gemcitabine 1000 mg/m2 The effective rates (RR) in the GemOx and Gem groups were 26.8% and 17.3% (P=0.04), respectively, with clinical benefit rates of 38.2% and 26.9% (P=0.03), and median progression-free time (mTTP) of 5.0 and 3.7 months (P=0.04); median survival time (MST) was prolonged in the GemOx group compared with the Gem group, with 9.5% and 9.5%, respectively. The median survival time (MST) was prolonged in the GemOx group compared with the Gem group, at 9.0 and 7.1 months, respectively, but the difference was not statistically significant (P=0.13). the GemOx group was generally better tolerated, with an increased incidence of grade III-IV toxic reactions compared with the Gem group; among them, the incidence of platelet drop was 14.0% and 3.2%, respectively, the incidence of vomiting was 8.9% and 3.2%, respectively, and the incidence of neurological symptoms was The incidence of neurological symptoms was 19.1% and 0%, respectively. (iii) Gemcitabine combined with capecitabine A European III randomized clinical study compared gemcitabine combined with capecitabine (GemCap) regimen with single-agent gemcitabine (Gem) in patients with advanced pancreatic cancer; 319 patients were randomized to GemCap group (Gem: 1000 mg/m2 d1, 8; Cap: 650 mg/m2 bid d1-14; repeated every 3 weeks) and Gem group (Gem: 1000 mg/m2; once weekly; stop for 1 week for 7 weeks; then once weekly for 3 weeks, repeated every 4 weeks); MST was 8.7 months in the GemCap group and 7.2 months in the Gem group (p=0.234); patients in better physical condition (KPS score of 90-100) had a significantly longer MST in the GemCap group than in the The MST was significantly longer in the Gem group than in the Gem group, with MSTs of 10.1 and 7.4 months, respectively (p=0.014); the side effects were similar in both groups, and the most common grade III - IV toxic reaction was neutrophil decline. In Cunningham's III randomized clinical study comparing gemcitabine combined with capecitabine (GEM-CAP) regimen with single-agent gemcitabine (GEM) for advanced pancreatic cancer, 563 patients were randomized to the GEM-CAP group (267 patients) and the GEM group (266 patients). The GEM-CAP group had a significantly higher efficiency than the GEM group, with 19.1% and 12.4%, respectively (P=0.034); the GEM-CAP group had an improved progression-free survival time (HR=0.78; P=0 .004) and a trend toward improved survival (HR=0.86; P=0.08). (iv) Gemcitabine in combination with cisplatin Whether gemcitabine in combination with cisplatin is superior to gemcitabine alone is controversial. In the GIP-1 study, comparing single-agent gemcitabine with gemcitabine in combination with cisplatin and 199 cases in the combination group; single-agent group: Gem 1000 mg/m2 once a week for 7 weeks with a 1-week stop, then once a week for 3 weeks, repeated every 4 weeks; combination group: gemcitabine usage as in the single-agent group; DDP: 25 mg/m2, d1, 8, 15; repeated every 4 weeks; efficiency The rates were similar, with 10.1% and 12.9% in the single-agent group and the combination group, respectively (P=0.37); mPFS was 3.9 and 3.8 months, respectively (P=0.8); MST was 8.3 and 7.2 months, respectively (P=0.37); non-hematologic toxic effects were similar in both groups, while hematologic toxicity was more pronounced in the combination group. Another randomized clinical study showed that the combination may be superior to gemcitabine alone. 195 patients with locally advanced or metastatic pancreatic cancer were randomized into gemcitabine combined with cisplatin (GemCis) and single-agent (Gem) groups; GemCis group specific dosing: Gem1000mg/m2 + DDP50mg/m2, d1, 15, repeated every 4 weeks; Gem single-agent group Specific dosing: Gem1000mg/m2, d1, 15, repeated every 4 weeks. The results showed that both mPFS and MST were prolonged in the combination group, with mTTP of 5.3 months versus 3.1 months (HR=0.75; P=0.053) and MST of 7.5 months versus 6.0 months (HR=0.80; P=0.15), and the incidence of grade III-IV toxic reactions was more than 15% in both groups; the authors concluded that, although no statistical difference was reached, the study results support the use of the combination regimen. (v) Gemcitabine combined with S1 In 2011, ASCO reported the final results of a multicenter randomized clinical study in which 106 patients with unresectable locally advanced and metastatic pancreatic cancer were enrolled and randomized to the gemcitabine monotherapy group and the gemcitabine combined with S1 group. GEM 1000 mg/m2, 30 min, iv. d1, 8, 15, repeated every 4 weeks in the single-agent group and GEM 1000 mg/m2, 30 min, iv. d1, 15 + S1 40 mg/m2, bid, d1-14, repeated every 4 weeks in the combination group. 58% of patients in the single-agent group were treated with S1 after disease progression. OS in the two groups was 8.8 months (95% CI: 7.0-10.6) and 13.5 months (95% CI: 7.0-10.6), respectively, with no statistically significant difference (P=0.104); 1-year survival rates were 30.2% and 50.8%, respectively, with a statistically significant difference (P=0.031). The investigators attributed the lack of statistically significant prolongation of OS to the small sample size, suggesting that gemcitabine combined with S1 may be the first-line standard chemotherapy regimen for advanced pancreatic cancer. Other multi-drug combination chemotherapy regimens In a multicenter phase III clinical study, 52 patients with advanced pancreatic cancer were treated with a four-drug combination regimen (PEFG) based on gemcitabine-based chemotherapy and 47 received single-agent gemcitabine chemotherapy. pEFG group: DDP 40 mg/m2 d1, EPI 40 mg/m2 d1, GEM 600 mg/m2d1, 8, 5-FU 200 mg/m2/d civ d1-28, every Repeated at 4 weeks. In the single-agent group, GEM 1000 mg/m2 was administered once weekly for 7 weeks with a 1-week stop, followed by once weekly for 3 weeks and repeated every 4 weeks. 8.5% (P=0.0008); the incidence of grade III-IV neutrophil decline and platelet decline was higher in the PEFG group than in the single-agent group (P<0.0001). The investigators concluded that the PEFG regimen could be used to treat advanced pancreatic cancer. A randomized phase III clinical study reported by ASCO in 2010 used FOLFIRIOX consisting of 5-FU/LV, irinotecan and oxaliplatin or single-agent gemcitabine for the treatment of metastatic pancreatic cancer. A total of 342 patients were enrolled and randomized into the FOLFIRIOX group (OXA 85 mg/m2 d1+IRI 180 mg/m2 d1+LV 400 mg/m2d1+5-FU 400 mg/m2 iv d1, 2400 mg/m2 civ46h; q2w) and the Gem group (Gem: 1000 mg/m2; once weekly; stop for 1 week for 7 weeks; then once weekly for 3 weeks, repeated every 4 weeks). The incidence of grade III-IV toxic reactions in the two groups was 12.3% and 1.6% for diarrhea, 15.6% and 6.3% for nausea, and 17.2% and 6.3% for vomiting, respectively. 17.2% and 6.3% for diarrhea, 15.6% and 6.3% for nausea, 17.2% and 6.3% for vomiting, 24% and 14.3% for malaise, 47.9% and 19.2% for neutropenia, and 5.7% and 0% for febrile granulocyte deficiency, respectively. This study showed that the FOLFIRIOX regimen was superior to single-agent gemcitabine in terms of OS, PFS and efficiency, and had manageable toxic effects, and may be a new standard regimen for the treatment of metastatic pancreatic cancer with high PS score. Combination of molecular targeted agents (a) Gemcitabine combined with erlotinib An international multicenter, double-blind, placebo-controlled, randomized phase III clinical study randomized 569 advanced pancreatic cancer cases into gemcitabine combined with erlotinib (G+E) and gemcitabine combined with placebo (G+P) groups. mPFS was significantly prolonged in the G+E group, with 3.75 and 3.55 months, respectively (HR= In the G+E group, mPFS was significantly longer, at 3.75 and 3.55 months (HR=0.77; P=0.004); survival was also significantly longer (HR=0.82), with MST of 6.24 and 5.91 months, respectively (P=0.038); 1-year survival rates were 23% and 17% (P=0.023); there was no statistical difference in efficiency between the two groups, but more people with stable disease in the G+E group than in the G+P group. Complications and overall survival were further reported in this study at ASCO 2010. Those ≥65 years of age often had higher ECOG (P=0.009), and those ≥65 years of age tended to have Charlson Comorbidity Index (CCI) > 0 (P=0.02), and the combination of erlotinib significantly prolonged survival in patients <65 years of age (HR=0.73; P=0.01) and CCI > (HR=0.71; P=0.03). (ii) Gemcitabine combined with bevacizumab In the CALGB 80303 phase III clinical study, 590 patients with advanced disease were randomized to the gemcitabine combined with bevacizumab group and the gemcitabine combined with placebo group. The combination group was administered GEM 1000 mg/m2, d1, 8, 15 + Bev 10 mg/kg, d1, 5, repeated every 4 weeks; the gemcitabine in the combination placebo group was administered as in the combination group. The combination of bevacizumab did not prolong the overall survival of patients, 5.7 months and 6.0 months in the two groups, but prolonged survival in locally advanced cases and in those with good functional status (PS=0), with P values of 0.009 and 0.0001, respectively. the study showed that the addition of bevacizumab in some specific patients prolonged survival. (iii) Gemcitabine combined with cetuximab SWOG S0205 study comparing gemcitabine combined with cetuximab (G+C) and gemcitabine alone for advanced pancreatic cancer.G+C: Gem: 1000 mg/m2 once a week for 7 weeks with 1 week off, then once a week for 3 weeks, repeated every 4 weeks; C225: first dose 400 mg/m2, then 250 mg/m2, repeated weekly; single agent C225: the first dose of 400 mg/m2, followed by 250 mg/m2, repeated weekly; GEM dosing in the single drug group was the same as that in the combined group. A total of 766 patients were enrolled. RESULTS: MST was 6.5 months in the combination group and 6.0 months in the single-agent group (P=0.14); mPFS was 3.5 and 3.0 months, respectively (P=0.058); efficiency was 7.0% in both groups; and the incidence of grade III-IV toxic reactions was 14.0% and 11.0%, respectively. The results of this phase III randomized study showed that the combination C225 toxic reactions were tolerable, with a tendency to prolong MST and mPFS, but the difference did not reach statistical significance. (iv) Gemcitabine in combination with bevacizumab and erlotinib (AviTA study) In the AviTA study reported by ASCO in 2008, a total of 607 metastatic pancreatic cancer patients who had not received prior chemotherapy and had a KPS score of 60-100 were randomized to receive a three-drug combination of gemcitabine, erlotinib, and bevacizumab (GEB) and a two-drug combination of gemcitabine and erlotinib (GEP). GEB: gemcitabine 1000 mg/m2 once a week for 7 weeks with 1 week off, then once a week for 3 weeks, repeated every 4 weeks; erlotinib 100 mg/d; bevacizumab 5 mg/kg, repeated every 2 weeks. RESULTS: The effective rates in the two groups were 13.5% and 8.6%, respectively, with MST of 7.1 and 6.0 months (P=0.21) and mPFS of 4.6 and 3.6 months (P=0.002), respectively. The study showed that the three-drug group had a significant advantage in terms of efficiency and mPFS, and there was a trend of prolongation of MST. (v) Gemcitabine combined with sorafenib (BAYPAN study) In a multicenter, randomized, double-blind, phase III clinical study reported by ASCO in 2011, comparing gemcitabine combined with sorafenib (GS group) and gemcitabine combined with placebo (GP group) for the first-line treatment of advanced pancreatic cancer, 104 patients were randomized into the GS group after receiving Gem 1000 mg/m2 once a week for 7 weeks with a 1-week stop. After treatment with Gem1000mg/m2 once a week for 7 weeks stopping for 1 week, 104 patients were randomized to the GS group (Gem1000mg/m2 once a week for 3 weeks stopping for 1 week + Sorafenib 400mg/day) and the GP group (Gem1000mg/m2 once a week for 3 weeks stopping for 1 week + placebo) with the study endpoint of PFS. By the median follow-up time of 27.7 months, 98 patients had disease progression and 86 patients died. The difference in PFS and MST between the two groups was not statistically significant; PFS was 3.8 months in the GS group versus 5.6 months in the GP group, P=0.601; MST was 8.5 months in the GS group versus 9.2 months in the GP group, P=0.146. This suggests that the addition of sorafenib did not result in a survival benefit for the patients. In the phase II clinical study by Rothenberg et al, treatment with gemcitabine in patients with 5-FU-resistant advanced pancreatic cancer resulted in palliative benefits such as pain reduction and improvement in KPS scores. Benefits. In a phase II study, patients with advanced pancreatic cancer that progressed after standard first-line gemcitabine regimen were treated with GEMOX (GEM + OXA) with an efficiency of 22.6%, TTP of 4.2 months and MST of 6 months, showing that the GEMOX regimen had better antitumor activity and mild toxic side effects. A phase II randomized clinical study by Korean scholars compared modified FOLFIRI and modified FOLFOX regimens for the treatment of gemcitabine-resistant advanced pancreatic cancer; a total of 61 patients were enrolled, 31 in the mFOLFORI group and 30 in the mFOLFOX group, with 6-month survival rates of 27% and 30%, disease control rates of 23% and 17%, and MSTs of The study showed that both regimens had moderate antitumor activity and tolerable side effects. A phase III clinical study evaluating 5-FU/calcium folinate versus 5-FU/calcium folinate in combination with oxaliplatin in gemcitabine-resistant pancreatic cancer, CONKO-003, has completed enrollment and is being followed up with promising results. In patients with pancreatic cancer, 41 patients were enrolled in 3 centers and received PEP02 120 mg/m2 administered intravenously over 90 minutes, repeated every 3 weeks; the effective rate was 5%, disease control rate was 50%; PFS was 9 weeks, MST was 21.6 weeks, and 3-month survival rate was 75%; the study achieved the expected 3-month survival rate of ≥65%, and the investigators concluded that irinotecan liposomes are useful for The study achieved an expected 3-month survival rate of ≥65%, and the investigators concluded that irinotecan liposomes are efficacious and tolerable in patients with metastatic pancreatic cancer with KPS ≥70 and toxic side effects. In a retrospective analysis, also from ASCO 2011, FOLFIRI was used as a second- or third-line regimen to treat patients with recurrent pancreatic cancer with gemcitabine in combination with platinum; 70 patients were included in the analysis, including 24 who had received first-line therapy, 40 who had received second-line therapy, and 6 who had received more than third-line therapy; the disease control rate was 44.3%, including 5 PR and 26 SD; the mTTP was 3.0. cases; mTTP was 3.2 months and MST was 6.7 months, while patients with poor physical status (PS=2) had significantly shorter TTP and OS, 0.9 months (P<0.001) and 2.5 months (P=0.001), respectively; the study analysis showed that for patients with good physical status (PS=0-1) on retreatment, the FOLFIRI regimen is not a better regimen. In conclusion, it is indisputable that chemotherapy or plus targeted therapy can benefit patients with locally advanced and metastatic pancreatic cancer. Gemcitabine remains the gold standard for the treatment of advanced pancreatic cancer. Multiple phase III randomized studies or meta-analyses have shown that gemcitabine-based combination regimens are superior to single-agent gemcitabine, especially in patients with better functional status. The vast majority of single-agent or combination regimens in second- and third-line therapy provide some clinical benefit only in patients with better physical status (KPS ≥ 70, PS0-1). Molecularly targeted drugs are a hot topic of current research, and erlotinib (in combination with gemcitabine) has been shown to be the only molecularly targeted drug that can prolong the survival of patients with advanced pancreatic cancer compared to gemcitabine alone, while other molecularly targeted drugs such as bevacizumab and cetuximab for advanced pancreatic cancer have also shown signs of improved efficiency and prolonged mPFS and MST, which may be achieved in future studies breakthroughs may be achieved in future studies.