Pancreatic cancer is a devastating disease with a dismal prognosis. Most of patients present with locally advanced or metastatic disease and are thus not candidates for surgical resection, thereby having to rely on palliative chemotherapy as the only treatment option. In this situation, the goals of chemotherapy should be to control tumor progression, decrease toxicity, and improve the survival rate. At present, gemcitabine monotherapy remains the standard treatment for patients with locally advanced or metastatic pancreatic cancer, but its efficacy is unsatisfactory. During the last decade, several randomized controlled clinical trials have evaluated gemcitabine in combination with various agents in an attempt to improve the prognosis of pancreatic cancer. The aim of this meta-analysis was to compare the therapeutic efficacy of gemcitabine-based combination treatments with gemcitabine alone in patients with locally advanced or metastatic pancreatic cancer. The results of this study showed that various combination therapies overall did not provide any major benefit compared with gemcitabine monotherapy.
Moreover, gemcitabine monotherapy had an almost 30% lower ORR than combination therapy regimens, but only had a 10% lower 1-year OS than combination therapy. According to the present data, 1-year OS in advanced or metastatic pancreatic cancer was low (less than 20%) after gemcitabine monotherapy; therefore, the combination therapy options studied did not improve outcome in a substantial way, the prognosis still being poor[21,31,42
]. In addition, there were no significant improvements found in this analysis in median PFS and median OS after combination therapy compared with monotherapy, except for gemcitabine plus fluoropyrimidine treatment. Our results are similar to previously published analyses[23,43,44
]. We also assessed the five most common toxicities related to chemotherapeutic treatment of locally advanced or metastatic pancreatic cancer, including hematological and gastrointestinal side effects. Grade 3-4 toxicities tended to be higher following combination therapy compared with monotherapy, and three of the five investigated toxicities reached significant differences. The RRs of vomiting, diarrhea, and thrombocytopenia in the monotherapy group were about 70% of that noted in the combination therapy group. Furthermore, subgroup analysis showed that the RR of vomiting after treatment with gemcitabine plus platinum was twice that of monotherapy. The results presented here showed that combination therapy induced more toxicity than gemcitabine alone. Similar results were found in a previous study[45
]. This finding might explain why combination therapy received higher ORR, but without affecting the overall prognosis, as toxicities counterbalanced the positive effects.
In the present analysis, we included several kinds of combination therapies with gemcitabine, which could provide different anti-tumor effects and different uptake and toxicity profiles, including platinum based agents, topoisomerase inhibitors, taxanes, bevacizumab, cetuximab and other biologically targeted agents. However, no significant differences were found between the subgroups, except for side-effects (vomiting). In addition, the analysis of heterogeneity was not significant in most subgroups. This is interesting, and indicates that effectiveness of the different combinations regarding outcomes could not clearly be shown. There are two possible reasons that could explain these results. One is related to gemcitabine-uptake receptors. The other one could be the inherent drug-resistant character of pancreatic carcinoma cells and the effect of the surrounding stroma.
Human equilibrative nucleoside transporter-1 (hENT-1) is the main membrane channel responsible for intracellular bioavailability of gemcitabine. Preclinical and clinical data have revealed that only a minority of patients have high hENT1 expression and reduced levels of hENT-1 expression correlate with increased resistance to gemcitabine[7
]. To increase gemcitabine efficiency and avoid overtreatment, determination of the hENT1 status at the time of diagnosis and modifying gemcitabine to allow it to bypass the receptor may represent a future mode of overcoming gemcitabine resistance[7
]. Multidrug resistance proteins, including ABC transporters, have also been implied in drug resistance in pancreatic cancer and limit the efficacy of gemcitabine[46
]. The pancreatic stellate cell has a key role in stroma formation and secretes factors that promote pancreatic tumor growth and resistance to radiation and gemcitabine chemotherapy[47
]. The hypoxic stroma could be a physical barrier preventing chemotherapeutic drugs from reaching the pancreatic cancer cells per se, and depletion of the stroma could enhance cancer drug delivery[48
]. Recently, cancer stem cells and epithelial to mesenchymal transition (EMT)-type cells have been implicated in metastasis formation and drug resistance[49
]. Selective targeting of cancer stem cells and EMT-type cells might represent a future strategy to enhance chemosensitivity. The plasma circulating time of gemcitabine is short and its rapid metabolism thus limits tumor uptake. Using novel formulas such as PEGylated gemcitabine may result in a prolonged circulation time, and possibly inducing cytotoxicity at lower concentrations than those required with treatment with the native drug[50
]. Pancreatic cancer, including its concurrent stroma, is complex; therefore, treatment with a single anti-tumor agent may not be effective enough. Determining the underlying mechanisms of drug resistance in pancreatic cancer will provide ways of overcoming chemoresistance and provide a foundation for novel therapies.
During the last decade, several meta-analyses have focused on the efficacy of combination therapy in locally advanced or metastatic pancreatic cancer[43,44,51-54
]. Most of these studies have reported positive trends or have concluded that combination treatments may improve outcome, but only a limited number of the studies have reported toxicity data, or have only focused on one anti-tumor agent. In the present study, we collected and analyzed the outcomes in different chemotherapeutic subgroups, as well as toxicity, to make the result more comprehensive and convincing. However, several limitations in this analysis should still be considered. Firstly, some endpoints were not evaluated in all of the included randomised controlled trials. Secondly, heterogeneity of certain endpoints in some subgroups might limit the comparability between studies and affect the validity, despite the use of randomized models.
In conclusion, we compared the outcomes of different combination therapies with gemcitabine monotherapy, including ORR, OS, PFS and major toxicity. The results showed that gemcitabine combination therapy leads to a modest improvement in survival, though with more toxicity reported compared with gemcitabine monotherapy.