Pancreatic ductal epithelial cell carcinoma (pancreatic cancer) is a highly lethal disease (incidence/mortality rate 1/0.95), and the latest global oncology statistics in 2011 show that its incidence is increasing year by year, and it is estimated that 266,000 patients will die from pancreatic cancer in 2011. Pancreatic cancer has become a disease that seriously endangers human health, and more and more scholars have joined the field of pancreatic cancer research, which has led to significant progress in related research. In this article, we review the research progress of pancreatic cancer from basic to clinical in 2011, in order to provide some ideas for the diagnosis and treatment of pancreatic cancer and further research.
Translational research.
With the continuous progress in biomedical research and innovation in research methods and techniques, significant progress has been made in basic and translational research on pancreatic cancer, and certain research results have even overturned the traditional views, providing new ideas and methods for the prevention, diagnosis and treatment of pancreatic cancer.
Early diagnostic markers.
The occurrence and development of pancreatic cancer is a process of continuous accumulation of genetic and epigenetic mutations. In recent years, whole genome sequencing studies have shown that it takes about 20 years from the onset of pancreatic cancer to the death of the patient, which overturns the traditional view that pancreatic cancer metastasizes at an early stage and suggests that physicians will have a wide window of time to prevent, diagnose and treat pancreatic cancer at an early stage. Therefore, research on early diagnostic markers of pancreatic cancer should be strengthened.
At present, the research of early diagnostic markers includes: (1) antibody microarray platform, scholars found that differential expression of c-MET in serum protein is closely related to the stage of pancreatic cancer patients and their survival rate; (2) microRNA (miRNA), research shows that miRNA-196a, miRNA-200a and b are highly expressed in the serum of pancreatic cancer patients, which may become a marker for early diagnosis; (3) genetic markers. (3) Genetic markers, scholars found that eight single nucleotide polymorphisms (SNPs) distributed in three chromosomal regions were associated with increased risk of pancreatic cancer; two SNPs were located between the non-transcribed region of chromosome 13q22.1 and the Kruppel-like transcription factors KLF5 and KLF12; KLF5 was overexpressed in pancreatic cancer and mediated the non-KRAS/RAF/ KLF5 is overexpressed in pancreatic cancer and mediates the non-KRAS/RAF/ERK signaling pathway; ④ Protein markers, scholars found that the combination of UL binding protein 2 (ULBP2) and glycoantigen-199 (CA-199) gave the best results in the diagnosis of pancreatic cancer; ⑤ Markers in pancreatic fluid, studies showed that matrix metalloproteinase 9 (MMP-9) expression was upregulated in the pancreatic fluid of pancreatic cancer patients, suggesting that it may be a marker for early diagnosis of pancreatic cancer .
Some progress has been made in the study of early diagnostic markers for pancreatic cancer, but the studies are mostly retrospective, and there is a lack of data on the sensitivity, specificity and safety of these markers for early diagnosis of pancreatic cancer, which still needs to be verified by more in-depth clinical studies. Although there is still no early diagnostic marker with high specificity and sensitivity for pancreatic cancer, it has become a hot spot in pancreatic cancer research because of the significance of such studies.
Prognostic and efficacy predictors.
In 2011, the research progress of prognostic and efficacy predictors of pancreatic cancer includes the following points: ① Mc Williams et al. screened 9 SNPs that could predict the efficacy of gemcitabine in 940 patients, among which the genes PYCARD (rs6507115) and MAPRE2 (rs8056505) were significantly associated with the efficacy of gemcitabine. (ii) In a phase III clinical study on erlotinib, researchers analyzed multiple indicators including K-ras exon 2 mutations, epidermal growth factor receptor (EGFR) expression, PTEN expression, EGFR intron 1 polymorphism and EGFR exon 13 R497 polymorphism, and showed that only K -ras mutation was associated with survival benefit, suggesting that K-ras mutation may be a predictor of erlotinib efficacy; ③ cytidine deaminase (CDA) inactivates gemcitabine, and CDA-related biomarkers predict gemcitabine efficacy and associated toxic effects; patients with low CDA plasma levels achieve longer survival; ④ patients with circulating tumor cell (CTC)-positive median progression-free The median progression-free survival (PFS) period of patients with positive CTC was significantly shorter than that of those with negative CTC, suggesting that CTC may be an independent prognostic factor for pancreatic cancer. All of the above studies are retrospective studies, and the inclusion of prognostic and efficacy predictors in prospective phase III clinical studies requires more careful clinical trial design.
Clinical individualized treatment studies.
Beatty GL et al. published in Science showed that activation of CD40 activated macrophages in pancreatic cancer tissues, reversed tumor immunosuppression, and promoted degradation of pancreatic cancer mesenchyme, increased the concentration of gemcitabine in cancer tissues, accomplished an efficient anti-tumor response, and prolonged patient survival. A study on albumin + paclitaxel + gemcitabine for pancreatic cancer reported in the Journal of Clinical Oncology (J Clin Oncol) also showed that targeting SPARC reduced the fibrosis of pancreatic cancer mesenchyme, increased the concentration of gemcitabine in cancer tissue by 2.1-fold, and led to an overall survival (OS) period of more than 1 year for patients with advanced pancreatic cancer, which is a landmark individualized treatment clinical translational study.
The above studies bring new inspiration for future clinical research of pancreatic cancer: (1) pancreatic cancer as a whole, in addition to cancer cells, the interstitial fluid as the tumor microenvironment also plays an important role in its development, therefore, in addition to the treatment of cancer cells, treatment to improve the tumor microenvironment will also become a new treatment strategy; (2) reversing immunosuppression is an important part of pancreatic cancer treatment; (3) low drug concentration in tumor tissues may be an important part of pancreatic cancer treatment. Low concentration of drugs in tumor tissues may be an important reason for the poor therapeutic effect of pancreatic cancer, so increasing the concentration of drugs in tumor tissues will become an important therapeutic strategy for pancreatic cancer.
Clinical research.
Clinical research on pancreatic cancer has made some progress, but still lags behind compared to other tumors. 2011 National Comprehensive Cancer Network (NCCN) guidelines for the diagnosis and treatment of pancreatic cancer have several highlights worth noting: ① more emphasis on multidisciplinary cooperation in the diagnosis and treatment process, especially in pathologically confirmed cases; ② emphasis on comprehensive assessment of physical status, including Eastern Cooperative Oncology Group (ECOG) score , pain control, biliary tract patency, and nutritional intake of the patient; (3) while recommending gemcitabine as the cornerstone treatment, the status of fluorouracil analogues (such as 5-FU and capecitabine) in the treatment of pancreatic cancer was re-recognized, especially in the selection of second-line treatment; (4) physicians were more encouraged to recommend patients to participate in clinical studies.
Surgical treatment.
Currently, surgery is the only way to eradicate pancreatic cancer, but only about 15% of pancreatic cancer patients can receive surgical treatment at the time of diagnosis. Recently, some progress has been made in the surgical treatment of pancreatic cancer, with the following three main points: ① Regarding the choice between pancreaticoduodenectomy (Whipple) and pylorus-preserving pancreaticoduodenectomy (PPPD), studies have shown that PPPD surgery has fewer postoperative complications than Whipple surgery; however, attention must be paid to the indications for PPPD surgery, and radical resection (R0) is the prerequisite for choosing this surgical approach. However, the indications for PPPD surgery should be noted, and radical resection (R0) is a prerequisite for this procedure. However, in pancreatic cancer, most studies have shown that expanded lymph node dissection does not improve patient survival and quality of life.
Although some progress has been made in the surgical treatment of pancreatic cancer, there is still a lack of uniform surgical indications, and it is still controversial whether an expanded surgical approach based on revascularization and expanded lymph node dissection can bring benefits to patients. Japanese scholars advocate a larger scope of surgery, while European and American scholars have reservations, so the standard surgical approach has to be confirmed by further phase III clinical studies.
Figure 1 Extent of resection for pylorus-preserving pancreaticoduodenectomy (PPPD) (blue area) Figure 2 Attachment of the remaining pancreatic tail to the small intestine after pylorus-preserving pancreaticoduodenectomy
Medical treatment.
Studies have confirmed that postoperative adjuvant therapy prolongs patient survival, but the optimal adjuvant treatment regimen remains controversial, with North American scholars preferring concurrent radiotherapy followed by chemotherapy, while European scholars preferring chemotherapy as the primary treatment. The standard postoperative treatment for resectable pancreatic cancer should include adjuvant chemotherapy, and for patients in good physical status, gemcitabine-based combination chemotherapy can be considered; for those in poor physical status, gemcitabine monotherapy is advocated, and the 2011 NCCN guidelines added 5-fluorouracil (5-FU) + calcium folinic acid (CF) regimen as an alternative to gemcitabine.
Eighty-five percent of pancreatic cancer patients are at an advanced stage at diagnosis, so palliative care for advanced pancreatic cancer occupies an important place in the treatment of pancreatic cancer. Previously, metastatic pancreatic cancer and locally advanced pancreatic cancer were collectively referred to as advanced or progressive pancreatic cancer, and they were mostly included together in clinical studies, but clinical studies in recent years have gradually separated the two.
1. Locally advanced pancreatic cancer: It refers to tumor encircling the superior mesenteric artery, celiac trunk or superior mesenteric vein or portal vein confluence, while there is no distant metastasis. About 25% of pancreatic cancer patients are locally progressive at the time of diagnosis, and the median OS period is about 9 months. The treatment of locally advanced pancreatic cancer is still controversial and has not made much progress in 2011. According to previous studies, the results of the E4201 study and the FFCD-SFRO study differed, with North America preferring a concurrent radiotherapy regimen and Europe preferring gemcitabine monotherapy. The results of LAP-07, a multicenter phase III clinical study initiated in 2008, are highly anticipated. The results of LAP-07, a multicenter phase III clinical study initiated in 2008, are expected.
Metastatic pancreatic cancer: About 60% of patients with pancreatic cancer are diagnosed with metastatic pancreatic cancer, and the common sites of metastasis are liver, lung and bone. 2011 has seen significant progress in clinical studies of metastatic pancreatic cancer. The results of GEST studies conducted in Japan and Taiwan showed that tegeo (S-1) alone was not inferior to gemcitabine alone and that the former could be administered orally with less hematologic toxicity reactions. Another phase I/II clinical study using albumin + paclitaxel + gemcitabine for advanced pancreatic cancer achieved a major breakthrough with an OS of 12.2 months for those treated with the combination regimen, a breakthrough of 1 year, and an OS of 17.8 months in the albumin + paclitaxel + gemcitabine group for patients with high SPARC protein expression. Currently, a phase III clinical study of albumin + paclitaxel + gemcitabine for advanced pancreatic cancer is underway. The above results show that individualized treatment with appropriate drugs based on the pathological or molecular characteristics of pancreatic cancer patients is still the future research direction.
3. Molecular targeted drug therapy: The research on targeted therapy for pancreatic cancer has not made a breakthrough in general, but some small samples of clinical studies have made some progress. A phase II clinical study of dual inhibition of EGFR signaling pathway by erlotinib + panitumumab combined with gemcitabine for advanced pancreatic cancer significantly prolonged the OS period (8.4 months vs. 4.0 months). This study suggests that the three-drug combination may be a first-line treatment option for advanced pancreatic cancer, subject to further confirmation in a large phase III clinical study. In addition, studies are still ongoing to select the appropriate population for the three-drug combination by biomarkers (K-ras). Another phase II clinical study of a monoclonal antibody targeting insulin growth factor receptor 1 (IGFR-1) showed that ganitumab (IGFR-1 monoclonal antibody) in combination with gemcitabine enhanced the efficacy of gemcitabine and improved the prognosis of patients with progressive pancreatic cancer, and a phase III clinical study is now underway. There is no major breakthrough in clinical studies of molecularly targeted drugs for pancreatic cancer. Better targets and targeted drugs should be searched for, and in designing clinical studies of molecularly targeted drugs, more reasonable treatment modalities and more specific patient selection should be sought to truly achieve individualized targeted therapy.
Radiotherapy.
Although radiotherapy is controversial in the comprehensive treatment of pancreatic cancer, with the advancement of radiotherapy technology and the standardization of clinical research, the status of radiotherapy in the treatment of pancreatic cancer will be gradually established. For patients with locally advanced pancreatic cancer in good physical status, simultaneous radiotherapy based on gemcitabine or 5-FU/CF, i.e. systemic chemotherapy with gemcitabine or 5-FU/CF before or after radiotherapy, has become one of the treatment options recommended by the 2011 NCCN guidelines.
Outlook.
In recent years, tremendous progress has been made in the diagnosis and treatment of cancer, but progress regarding the diagnosis and treatment of pancreatic cancer is still limited, and the 5-year OS rate for pancreatic cancer patients has only increased from 2% to 5%, while the incidence of pancreatic cancer is rapidly increasing. The hope of breaking the bottleneck of pancreatic cancer diagnosis and treatment lies in the following: based on basic research, we can deeply understand the mechanism of pancreatic cancer development, so as to prevent and diagnose it at an early stage; we must conduct a more comprehensive assessment of pancreatic cancer patients (including stage and physical status), and on this basis, we can choose individualized treatment methods (including surgery, medical treatment and radiotherapy, etc.); we can develop new targets and new drugs for pancreatic cancer treatment, and finally achieve prolong the OS period and improve the quality of life of patients.