Advances in early diagnosis and therapy of pancreatic cancer

Beijing, China

Advances in early diagnosis and therapy of pancreatic cancer

Qiang Xu, Tai-Ping Zhang and Yu-Pei Zhao

Beijing, China

BACKGROUND: Pancreatic cancer remains a devastating disease with a 5-year survival rate of less than 5%. Recent advances in diagnostic methods and therapeutic approaches have increased the possibility of improving the existing poor prognosis.

DATA SOURCES: English-language articles reporting early diagnosis and therapy of pancreatic cancer were searched from the MEDLINE and PubMed databases, Chinese-language articles were from CHKD (China Hospital Knowledge Database). RESULT: The current literature about pancreatic cancer was reviewed from three aspects: statistics, screening and early detection, and therapy.

CONCLUSIONS: Early detection and screening of pancreatic cancer currently should be limited to high risk patients. Surgical resection is the only curative approach available, with some recent improvement in outcomes. Gemcitabine has been a standard treatment during the last decade. Gemcitabinebased combination treatment, especially combined with newer molecular targeted agents, is promising. The rationale for radiotherapy is controversial, but with the recent development of modern radiation delivery techniques, radiotherapy should be intensified. Patients with borderline pancreatic cancer could benefit from neoadjuvant therapy but more evidence is needed and the best neoadjuvant regimen is still to be determined.

(Hepatobiliary Pancreat Dis Int 2011; 10: 128-135)

pancreatic neoplasm; early diagnosis; biomarkers; surgery; adjuvant therapy; neoadjuvant therapy; borderline resectable tumor

Introduction

According to Cancer Statistics 2009, pancreatic cancer was expected to account for 6% of all cancer deaths, and is the fourth leading cause of cancer death in the USA.[1]A total of 42 470 new cases of pancreatic cancer, about 21 050 in males and 21 420 in females, were expected to be newly diagnosed in 2009. It was estimated that 35 240 new deaths were expected to occur in 2009, with 18 030 in males and 17 210 in females. There have been notable improvements since 1975 in relative 5-year survival rates for many cancer sites, and for all cancers combined. The improvement in survival reflects a combination of earlier diagnoses and improved treatments. The relative 5-year survival rate of pancreatic cancers has not improved substantially during the past 30 years, improving from 3% for patients diagnosed in 1975-1977 to 5% for those diagnosed in 1996-2004.[1,2]

In China, the incidence of pancreatic cancer has been increasing steadily. In Shanghai, age-adjusted incidence rates of pancreatic cancer increased by 40%-50% between 1972-1974 and 1993-1994, with the average annual rates increasing from 4.0 to 6.1 per 100 000 in males and from 3.1 to 4.5 per 100 000 in females.[3]

Screening and early detection

Pancreatic cancer has a dismal prognosis because cancer-specific symptoms occur only at an advanced stage. At the time of diagnosis, the majority of cancers of the pancreas are diagnosed at stage IV (49.5%), or the stage of disease is unknown (18.8%). In comparison, very few cancers of the pancreas are diagnosed in early stages: stage IA and stage IB comprise only 0.7% and 2.7% of diagnoses, respectively.[4]

By the time of diagnosis, less than 15% of patients have surgically resectable disease. The median survival of unresectable pancreatic cancer is 4-6 months. Although the overall 5-year survival of large resected pancreatic cancers (median size 30 mm) is only 10%-20%, it is 30%-60% after resection of small pancreatic cancers(tumor size ≤20 mm), and exceeds 75% when minute pancreatic cancers (≤10 mm in size) are resected.[5,6]It is clear that, in order to substantially affect long-term survival, we have to detect pancreatic cancer earlier.

Defining populations at high risk

Since patients seldom exhibit disease-specific symptoms during the early phase of the disease, screening needs to be done in asymptomatic individuals. However, given the low incidence and prevalence of pancreatic cancer, it would not be cost-effective or worthwhile to screen the general population, since the yield would be extremely low. For screening to be costeffective, it should be targeted to individuals at high risk for developing pancreatic cancer.

In one study from the Mayo Clinic, new-onset of diabetes mellitus was used as a potential clue to the early diagnosis of pancreatic cancer.[5]Although diabetes seems to be associated with early-stage pancreatic cancer, further study of a population of patients with new-onset diabetes will be needed before screening can become cost-effective. The pathogenesis of pancreatic cancerassociated diabetes remains to be elucidated. The high prevalence of diabetes in pancreatic cancer suggests that β-cell dysfunction, probably related to tumor-secreted products, is the main defect in pancreatic cancerassociated diabetes. Future studies should focus on understanding the pathogenesis of pancreatic cancerassociated diabetes and identifying biomarkers that can distinguish it from type-2 diabetes mellitus.

In our view, populations at higher risk include: 1) patients ＞40 years of age and presenting with nonspecific abdominal symptoms; 2) patients with relatives diagnosed with pancreatic cancer; 3) patients with newonset diabetes mellitus, especially those ＞60 years of age, lacking a family history of diabetes mellitus, with no obesity and rapidly developing insulin-resistance; 4) patients with chronic pancreatitis, especially hereditary chronic pancreatitis and calcareous chronic pancreatitis; 5) patients with intraductal papillary mucinous tumor; 6) patients with familial adenomatous polyposis; 7) patients who have had distal subtotal gastrectomy for benign disease, especially 20 years after the resection; and 8) patients with heavy tobacco or alcohol use or long-term contact with hazardous chemical substances.[7]

Imaging studies

Current imaging studies such as abdominal CT, abdominal MRI or transabdominal ultrasound are inadequate for the detection of pancreatic cancer at an early stage, because these imaging techniques do not reliably detect tumors ＜1-2 cm in size.[8]It is also recognized that there have been improvements in imaging technology, such as the development of 64-slice multi-detector CT scans and 3D-MRI scanners; however, none of these imaging studies has to date been shown to reliably detect a small tumor of ＜1 cm in size in an asymptomatic patient population.

To date, endoscopic ultrasound (EUS) and helical CT scans are the most sensitive imaging modalities for detecting pancreatic tumors, and should be considered first line when there is a clinical suspicion of pancreatic cancer.[9]EUS seems to be one of the most promising techniques for early diagnosis. With or without fine needle aspiration, it has a high sensitivity, however its accuracy in TNM-staging differs.[10]EUS, when compared to CT, MRI and angiography, shows the highest accuracy in assessing tumor size and lymph node involvement, whereas helical CT has the highest accuracy in assessing the extent of primary tumor, locoregional extension, vascular invasion, distant metastasis, tumor TNM-staging and tumor resectability. The evaluation of tumor resectability should be done by a minimum of two imaging techniques, in which the combination of CT and EUS proves to be the method with highest accuracy at lowest cost. The detection of distant metastases is not possible with EUS. A normal EUS examination seems to exclude a pancreatic tumor with a high probability. Quality of EUS shows a high inter-observer variance; accuracy seems to be dependant on further clinical or imaging information. Chronic or recent episodes of acute pancreatitis, diffusely infiltrating carcinoma, and a prominent ventral/dorsal split are additional reasons for failure to diagnose tumor accurately. New techniques like contrast-enhanced EUS or additional 3D reconstructions look promising for improving EUS.[10,11]

Biomarkers

To date, the clinical role of tumor markers has been limited. No tumor marker has been shown to be useful in the screening of an asymptomatic population. The standard serum marker, salivated Lewis blood group antigen CA19-9, is widely used, but its use is limited to monitoring responses to therapy, not as a diagnostic marker.[12,13]As a marker for early pancreatic cancer, there are some important weaknesses that can be summarized as follows: a) Approximately 10% of the population with the Lewis-negative genotype is not able to produce CA19-9 secondary to a lack of the enzyme involved in its synthesis, even if they have advanced pancreatic cancer. Recently it has been reported that patients with undetectable CA19-9 have a better prognosis than those with elevated levels.[14,15]b) Patientswith small pancreatic cancers often show false negative CA19-9 values, thus eliminating its value in early diagnosis. c) CA19-9 elevation is common in patients with obstructive jaundice even without malignancy because of the reduction in clearance by the cholestatic liver. d) False positive CA19-9 elevation is also frequently observed in patients with cancers of the upper gastrointestinal tract, ovarian cancer, hepatocellular cancer, benign conditions of the hepatobiliary system and chronic pancreatitis.[16]Thus CA19-9 is considered the standard for monitoring response to chemotherapy and recurrence following surgical resection in patients with pancreatic cancer, but not for the initial diagnosis of the disease.

Due to the inability of CA19-9 to identify early potentially curable disease, several other serologic markers have been studied, including carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), MIC1, carcinoembryonic antigen, alpha-fetoprotein, pancreatic associated antigen (SPan-1), CA50 antigen, DU-PAN-2, alpha4GnT, cytokeratin-19 (CK-19) mRNA, elastase-1, tissue polypeptide antigen and tissue polypeptide-specific antigen.[17]Unfortunately, none of these markers have achieved the levels of sensitivity and specificity necessary to be recommended as a screening tool for asymptomatic patients in the general population.

Recently, Gold et al[13]developed the monoclonal antibody PAM4 which is highly specific for a MUC1 produced by pancreatic cancer. This antigen is identified in over 90% of pancreatic cancer and its precursor lesions, but is not detected in normal pancreas. They demonstrated that the sensitivity and specificity of the immunoassay for pancreatic cancer were 77% and 95%, respectively, with a positive likelihood ratio of 16.8. In their study, both immunohistochemical and enzyme immunoassays were used to detect and/or quantify PAM4-mucin in tissue and sera, respectively, of normal and cancer patients in whom staging of cancer is known. The overall sensitivity and specificity of the assay were 82% and 85%, respectively, which are consistent with previous results. An exciting finding in their study is that 92% of stage I cancer cases were above the cutoff value for a positive result. Mean antigen concentration in the serum correlated well with stage of disease. The data suggest that PAM4 has potential utility as a biomarker in the early detection of pancreatic cancer.

Genetic and epigenetic markers have been extensively investigated in pancreatic fluid. Protein markers require accurate quantification, and their levels may be quite variable in pancreatic fluid in normal individuals, whereas initial studies of genetic and epigenetic markers anticipate that the mere detection of such alterations would have some diagnostic value. Some of the genetic and epigenetic markers that have been investigated in pancreatic fluid include mutant K-ras, p53 mutations, DNA methylation alterations, and mitochondrial DNA mutations.

Over 300 microRNAs have been identified, and widespread alterations in these microRNAs have been identified in various types of cancer. While the expression of most microRNAs appears to be reduced in cancer, and several are overexpressed and could be potential targets for early detection assays.[12]

In summary, many new protein-, DNA-, and RNA-based markers are under investigation as markers of invasive pancreatic cancer. While some of the newly described markers are promising, many require further validation using optimal laboratory methods and suitable patient populations before they can be considered ready for use in clinical settings. Since the best chance of cure of pancreatic cancer is when the cancer is at an early stage, clinical studies involving pancreatic cancer markers must focus their efforts on patients with early stage pancreatic cancer.

Others

In addition, metabonomics is an area of study being developed in other areas of oncology, such as breast cancer. The comparison of metabolic profiles between cancer patients and normal patients has the potential to allow clinicians to detect pancreatic cancer at its early stage. Bathe et al found the metabolic profiles of patients with pancreatic cancer were significantly different from those of patients with benign disease. They concluded that more studies are needed to develop metabonomics as a valuable modality for the early diagnosis of pancreatic cancer.[16]

At present, the use of biomarkers and imaging techniques are not recommended as routine screening tools for screening asymptomatic patients in the general population. Screening of high risk patients with EUS is gaining wider acceptance, but evidence of efficacy and cost-effectiveness is still needed. Continued efforts are needed to discover effective test to identify patients with nonhereditary risk factors who will benefit from screening and also to develop less invasive and more cost-effective screening modalities aimed at controlling pancreatic cancer.

Therapy

Surgery

Pancreatic cancer is a devastating disease with a poorprognosis for most patients. Surgical resection remains the cornerstone of treatment, providing the only realistic hope for long-term survival.[18,19]Surgical resection is the only curative approach available for patients suffering from pancreatic cancer. However, resection rates remain low, not only because advanced disease is present in the majority of patients, but also because nonspecialized centers often have insufficient experience with radical surgery. The value of re-exploration for pancreatic ductal adenocarcinoma after the initial diagnosis of unresectability is unclear. In one study, 33 patients who were re-explored after an initial diagnosis of unresectability were analyzed. At the time of reoperation, a resectable tumor was found in 18 patients. Analysis of the reasons arguing against initial resection showed that, if the patients had been sent to a tertiary referral center for pancreatic surgery, a different decision in favor of resection would likely have been made in 14 of the 33 patients. Reoperation for pancreatic ductal adenocarcinoma that is initially deemed unresectable can be safely performed in a selected group of patients by experienced surgeons, supporting the concept of patient centralization in pancreatic surgery.[18,19]

With improvements in the safety of Whipple resection in recent decades, surgeons have continued to explore the role of more extensive lymphadenectomy in hopes of improving long-term survival. Available data from controlled randomized prospective trials indicate that pancreaticoduodenectomy with extended lymphadenectomy confers no survival advantage over pancreaticoduodenectomy with standard lymphadenectomy. Morbidity and mortality rates are comparable. Postoperative diarrhea in the early months after operation is problematic in patients undergoing extended lymphadenectomy. In none of the studies was a benefit in long-term survival demonstrated. Standard pancreaticoduodenectomy continues to be the operation of choice for adenocarcinoma of the head of the pancreas.[20]

The retroperitoneal margin is frequently microscopically tumor positive in non-curative periampullary adenocarcinoma resections. One study was aimed at determining whether retroperitoneal margin involvement independently predicts survival after pancreaticoduodenectomy. It was shown that tumor involvement of the retroperitoneal margin independently predicted a poor prognosis after pancreaticoduodenectomy for adenocarcinoma. In microscopically curative (R0) resections, pancreatic tumor origin was the only factor that independently predicted a poor prognosis.[21-23]

Adjuvant therapy

The high risk of local and systemic disease recurrence as well as overall poor prognosis has long been the rationale for adjuvant therapy after resection of pancreatic cancer.

Drug therapy

Gemcitabine has been a standard treatment for advanced pancreatic cancer since it was shown a decade ago to result in a superior clinical response and survival compared with bolus 5-fluorouracil (5-FU). Since then, clinical trials have explored the pharmacokinetic modulation of gemcitabine by fixed dose administration and the combination of gemcitabine with other cytotoxics.[24]

At present, a 6-month course of standard-infusion gemcitabine can be considered an appropriate treatment option, but the objective tumor response rate is low. Various combinations with numerous cytostatic agents (5-FU, cisplatin, oxaliplatin, epirubicin, irinotecan, capecitabine, docetaxel, and mitomycin C), have been tested in order to improve the therapeutic results, but there was no clear benefit in overall survival. However, positive results were shown in the objective response rates and progression-free survival times.[25]Secondline therapies, after the failure of a first-line therapy, are probably effective; however, a standard for secondline therapies has not yet been established.[26-28]For that reason, continuous search for other agents is mandatory.

In recent decades, our understanding of the molecular mechanisms of cancer progression has expanded substantially, making possible the development of novel therapeutic approaches. Epidermal growth factor receptor blockade, inhibition of angiogenesis, modulation of tumor response through the extracellular matrix, inhibition of cyclooxygenase-2, farnesyl transferase inhibitors, signal transduction inhibitors, ablation of the hormonal influence and some other aspects have all been studied, but to date, no specific breakthrough in the treatment of pancreatic carcinoma has been proven.[29]

Against a background of numerous negative randomized trials of gemcitabine-based combination treatment, two trials have recently reported modest survival improvements: the United Kingdom National Cancer Research GEMCAP trial of gemcitabine with the orally administered precursor of 5-FU-capecitabine, and the National Cancer Institute of Canada Clinical Trials Group PA.3 trial in which the tyrosine kinase inhibitor erlotinib was used with gemcitabine.

To date, the role of molecular targeted therapy in pancreatic carcinoma is promising, especially in the study of EGFR-blockade, but the results are not convincingly superior to standard chemotherapeutictreatments. Pancreatic adenocarcinoma remains a great challenge for the field of oncology, and continuous search for better molecules and/or combinations is inevitable.

Further research focused on new combinations, incorporating the new targeted therapies, and identifying potential predictive factors of response are required to be able to offer effective tailored therapies to our patients.[30-32]

Radiotherapy

The preponderance of available data supports the routine use of adjuvant chemotherapy after surgical resection for pancreatic adenocarcinoma. The use of adjuvant radiotherapy for pancreatic cancer, however, is controversial. Currently, the addition of radiotherapy depends upon, to some degree, the side of the Atlantic Ocean on which a patient is being treated.[33]Chemoradiotherapy followed by chemotherapy is considered the optimal therapy in North America (Gastrointestinal Tumor Study Group, GITSG; Radiation Therapy Oncology Group, RTOG) while chemotherapy alone is the current standard in Europe (European Study Group for Pancreatic Cancer, ESPAC-1; Charité Onkologie, CONKO).[34-38]

In our view, in the absence of adjuvant therapy, local failure rates can exceed 50% after resection of pancreatic cancer. The rationale for adjuvant radiotherapy for pancreatic cancer is to improve locoregional control. Modern radiation delivery techniques, such as intensitymodulated radiation therapy, or image-guided and stereotactic body radiation therapy, permit dose escalation in order to reduce normal tissue toxic effects and simultaneously deliver increased doses of radiation to affected areas.[39,40]It is clear that breakthroughs in the treatment of this devastating disease would come mostly from advances in systemic therapy, so radiotherapy should not be abandoned, but rather, intensified.

Intraoperative radiotherapy has been considered for treatment of pancreas cancer, since local recurrence rates are very high. In general, intraoperative radiotherapy can slightly increase survival rates among patients with pancreatic cancer in localized stages. There is no clear evidence to indicate that intraoperative radiotherapy is more effective than other therapies in treating pancreatic cancer in locally advanced and metastatic stages.[41]

Neoadjuvant therapy for borderline resectable tumor

The improvement of helical dual phase scanning sensitivity and surgeons' experience has advanced the classification from resectable and unresectable to resectable, borderline and unresectable.[42,43]The borderline tumors are defined as those that abut the superior mesenteric artery, abut or encase the common hepatic artery over a short segment, or occlude the superior mesenteric vein-portal vein confluence, with suitable vein above and below such that venous reconstruction is possible.[44]

A few studies[44-51]were conducted to determine the effects of neoadjuvant therapy, which are summarized in the Table. Katz et al[44]reported 160 patients with borderline resectable pancreatic adenocarcinoma, of whom 125 (78%) completed preoperative therapy and restaging, and 66 (41%) underwent pancreatectomy. Vascular resection was required in 18 (27%) of the 66 patients, and 62 (94%) underwent a margin-negative pancreatectomy. A partial pathologic response to induction therapy was seen in 37 (56%) of the 66 patients. Median survival was 40 months for the 66 patients who completed all therapy and 13 months forthe 94 patients who did not undergo pancreatectomy (P＜0.001). Gillen et al[52]meta-analyzed a total of 111 studies (n=4394) including 56 phase I-II trials in which neoadjuvant therapy was applied. Neoadjuvant chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to 63 Gy. In patients with initially staged resectable tumors, resection frequencies and survival after neoadjuvant therapy are similar to those of patients with primarily resected tumors and adjuvant therapy. Approximately 33.2% of initially staged nonresectable tumor patients would be expected to have resectable tumors following neoadjuvant therapy, with comparable survival (median survival following resection: 20.5 months; range 9-62 months) as initially resectable tumor patients. Averaged complete and partial response probabilities were 4.8% and 30.2% for the initially non-resectable (borderline resectable/ unresectable) tumors, whereas the progressive disease fraction was estimated to be 20.8%. Compared with monotherapy, combination chemotherapies resulted in higher estimated response and resection probabilities for patients with initially non-resectable tumors.

Table. Patients receiving neoadjuvant chemoradiotherapy for locally advanced pancreatic head cancer

It seems that patients with borderline resectable or unresectable tumors are likely to benefit from surgery followed by neoadjuvant therapy. Besides, some investigators regard that neoadjuvant therapy makes sense, particularly since delayed recovery after surgery precludes adjuvant therapy in approximately 30% of patients who undergo elective pancreaticoduodenectomy as the initial treatment.[53]However, at present there is no high-level evidence of any benefit deriving from neoadjuvant therapy for pancreatic cancer.[54]Well designed trials are needed and the best neoadjuvant regimen is still to be determined.

Conclusion

Pancreatic cancer remains a highly challenging problem in oncology. Early detection and screening in the current state should be limited to high risk patients. Continued efforts are needed to discover effective tests to identify patients with high risk factors who will benefit from screening, and also to develop less invasive and more cost-effective screening modalities aimed at controlling pancreatic cancer. Oncologists continue to search for therapies that are more effective than those currently available, in order to improve the existing poor prognoses. In recent decades our understanding of the molecular mechanisms of cancer progression has expanded substantially, making possible the development of novel therapeutic approaches. To date, the role of molecular targeted therapy in pancreatic carcinoma is promising. In addition, with the development of the modern radiation delivery techniques, the use of radiotherapy should likely be intensified. As of now, the available data strongly suggest that patients with borderline resectable or unresectable tumors should be included in neoadjuvant protocols and subsequently be reevaluated for resection, but well designed trials are needed to compare neoadjuvant therapy (plus potential subsequent surgery) with immediate surgery (plus adjuvant or palliative therapy). Only then will it be possible to judge the value of adding the neoadjuvant approach to the multimodal treatment concept of pancreatic cancer.

Funding: None.

Ethical approval: Not needed.

Contributors: XQ wrote the main body of the article under the supervision of ZYP. ZTP and ZYP provided advice on medical aspects. ZYP is the guarantor.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received May 12, 2010

Accepted after revision January 12, 2011

Author Affiliations: Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medial Sciences, Beijing 100730, China (Xu Q, Zhang TP and Zhao YP)

Yu-Pei Zhao, MD, Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medial Sciences, Beijing 100730, China (Tel: 86-10-65296007; Email: zhao8028@263.net)

? 2011, Hepatobiliary Pancreat Dis Int. All rights reserved.