Pancreatic cancer

SEMINAR

Seminar

Pancreatic cancer

Donghui Li, Keping Xie, Robert Wolff, James L Abbruzzese Pancreatic cancer remains a major unsolved health problem, with conventional cancer treatments having little impact on disease course. Almost all patients who have pancreatic cancer develop metastases and die. The main risk factors are smoking, age, and some genetic disorders, although the primary causes are poorly understood. Advances in molecular biology have, however, greatly improved understanding of the pathogenesis of pancreatic cancer. Many patients have mutations of the K-ras oncogene, and various tumour-suppressor genes are also inactivated. Growth factors also play an important part. However, disease prognosis is extremely poor. Around 15–20% of patients have resectable disease, but only around 20% of these survive to 5 years. For locally advanced, unresectable, and metastatic disease, treatment is palliative, although fluorouracil chemoradiation for locally advanced and gemcitabine chemotherapy for metastatic disease can provide palliative benefits. Despite pancreatic cancer’s resistance to currently available treatments, new methods are being investigated. Preoperative chemoradiation is being advocated, with seemingly sound reasoning, and a wider role for gemcitabine is being explored. However, new therapeutic strategies based on the molecular biology of pancreatic cancer seem to hold the greatest promise. Pancreatic cancer is one of the most lethal human cancers and continues to be a major unsolved health problem at the start of the 21st century. It has been estimated that this disease causes 30 000 deaths per year in the USA; this number has been quite steady over the past 3–5 years.1 Despite efforts in the past 50 years, conventional treatment approaches, such as surgery, radiation, chemotherapy, or combinations of these, have had little impact on the course of this aggressive neoplasm. Therefore, only by developing a detailed understanding of the molecular biology of pancreatic cancer will we be in a position to effectively diagnose, prevent, and treat this disease. Close to 100% of patients with pancreatic cancer develop metastases and die because of the debilitating metabolic effects of their unrestrained growth. Thus, a critical requirement for progress will be the development of effective systemic treatments capable of reversing the aggressive biology of this disease.

Epidemiology and molecular epidemiology In many studies risk factors associated with pancreatic cancer have been explored (panel). The only risk factors consistently reported are age and cigarette smoking.2 Cigarette smoking is estimated to account for 25–29% of pancreatic cancer incidence, with reported odds ratios ranging from 1·6 to 5·4.3 Another risk factor for pancreatic cancer might be family history.4,5 Several genetic syndromes are associated with an increased risk of pancreatic cancer, including hereditary pancreatitis, hereditary non-polyposis colorectal cancer, ataxiatelangiectasia, Peutz-Jeghers syndrome, familial breast cancer, and familial atypical multiple-mole melanoma.4 In epidemiological studies of pancreatic cancer, a protective Lancet 2004; 363: 1049–57 Department of Gastrointestinal Medical Oncology, University of Texas, M D Anderson Cancer Center, 1515 Holcombe Boulevard, Box 426, Houston, TX 77030, USA (D Li PhD, K Xie MD, R Wolff MD, Prof J L Abbruzzese MD) Correspondence to: Prof James L Abbruzzese (e-mail: [email protected])

Risk factors for pancreatic cancer Demographic factors Old age (most reliable and important predictor) Sex (more common in males than in females) Ethnic origin (mortality highest in black populations) Genetic factors and medical conditions Family history Hereditary pancreatitis Hereditary non-polyposis colorectal cancer Ataxia-telangiectasia Peutz-Jeghers syndrome Familial breast cancer Familial atypical multiple mole melanoma Chronic pancreatitis Diabetic mellitus Gastrectomy Deficiency in carcinogen metabolism and DNA repair Environmental and lifestyle factors Cigarette smoking Occupational exposures Low dietary intake of fruits and vegetables Food preparation and cooking methods (grilling or charring confers the highest risk)

Search strategy and selection criteria We identified reports by MEDLINE search through the PubMed database (1986–2002) by combining the keywords “pancreatic cancer” with the following topics: carcinogenesis, angiogenesis, progression, metastasis, pathology, pathobiology, pathophysiology, molecular genetics, and genetics. We searched citation lists in retrieved papers to identify additional references. Papers were selected on the basis of the best available evidence for each specific question discussed. To limit the number of references, review articles or the latest publications in a series of articles from the same laboratory were given preference. Only English language papers were included.

THE LANCET • Vol 363 • March 27, 2004 • www.thelancet.com

For personal use. Only reproduce with permission from The Lancet.

1049

SEMINAR

role has been noted for diets high in fruits and vegetables.6,7 This effect might be related to dietary intake of folate and other methyl-donor groups.8 Occupational exposure to carcinogens has long been suspected as a causal factor for pancreatic cancer, but evidence is insufficient to identify any specific exposure as likely to substantially increase the risk of pancreatic cancer.9–11 In sum, the primary causal factors for pancreatic cancer are poorly understood. Research efforts aimed at quantifying risk factors and identifying individuals at high risk are critical to the eventual prevention of this disease. In the past few years, some major advances have been made in the understanding of environment-susceptibility interactions in human cancers. Studies in pancreatic cancer have involved detection of DNA damage derived from carcinogen exposure and endogenous metabolic processes. To test the hypothesis that exposure to carcinogens contributes to human pancreatic cancer, and to shed a light on the carcinogens involved, the variety of DNA damage in human pancreatic tissues has been assessed.12–15 For example, smoking-related aromatic DNA adducts,12 and other types of DNA damage13–15 have been detected. These observations suggest that the human pancreas is susceptible to carcinogen exposure and DNA damage, which might contribute to genetic mutation, and in turn cancer development. In many studies of smoking-related human cancers, genetic variability in carcinogen metabolism and DNA repair affects individual susceptibility to carcinogen exposure and cancer risk. However, few such studies have been done in pancreatic cancer. In small-scale casecontrol studies no significant association has been noted between the risk of pancreatic cancer and polymorphisms of drug-metabolising enzymes.16,17 In a large-scale population-based case-control study, however, a significant interaction was reported between the GSTT1 null genotype and cigarette smoking in pancreatic cancer.18 Evidence from the same study also showed a significant interaction between heavy smoking and an Arg399Gln polymorphism of the DNA repair gene XRCC1.19 Jiao and colleagues20 identified a significant association between a functionally important codon 143 (Ile/Val) polymorphism of the O6-alkylguanine DNA transferase gene and risk of pancreatic cancer in a hospital-based case-control study. These data support the hypothesis that individuals who have deficient carcinogen detoxification and DNA repair capacities are at increased risk of pancreatic cancer. More studies are needed to elucidate the role of other genes and pathways that are important in pancreatic carcinogenesis. In studies of the spectra of tumour-suppressor-gene mutations, specific endogenous or exogenous mutagens have induced characteristic patterns of DNA alteration. These changes can be used as a fingerprint of exposure. Pancreatic cancer has the highest frequency (>85%) of K-ras mutation among all human cancers, which has been associated with cigarette smoking or alcohol consumption.21,22 The risk of mutation is three times higher in alcohol drinkers than in non-drinkers. Serum concentrations of organochlorine compounds are also significantly associated with K-ras mutations in pancreatic cancer.23 Furthermore, a specific association has been noted between serum concentrations of DDT and DDE and G-to-T transversion at codon 12 of the K-ras gene. The same investigators have also noted an association between occupational exposure to organic solvent and K-ras mutations in pancreatic cancer.24 These results support the hypothesis that K-ras mutations can be related to lifestyle and environmental factors in pancreatic

1050

cancer. Even though the mechanisms underlying the association between K-ras mutation and these environmental factors are not fully understood, the opportunity exists to reduce pancreatic cancer incidence through dietary change and limiting exposure to carcinogens.

Pathophysiology and molecular biology Molecular pathology In the past few years, our knowledge of the pathogenesis of pancreatic cancer has been significantly advanced due to the rapid accumulation of our understanding of the molecular biology of the disease. Like many other malignant diseases, pancreatic ductal carcinoma results from the accumulation of acquired mutations (table 1). The multigenic nature of most pancreatic ductal cancers is reflected in the abnormalities of three broad classifications of genes—ie, oncogenes, tumour-suppressor genes, and genomic maintenance genes.25,26 The accumulated mutations in such genes are believed to occur in a predictable time course. On the basis of the understanding of the histological and molecular genetic profiles, a progression model has been developed that describes pancreatic ductal carcinogenesis: the pancreatic ductal epithelium progresses from normal to increasing grades of pancreatic intraepithelial neoplasia, to invasive cancer (figure 1).27 A few pancreatic cancers aggregate in families and have aided our understanding of pancreatic tumorigenesis. Most pancreatic cancers, however, occur sporadically. Since the identification of the first notable genetic alteration—mutation of the K-ras oncogene mutation— there has been an explosion in our understanding of pancreatic cancer genetics. More than 85% of pancreatic ductal cancers have an activating point mutation in the Kras gene at a very early stage of pancreatic-cancer development.28 The detection of K-ras mutations in the duodenal juice, pancreatic juice, and stool of patients with pancreatic cancer has been proposed as an early detection strategy.29,30 The p16 tumour-suppressor gene is inactivated in around 95% of pancreatic cancers.31,32 and typically occurs later in pancreatic carcinogenesis.33 The second most frequently inactivated tumour-suppressor gene is TP53, a

Oncogenes K-ras HER2/neu AKT2 MYB

Chromosomal location

Alteration frequency (%)

12p 17q 19q 6q

75–100 65–70 10–20 10

Tumour-suppressor and genome-maintenance genes TP53 17p 40–75 CDKN2A* 9p 27–98 CDKN2A† 9p 27–82 CDKN2B 9p 27–48 MADH4 18q 50–55 FHIT 3p 66–70 RBI 13q 0–10 BRCA2 13q 7–10 STK11 19q 5 MAP2K4 17p 4 ALK5 9q 1 TGFBR2‡ 3p 1 TGFBR2§ 3p 3 MLH1 3p 3 *p16INK4a. †p19ARF. ‡MSI–. §MSI+. Modified from Mangray S, King TC. Molecular pathobiology of pancreatic adenocarcinoma. Front Biosci 1998; 3: D1148–60, and Sohn TA, Yeo CJ. The molecular genetics of pancreatic ductal carcinoma: a review. Surg Oncol 2000; 9: 95–101.

Table 1: Commonly altered oncogenes and tumour-suppressor genes in human pancreatic adenocarcinoma



SEMINAR

Rights were not granted to include this image in electronic media. Please refer to the printed journal.

Figure 1: Progression model of pancreatic cancer PanIN=pancreatic intraepithelial neoplasia. Reproduced with permission from Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000; 6: 2969–72. Artwork by Jennifer Parsons.

well-characterised tumour-suppressor located on chromosome 17p. Its inactivation is a late event in tumorigenesis. The MADH4 gene (DPC4 or SMAD4) is inactivated in 55% of pancreatic adenocarcinomas.34 Like TP53, MADH4 inactivation is a late event in pancreatic tumorigenesis. Other less-common genetic alterations continue to be described in pancreatic cancer.35–39 Rozenblum and colleagues,40 in a comprehensive mutational analysis of 42 pancreatic ductal cancers, noted that all tumours harboured mutations in the K-ras oncogene. The individual mutational frequencies of tumour-suppressor genes p16, TP53, MADH4, and BRCA2 were 82%, 76%, 53%, and 10%, respectively. Molecular biology At the genetic level, pancreatic cancer is a wellcharacterised neoplasm. By contrast, the molecular mechanisms linking the genetic changes to the aggressive nature of this disease remain poorly understood. The biology of pancreatic cancer is thought to be related to mutation and inactivation of oncogenes and tumour suppressor genes, as well as abnormalities in growth factors and their receptors, which affect the downstream signal transduction pathways involved in the control of growth and differentiation.39 These perturbations confer a tremendous survival and growth advantage to pancreaticcancer cells, as manifested by development of invasive and metastatic phenotypes that are resistant to all conventional treatments. Studies have established that human pancreatic cancer overexpresses many growth factors and their receptors, including the epidermal growth factor family,41 vascular endothelial growth factor,42,43 fibroblast growth factor,44 and many cytokines, such as transforming growth factor ,45 interleukin 1,46 interleukin 6,47 tumour necrosis factor ,48 and interleukin 8.49 The abundance of growth-promoting factors and the disturbance of growthinhibitory factors lead to evasion of programmed cell death, self-sufficiency in growth signals, angiogenesis, and metastasis. Some mechanisms have already been identified for the aberrant expression of these cytokines. For example, increasing evidence suggests that expression of vascular endothelial growth factor is regulated mainly by hypoxia, which is a common feature of most solid tumours, including pancreatic cancers. Shi and colleagues50

showed that expression of vascular endothelial growth factor can be significantly up-regulated by low extracellular pH, or acidosis, which occur frequently within the expanding tumour mass, particularly in regions surrounding necrotic areas within tumours. They showed also that acidosis activates the interleukin-8 gene. Vascular endothelial growth factor and interleukin 8 are key angiogenic molecules for pancreatic cancer. In detailed molecular biology studies, up-regulation of these genes by acidosis can be mediated through transactivation and cooperation of transcription factors, NF-B and AP-1.51 In many types of tumours, raised vascular endothelial growth factor production can frequently be detected in tumour cells located in the extreme periphery of the tumour, in which there is no apparent hypoxia and acidosis. These observations are consistent with the finding that exogenous factors such as hormones, cytokines, and growth factors modulate expression of vascular endothelial growth factor, thereby affecting angiogenesis.52 Also, many tumour cells can constitutively express vascular endothelial growth factor in vitro with no apparent external stimuli, which is consistent with the finding that loss or inactivation of tumour-suppressor genes and activation of oncogenes are associated with overexpression of vascular endothelial growth factor.53 In fact, analyses of vascular endothelial growth factor promoters have revealed several potential transcriptionfactor binding sites, such as HIF-1, AP-1, AP-2, Egr-1, Sp1, and many others,54 which suggests that multiple signal-transduction pathways are involved in transcription regulation of this growth factor. For example, the differential constitutive Sp1 activation is essential for different degrees of vascular endothelial growth factor expression.43 Constitutively activated Stat3 also directly contributes to the constitutive vascular endothelial growth factor expression in human pancreatic-cancer cells.55 Without apparent external stimuli, human pancreatic cancer also constitutively expresses interleukin 8 through constitutively activated NF-B and AP-1.51,56 All of these factors might contribute to the aggressive growth and drug resistance characteristic of pancreatic adenocarcinoma. An important focus of current pancreatic-cancer research seeks to understand the upstream molecular mechanisms leading to constitutive activation of these transcription factors.



1051

SEMINAR

less common manifestation is pancreatitis, which can occur if there is substantial obstruction of the pancreatic duct.58 Therefore, for patients with no known risk factor for pancreatitis, a pancreatic neoplasm should be considered as a potential underlying cause. For pancreatictail lesions initial symptoms might be related to the primary tumour, with pain in the left side of the abdomen or left upper quadrant, but these patients more commonly present with symptoms attributable to metastatic disease.

Cytokines, growth factors, hypoxia, acidosis, and free radicals

Activated oncogenes and inactivated tumoursuppressor genes

Constitutive (genetic)

Inducible (epigenetic) AP-1, NF-B, Sp1, Stat3

Downstream genes expressed

Cell cycle

Cell survival

Adhesion

Invasiveness

Angiogenesis

Diagnosis and staging For patients who present with painless jaundice, the diagnostic work-up is generally straightforward. CT of the Tumour growth and metastasis abdomen is recommended as the first diagnostic procedure rather than endoscopic retrograde cholangiopancreatogFigure 2: Molecular biology of pancreatic tumour growth and metastasis raphy because the appearance of the biliary tree and the pancreas are better defined before endoscopic Aberrant expression of multiple-metastases-related retrograde cholangiopancreatography and stent placeproteins, such as interleukin 8 and vascular endothelial ment. Once the biliary tree has been manipulated, growth factor, might result from the alterations of several visualisation of small tumours might be obscured on CT transcription-factor activities. To synthesise these because of the presence of the stent or inflammatory observations two potential pathways are proposed changes caused by instrumentation of the bile duct. After (figure 2). One mechanism relates to the genetic the pancreatic and peripancreatic anatomy has been mutations of oncogenes, suppressor genes, or both, such defined on CT, endoscopic retrograde cholangiopanas K-ras and TP53, resulting in constitutive activation of creatography with stent placement is appropriate to the transcription factors. This effect could be especially manage obstructive jaundice.59 This approach is not, true in the early stage of pancreatic cancer growth. In the late stage of pancreatic cancer development, however, however, without controversy. In a meta-analysis, important stress factors, such as hypoxia and acidosis, Sewnath and colleagues60 suggested that preoperative which are frequently encountered in the tumour biliary stenting carries no benefit and should not be done microenvironment, further upregulate those metastasesroutinely. This controversy is inextricably linked to the related proteins through activation of many transcription uncertainty surrounding the relative usefulness of factors. Therefore, at advanced stages, uncontrolled neoadjuvant compared with adjuvant treatment for tumour growth and the consequent development of a resectable pancreatic cancer. A prospective trial of the role stress environment might increase tumour angiogenesis, of preoperative biliary decompression in patients with growth, and development of metastases. Understanding resectable pancreatic cancer will be needed before the expression and regulation of these molecules might consensus can be achieved.61,62 Currently, for patients who shed more light on the pathophysiology of pancreatic seem to have a localised, potentially resectable neoplasm, cancer, and suggest new targets for preventive and placement of a plastic stent by an experienced treatment approaches to pancreatic cancer. gastroenterology team and subsequent referral to a highvolume pancreatic surgical centre or immediate surgical intervention is recommended. If tumours are locally Diagnosis and management advanced and unresectable or if metastatic disease is For most patients diagnosed as having cancer of the present, insertion of an expandable metal stent might be exocrine pancreas life expectancy is measured in months. preferable for durability, compared with plastic stents.63 Three factors underlie this poor outlook. First, pancreatic cancer disseminates to distant sites early in its natural When pain is the presenting symptom without jaundice, history. Second, as the disease progresses it is associated the differential diagnosis possibilities are broader. with substantial morbidity, characterised by cachexia and Nevertheless, CT scanning will generally be required asthaenia. Third, pancreatic cancer is resistant to most ultimately to visualise pathology within the pancreas if forms of treatment studied to date. other diagnostic assessments do not explain the patient’s symptoms. Symptoms Once a pancreatic mass has been identified, we prefer For tumours located in the head and body of the pancreas to make a tissue diagnosis. Tissue can be obtained by CTsymptoms are generally precipitated by compression of guided fine-needle aspiration, transabdominal ultrasoundsurrounding structures: the bile duct, mesenteric and guided fine-needle aspiration, or fine-needle aspiration coeliac nerves, the pancreatic duct, and the duodenum.57 under endoscopic ultrasound guidance.64 For patients who These effects eventually bring patients to medical have potentially resectable pancreatic cancers, endoscopic attention and the diagnosis of pancreatic cancer can ultrasound-guided biopsy offers the opportunity to generally be made quickly. When a pancreatic-head visualise the pancreatic mass, to judge its relation with the tumour is quite small, painless jaundice might be the only surrounding vasculature, and to obtain a tissue diagnosis sign. Many patients however, experience an antecedent without the risk of tumour seeding along the needle period of abdominal or back pain, followed by the tract.65 With use of these techniques, pancreatic biopsy development of obstructive jaundice. Other signs can be samples obtained during laparotomy are rarely required the development of diabetes mellitus or malabsorption. A and should be discouraged. For patients presenting with

1052



SEMINAR

liver metastases and an obvious pancreatic mass, liver biopsy is an appropriate alternative, and if positive for adenocarcinoma, is acceptable as evidence of metastatic pancreatic cancer. Thin-cut dynamic multiphase helical CT scan of the abdomen and pelvis is the most important staging study.66 Such imaging can generally show the tumour and its relation to the surrounding structures, including the superior mesenteric artery and vein, the portal vein, and the coeliac axis. Tumours invading the superior mesenteric artery or coeliac axis are unresectable since surgery with curative intent (negative margins) is impossible. Moreover, a positive surgical margin, whether gross or microscopic, predicts survival similar to that of patients who have locally advanced disease. Thus, tumour debulking in this disease has minimum impact on survival, and is frequently associated with substantial morbidity.67 Abdominal CT scan is also useful in revealing hepatic metastases, peritoneal implants, regional adenopathy, and ascites. Laparoscopy is frequently recommended to rule out the presence of small liver or peritoneal metastases for patients who seem to have resectable disease on the basis of preoperative imaging studies.68 Currently, with the effective use of the diagnostic and staging studies, surgical procedures, such as exploratory laparotomy or diagnostic laparotomy, should be avoided. Management In developing treatment algorithms, pancreatic cancer should be separated into different patient populations based on the extent of disease at presentation. We recommend classifying pancreatic cancer into localised and potentially surgically resectable, locally advanced and surgically unresectable, or metastatic. Resectable disease Resectable pancreatic cancer is defined, based on preoperative work-up, as a pancreatic tumour without evidence of involvement of the superior mesenteric artery or coeliac axis, a patent superior mesenteric-portal venous confluence, and no evidence of distant metastatic disease. Around 15–20% of patients have resectable pancreatic cancer. In optimally staged patients, the 5-year survival rate is 20%.69 Recognised prognostic factors include surgical margin status, nodal status, and tumour size.69 Analysis of large medical databases has established that the operative mortality of this procedure is significantly less in high-volume referral centres (4%) compared with hospitals in which pancreaticoduodenectomy is done infrequently.70 In the USA, adjuvant treatment with fluorouracil-based chemoradiation is frequently recommended.71,72 However, in the ESPAC-1 trial73 the role of chemoradiation as a component of adjuvant therapy was questioned, and the researchers supported chemotherapy instead. Despite its size, the ESPAC-1 trial is itself controversial because of the use of different randomisation options based on physicians’ preferences. Patients were also allowed to receive additional treatment, termed background treatment, which adds additional uncertainty to the study’s conclusions. Although the ESPAC-1 approach is argued to represent real-life clinical practice and its results to be applicable to a wide population of patients,74 the combination of rigorous clinical research and standard clinical practice make this trial difficult to interpret. Other issues including pathology, surgical, and radiation quality control have been raised.75,76 Hopefully, the ESPAC-3 trial,77 in which 990 patients have been randomly assigned postoperative chemotherapy with fluorouracil and leucovorin or

gemcitabine, and the Radiation Therapy Oncology Group trial (R9704) in the USA, in which patients were randomised to postoperative gemcitabine or fluorouracil in conjunction with fluorouracil-based chemoradiation, will shed more light on this controversial area of oncology practice. Locally advanced or unresectable pancreatic cancer Locally advanced pancreatic cancer is defined as a tumour that encases a vascular structure, such as the superior mesenteric artery, coeliac axis, or superior mesenteric vein-portal vein confluence. Tumours associated with bulky peripancreatic lymphadenopathy are also deemed unresectable. However, there should be no evidence of distant metastatic disease to the chest, liver, or peritoneum. The standard care for unresectable pancreatic cancer is fluorouracil-based chemoradiation. This intervention provides a survival advantage and offers a palliative benefit. In general, chemoradiation should be considered for patients with adequate performance status to undergo a course of treatment. In the early to mid1980s the Gastrointestinal Tumor Study Group (GITSG)78 did a three-treatment-group randomised trial in patients with locally advanced pancreatic cancer. Patients received radiation alone to a dose of 60 Gy, fluorouracil plus intermediate-dose radiation to 40 Gy, or fluorouracil plus radiation to 60 Gy. Those receiving fluorouracil with radiation had a median survival of 42–44 weeks; those undergoing radiation alone had a median survival of 23 weeks. Thus, the combination of fluorouracil with radiation doubles survival duration compared with radiation alone. Patients who have locally advanced pancreatic cancer generally experience notable pain. Although the palliative benefit of radiation has not been extensively studied, radiation seems to provide pain relief in 50–85% of patients.79 Unfortunately, despite the potential for palliation with chemoradiation for locally advanced disease, this intervention rarely controls pancreatic cancer. Within months of completing this treatment, patients frequently have evidence of local tumour progression (biliary obstruction, relapsing pain, gastric outlet obstruction) or new metastatic disease to the liver or peritoneum. Further systemic treatment at that juncture might provide some transient benefit, but the clinical course of such patients is generally poor. For these reasons, patients who have locally advanced disease are an attractive population to consider for treatment with novel agents. These patients harbour subclinical metastatic disease that will eventually become manifest. With use of molecular treatments the onset of overt metastatic disease might be delayed and survival prolonged without resorting to more toxic conventional agents after chemoradiation. Metastatic pancreatic cancer Metastatic pancreatic cancer is a progressive, debilitating disease that is characterised by pain, asthaenia, anorexia, and cachexia. Sudden changes in a patient’s clinical status are common, and patients can have continuing problems with pain, thromboembolic events, and biliary or gastric outlet obstruction. In addition, peritoneal carcinomatosis with intestinal dysmotility or intractable ascites is common and difficult to manage. Survival is dependent on tumour burden and performance status at presentation. Chemotherapy is never curative for metastatic disease, and its potential palliative benefit must be carefully weighed against toxic effects. In the era of accurate cross-sectional imaging, single-agent chemotherapy produces low objective response rates.



1053

SEMINAR

Gemcitabine is a deoxycytidine analogue with structural and metabolic similarities to cytarabine. As a prodrug, gemcitabine must be phosphorylated to its active metabolites gemcitabine diphosphate and gemcitabine triphosphate. Gemcitabine diphosphate inhibits ribonucleotide reductase and depletes intracellular pools of all the deoxynucleotide triphosphates necessary for DNA synthesis. Gemcitabine triphosphate may be incorporated into an elongating DNA chain and leads to premature chain termination. In addition, the triphosphate form of gemcitabine can impede normal DNA repair, which may explain the drug’s radiosensitising properties, and its apparent synergy with other chemotherapeutic agents. In a randomised trial, weekly gemcitabine was compared to weekly bolus fluorouracil in previously untreated patients.80 Survival among patients treated with gemcitabine improved slightly compared with that among those treated with fluorouracil (median survival 5·6 vs 4·4 months). In addition, more clinically meaningful effects on diseaserelated symptoms (pain, performance status, weight) were seen with gemcitabine than with fluorouracil (24 vs 4%). Treatment with gemcitabine was associated with a survival advantage at 1 year (18%) compared with fluorouracil (2%). Clinical benefit has also been documented for patients who were treated with gemcitabine after experiencing disease progression while receiving fluorouracil.81 However, overall survival for these patients receiving gemcitabine as a second-line treatment is poor. Gemcitabine is currently the standard care for metastatic pancreatic cancer.

Future directions in clinical management Preoperative chemoradiation for resectable pancreatic cancer In single-institution and multicentre trials 20–30% of patients who undergo pancreaticoduodenectomy are not eligible for postoperative chemoradiation. Therefore, preoperative chemoradiation for patients with resectable disease has been advocated by some groups. The rationale for this approach is sound. First, all patients who have potentially resectable disease receive the treatment. Second, a subset of patients will develop overt metastatic disease in the 8–12 weeks of preoperative treatment and, therefore, become non-surgical patients and will be spared the morbidity of a pancreaticoduodenectomy. Finally, findings from trials of preoperative treatment suggest lower rates of locoregional failure with this approach. Most preoperative regimens consist of treatment with combined methods, with use of various radiosensitisers, including fluorouracil, cisplatin, paclitaxel, and gemcitabine.82–85 The toxic effects of this treatment approach is notable, with hospital admission being required for up to 50% of patients. However, although a survival benefit has not been established for patients undergoing resection, such an approach does keep unnecessary surgery to a minimum, and probably

improves locoregional control compared with immediate surgery. Gemcitabine as a radiation sensitiser Gemcitabine is a potent radiation sensitiser and has better systemic activity than fluorouracil. Clinical trials of gemcitabine combined with radiation as a component of preoperative treatment for patients with locally advanced and potentially resectable disease are now underway. Although early results of gemcitabine-based chemoradiation regimens are encouraging, this approach remains investigational, with no clear dose or schedule of chemotherapy or radiation currently accepted as standard.86–89 Gemcitabine as an adjuvant treatment The role of radiation therapy as a component of adjuvant therapy remains debatable, but it is generally accepted that gemcitabine is a better systemic agent than fluorouracil in advanced disease. Therefore, the Radiation Therapy Oncology Group is doing a randomised trial of fluorouracil compared with gemcitabine as systemic therapy after pancreaticoduodenectomy for pancreatic cancer. All patients have been randomised to either systemic weekly gemcitabine or infusional fluorouracil before and after fluorouracil-based chemoradiation. The preliminary results are anticipated within the next 1–2 years. Gemcitabine-based combination chemotherapy Since gemcitabine alone has little activity in pancreatic cancer, gemcitabine in combination with other cytotoxic agents is being investigated. These studies include combining gemcitabine with docetaxel, cisplatin, oxaliplatin, fluorouracil, and irinotecan.90–98 In phase II trials to date, the response rate for gemcitabine combinations have generally been higher than with gemcitabine alone. However, no randomised phase III trial has yet established a survival benefit for combination therapy compared with gemcitabine alone. Targeted therapy Although new conventional cytotoxic agents or other gemcitabine combinations might improve survival for patients with pancreatic cancer, they are likely to produce small incremental advances. Thus, intense interest has focused on the emerging molecular biology of pancreatic cancer. Molecular defects correlating with tumour growth, resistance, invasion, and angiogenesis have been elucidated. As molecular targets are identified, interventions with specific agents might be targeted to improve tumour control (table 2).99 Trials have been done of several biological agents for pancreatic cancer. Although early efforts with farnesyl transferase inhibitors have proved disappointing,100 more promising examples of this strategy include inhibition of members of the ErbB family of receptors, ErbB-1

Activity Target Epidermal growth-factor receptor

Signal transduction or proliferation, ? radioprotection and angiogenesis HER2/neu Signal transduction or proliferation Vascular endothelial growth factor Angiogenesis K-ras oncogene Cox-2 Matrix metalloproteinases

Signal transduction or proliferation Prostaglandin synthesis Invasion

Drug Monoclonal antibody: C225; receptor tyrosine kinase inhibitors: ZD1839 and OSI-774 Monoclonal antibody: trastuzumab Monoclonal antibody: bevacizumab; receptor tyrosine kinase inhibitors: SU5416, SU6668, and others Farnesyl transferase inhibitors and antisense oligonucleotides Celecoxib and rofecoxib Matrix metalloproteinases inhibitors: marimastat and others

Table 2: Molecular targets for potential exploitation with novel agents

1054



SEMINAR

(epidermal growth factor receptor) and ErbB-2 (HER2), with monoclonal antibodies. Cetuximab, a humanised monoclonal antibody to epidermal growth factor receptor, and trastuzumab, an antibody to HER2, have been combined with gemcitabine in patients with advanced disease.101,102 Early results suggest increased activity with these two drugs, and with cetuximab a longer period of disease stabilisation. Other small molecules that inhibit the epidermal growth factor receptor, such as ZD1839 and OSI-774 are also being investigated for activity in advanced pancreatic cancer. Another group of drugs with potential therapeutic application include the matrix metalloproteinase inhibitors, which are designed to inhibit the degradative enzymes central to pancreatic cancer cell invasion, and possibly tumour angiogenesis. The initial trials of first-generation metalloproteinase inhibitors have been disappointing,103 but development of these and other novel agents alone and in combination with gemcitabine continues to be a high priority.

The way forward Pancreatic cancer will remain a challenging problem into the 21st century. However, improvements in early detection, screening, and staging of patients will be expected to facilitate progress in the management of patients with this disease. Most promising, is the potential to base treatment on our rapidly evolving understanding of the molecular biology of pancreatic cancer. Already various agents are being developed that target signaltransduction pathways or nuclear transcription factors. In addition to the agents we describe, farnesyl transferase inhibitors, that target the RAS oncoprotein, Raf-1 inhibitors, NF-B inhibitors, and Sp-1 inhibitors are being studied and developed. Additional progress in understanding the nature and sequence of the molecular events in the development of carcinoma of the pancreas ultimately will permit the development of an array of treatments that will inhibit specific pathways that mediate the aggressive biology of pancreatic cancer.

9 10

11

12

13

14

15

16

17

18

19

20

21

22

Conflict of interest statement None declared.

23

Acknowledgments All authors derived some support from the Lustgarten Foundation for Pancreatic Cancer Research, the Eli Lilly Research Foundation, and the Topfer Family Fund for Pancreatic Cancer Research. The funding source had no influence on the decision to submit this manuscript for publication or the writing of the report.

24

25 26

References 1 2

3

4

5 6

7

8

Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003; 53: 5–26. Anderson KE, Potter JD, Mack TM. Pancreatic cancer. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer epidemiology and prevention. Oxford: Oxford University Press, 1996: 725–71. Fryzek JP, Garabrant DH, Greenson JK, Schottenfeld D. A review of the epidemiology and pathology of pancreas cancer. Gastrointest Cancer 1997; 2: 99–110. Hruban RH, Petersen GM, Ha PK, Kern SE. Genetics of pancreatic cancer: from genes to families. Surg Oncol Clin N Am 1998; 7: 1–23. Schenk M, Schwartz AG, O’Neal E, et al. Garabrant familial risk of pancreatic cancer. J Natl Cancer Inst 2001; 93: 640–44. Ji BT, Chow WH, Gridley G, et al. Dietary factors and the risk of pancreatic cancer: a case-control study in Shanghai, China. Cancer Epidemiol Biomarkers Prev 1995; 4: 885–93. Ghadirian P, Baillargeon J, Simard A, et al. Food habits and pancreatic cancer: a case-control study of the francophone community in Montreal, Canada. Cancer Epidemiol Biomarkers Prev 1995; 4: 895–99. Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, Albanes D. Dietary and other methyl-group availability

27 28

29

30

31

32

33

factors and pancreatic cancer risk in a cohort of male smokers. Am J Epidemiol 2001; 153: 680–87. Kauppinen T, Partanen T, Degerth R, et al. Pancreatic cancer and occupational exposures. Epidemiology 1995; 6: 498–502. Garabrani DH, Held J, Langholz B, et al. DDT and related compounds and risk of pancreatic cancer. J Natl Cancer Inst 1992; 84: 764–71. Fryzek J, Garabrant DH, Harlow SD, et al. A case-control study of self-reported exposures to pesticides and pancreas cancer in Southern Michigan. Int J Cancer 1997; 72: 62–67. Wang MY, Abbruzzese JL, Friess H, et al. DNA adducts in human pancreatic tissues and their potential role in carcinogenesis. Cancer Res 1998; 58: 38–41. Li D, Firozi PF, Zhang WQ, et al. DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. Mutat Res 2002; 513: 37–48. Thompson PA, Seyedi F, Lang NP, et al. Comparison of DNA adduct levels associated with exogenous and endogenous exposures in human pancreas in relation to metabolic genotype. Mutat Res 1999; 424: 263–74. Kadlubar FF, Anderson KE, Häussermann S, et al. Comparison of DNA adduct levels associated with oxidative stress in human pancreas. Mutat Res 1998; 405: 125–33. Bartsch H, Malaveille C, Lowenfels AB, et al. Genetic polymorphism of N-acetyltransferases, glutathione S-transferase M1 and NAD(P)H:quinone oxidoreductase in relation to malignant and benign pancreatic disease risk: the International Pancreatic Disease Study Group. Eur J Cancer Prev 1998; 7: 215–23. Liu G, Ghadirian P, Vesprini D, et al. Polymorphisms in GSTM1, GSTT1 and CYP1A1 and risk of pancreatic adenocarcinoma. Br J Cancer 2000; 82: 1646–49. Duell EJ, Holly EA, Bracci PM, Liu M, Wiencke JK, Kelsey KT. A population-based, case-control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk. J Natl Cancer Inst 2002; 94: 297–306. Duell EJ, Holly EA, Bracci PM, Wiencke JK, Kelsey KT. A population-based study of the Arg399Gln polymorphism in X-ray repair cross-complementing group 1 (XRCC1) and risk of pancreatic adenocarcinoma. Cancer Res 2002; 62: 4630–36. Jiao L, Firozi PF, Connor T, Li, D. Codon 143 polymorphism of AGT gene in pancreatic cancer. Proc Am Assoc Cancer Res 2001; 42: A1844. Malats N, Porta M, Corominas JM, et al. K-ras mutations in exocrine pancreatic cancer: association with clinico-pathological characteristics and with tobacco and alcohol consumption. Int J Cancer 1997; 70: 661–67. Berger DH, Chang H, Wood M, et al. Mutational activation of K-ras in non-neoplastic exocrine pancreatic lesions in relation to cigarette smoking status. Cancer 1999; 85: 326–29. Porta M, Malats N, Jariod M, et al. Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer. Lancet 1999; 354: 2125–29. Alguacil J, Porta M, Malats N, et al. Occupational exposure to organic solvents and K-ras mutations in exocrine pancreatic cancer. Carcinogenesis 2002; 23: 101–06. Sohn TA, Yeo CJ. The molecular genetics of pancreatic ductal carcinoma: a review. Surg Oncol 2000; 9: 95–101. Sakorafas GH, Tsiotos GG. Molecular biology of pancreatic cancer: potential clinical implications. BioDrugs 2001; 15: 439–52. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000; 6: 2969–72. Almoguerra C, Shibata D, Forrester K, et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988; 53: 549–54. Wenger FA, Zieren J, Peter FJ, Jacobi CA, Muller JM. K-ras mutations in tissue and stool samples from patients with pancreatic cancer and chronic pancreatitis. Langenbecks Arch Surg 1999; 384: 181–86. Uehara H, Nakaizumi A, Tatsuta M, et al. Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations. Am J Gastroenterol 1999; 94: 2513–18. Caldas C, Hahn SA, da Costa LT, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genetics 1994; 8: 27–32. Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997; 57: 3126–30. Wilentz RE, Iacobuzio-Donahue CA, Aragani P, et al. Loss of expression of DPC4 in pancreatic intrapithelial neoplasia (PanIN): evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000; 60: 2002–06.



1055

SEMINAR

34 Hahn SA, Schutte M, Hoque ATMS, et al. DPC4, a candidate tumor-suppressor gene at 18q21.1. Science 1996; 271: 350–53. 35 Su GH, Hilgers W, Shekher MC, et al. Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res 1998; 58: 2339–42. 36 Su GH, Hruban RH, Bansal RK, et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 1999; 154: 1835–84. 37 Ozkelik H, Schmocker B, Di Nicola N, et al. Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 1997; 16: 17–18. 38 Goggins M, Schutte M, Lu J, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 1996; 56: 5360–64. 39 Goggins M, Hruban RH, Kern SE. BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications. Am J Pathol 2000; 156: 1767–71. 40 Rozenblum E, Schutte M, Goggins M, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 1997; 57: 1731–34. 41 Korc M. Role of growth factors in pancreatic cancer. Surg Oncol Clin N Am 1998; 7: 25–41. 42 Luo J, Guo P, Matsuda K, et al. Pancreatic cancer cell-derived vascular endothelial growth factor is biologically active in vitro and enhances tumorigenicity in vivo. Int J Cancer 2001; 92: 361–69. 43 Shi Q, Le X, Peng Z, et al. Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res 2001; 61: 4143–54. 44 Yamanaka Y, Friess H, Buchler M, et al. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res 1993; 53: 5289–96. 45 Kleeff J, Ishiwata T, Friess H, et al. The TGF- signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 1999; 18: 5363–72. 46 Blanchard JA 2nd, Barve S, Joshi-Barve S, Talwalker R, Gates LK Jr. Cytokine production by CAPAN-1 and CAPAN-2 cell lines. Dig Dis Sci 2000; 45: 927–32. 47 Saito K, Ishikura H, Kishimoto T, et al. Interleukin-6 produced by pancreatic carcinoma cells enhances humoral immune responses against tumor cells: a possible event in tumor regression. Int J Cancer 1998; 75: 284–89. 48 Watanabe N, Tsuji N, Kobayashi D, et al. Endogenous tumor necrosis factor functions as a resistant factor against hyperthermic cytotoxicity in pancreatic carcinoma cells via enhancement of the heart shock element-binding activity of heat shock factor 1. Chemotherapy 43: 406–14, 1997. 49 Shi Q, Abbruzzese J, Huang S, Fidler IJ, Xie K. Constitutive and inducible interleukin-8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 1999; 5: 3711–21. 50 Shi Q, Le X, Wang B, et al. Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene 2001; 20: 3751–56. 51 Xie K. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev 2001; 12: 375–91. 52 Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13: 9–22. 53 Rak J, Filmus J, Finkenzeller G, Grugel S, Marme D, Kerbel RS. Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev 1995; 14: 263–77. 54 Tischer E, Mitchell R, Hartman T, et al. The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991; 266: 11947–54. 55 Wei D, Le X, Zheng L, et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 2003, 22: 319–29. 56 Le X, Shi Q, Wang B, et al. Molecular regulation of constitutive expression of interleukin-8 in human pancreatic adenocarcinoma. J Interferon Cytokine Res 2000; 20: 1532–40. 57 Evans DB, Abbruzzese JL, Rich TR. Cancer of the pancreas. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer principles and practice of oncology, 5th edn. Philadelphia: Lippincott Raven, 1997: 1054–87. 58 Lin A. Pancreatic carcinoma as a cause of unexplained pancreatitis: report of ten cases. Ann Intern Med 1990; 113: 166–67. 59 Pisters PW, Hudec WA, Hess KR, et al. Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients. Ann Surg 2001; 234: 47–55. 60 Sewnath ME, Karsten TM, Prins MH, et al. A meta-analysis on the

1056

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

efficacy of preoperative biliary drainage for tumors causing obstructive jaundice. Ann Surg 2002; 236: 17–27. Pisters PW, Lee JE, Vauthey JN, Evans DB. Comment and perspective on Sewnath and colleagues’ recent meta-analysis of the efficacy of preoperative biliary drainage for tumors causing obstructive jaundice. Ann Surg 2003; 237: 594–95. Gouma DJ, Obertop H. Comment and perspective on Sewnath and colleagues’ recent meta-analysis of the efficacy of preoperative biliary drainage for tumors causing obstructive jaundice. Ann Surg 2003; 237: 595–96. Davids PH, Groen AK, Rauws EA, et al. Randomized trial of selfexpanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet 1992; 340: 1488–92. Di Stasi M, Lencioni R, Solmi L, et al. Ultrasound-guided fine needle biopsy of pancreatic masses: results of a multicenter study. Am J Gastroenterol 1998; 93: 1329–33. Gress F, Gottlieb K, Sherman S, Lehman G. Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med 2001; 134: 459–64. Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al. Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg 1994; 167: 104–11. Millikan KW, Deziel DJ, Silverstein JC, et al. Prognostic factors associated with resectable adenocarcinoma of the head of the pancreas. Am Surg 1999; 65: 618–24. Jimenez RE, Warshaw AL, Fernandez-Del Castillo C. Laparoscopy and peritoneal cytology in the staging of pancreatic cancer. J Hepatobiliary Pancreat Surg 2000; 7: 15–20. Yeo CJ, Cameron JL, Lillemore KD, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas: 201 patients. Ann Surg 1995; 221: 721. Lieberman MD, Kilburn H, Lindsey M, et al. Relation of perioperative deaths to hospital volume among patients undergoing pancreatic resection for malignancy. Ann Surg 1995; 222: 638–45. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987; 59: 2006–10. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection for the cancer of the pancreas and peri-ampullary region: phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Ann Surg 1999; 230: 776–84. Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001; 358: 1576–85. Neoptolemos JP, Stocken D, Dunn JA. ESPAC-1 trial of adjuvant therapy for resectable adenocarcinoma of the pancreas. Ann Surg 2002; 236: 694–96. Evans DB, Hess KR, Pisters PW. ESPAC-1 trial of adjuvant therapy for resectable adenocarcinoma of the pancreas. Ann Surg 2002; 236: 694–96. Abrams RA, Lillemoe KD, Piantadosi S. Continuing controversy over adjuvant therapy of pancreatic cancer. Lancet 2001; 358: 1565–66. Neoptolemos JP, Cunningham D, Friess H, et al. Adjuvant therapy in pancreatic cancer: historical and current perspectives. Ann Oncol 2003; 14: 675–92. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil. Cancer 1981; 48: 1705–10. Minsky BD, Hilaris B, Fuks Z. The role of radiation therapy in the control of pain from pancreatic carcinoma. J Pain Symptom Manage 1988; 3: 199–205. Burris HA III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 2403–13. Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 1996; 7: 347–53. Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson AB. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1998; 16: 317–23. White R, Lee C, Anscher M, et al. Preoperative chemoradiation for patients with locally advanced adenocarcinoma of the pancreas. Ann Surg Oncol 1999; 6: 38–45. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with



SEMINAR

85

86

87

88

89

90

91

92

93

94

pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 1997; 15: 928–37. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin Oncol 2002; 20: 2537–44. Wolff RA, Evans DB, Crane CH, et al. Initial results of preoperative gemcitabine-based chemoradiation for resectable pancreatic adenocarcinoma. Proc Am Soc Clin Oncol 2002; 21: 130a (abstr 516). Wolff RA, Evans DB, Gravel DM, et al. Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. Clin Cancer Res 2001; 7: 2246–53. Blackstock AW, Bernard SA, Richards F, et al. Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. J Clin Oncol 1999; 17: 2208–12. McGinn CJ, Zalupski MM, Shureiqi I, et al. Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2001; 19: 4202–08. Ryan DP, Kulke MH, Fuchs CS, et al. A phase II study of gemcitabine and docetaxel in patients with metastatic pancreatic carcinoma. Cancer 2002; 94: 97–103. Philip PA, Zalupski MM, Vaitkevicius VK, et al. Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma. Cancer 2001; 92: 569–77. Louvet C, Andre T, Lledo G, et al. Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study. J Clin Oncol 2002; 20: 1512–18. Louvet C, Andre T, Hammel P, et al. Phase II trial of bimonthly leucovorin, 5-fluorouracil and gemcitabine for advanced pancreatic adenocarcinoma (FOLFUGEM). Ann Oncol 2001; 12: 675–79. Rocha Lima CM, Savarese D, Bruckner H, et al. Irinotecan plus gemcitabine induces both radiographic and CA 19-9 tumor marker

responses in patients with previously untreated advanced pancreatic cancer. J Clin Oncol 2002; 20: 1182–91. 95 Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer 2002; 94: 902–10. 96 Berlin JD, Catalano P, Thomas JP, et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 2002; 20: 3270–75. 97 Stehlin JS, Giovanella BC, Natelson EA, et al. A study of 9-nitrocamptothecin (RFS 2000) in patients with advanced pancreatic cancer. Int J Oncol 1999; 14: 821–31. 98 Sharma S, Kemeny N, Schwartz GK, et al. Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks. Clin Cancer Res 2001; 7: 3963–70. 99 Fan Z, Mendelsohn J. Therapeutic application of anti-growth factor receptor antibodies. Curr Opin Oncol 1998; 10: 67–73. 100 Van Cutsem E, Karasek P, Oettle H, et al. Phase III trial comparing gemcitabine plus R115777 (Zarnestra) versus gemcitabine plus placebo in advanced pancreatic cancer (PC). Proc Ann Meeting Am Soc Clin Oncol 2002, 21: 130 (abstr). 101 Abbruzzese JL, Rosenberg A, Xiong Q, et al: Phase II study of anti-epidermal growth factor receptor cetuximab (IM-C225) in patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 2001; 20: 130a (abstr 518). 102 Safron H, Ramanathan R, Schwartz J, et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Proc Am Soc Clin Oncol 2001; 20: 130a (abstr 517). 103 Bramhall SR, Schulz J, Nemunaitis J, et al. A double-blind placebocontrolled, randomized study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002; 87: 161–67.



1057