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CA Cancer J Clin 2005; 55:352-367
doi: 10.3322/canjclin.55.6.352
© 2005 American Cancer Society
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 Multimodality Approaches for Pancreatic Cancer
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Multimodality Approaches for Pancreatic Cancer

Gary Y. Yang, MD, Timothy D. Wagner, MD, MBA, Martin Fuss, MD and Charles R. Thomas, Jr., MD


Dr. Yang is Assistant Professor, Residency Program Director, Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, NY.
Dr. Wagner is Chief Resident, Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, NY.
Dr. Fuss is Associate Professor, Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio Cancer Institute, San Antonio, TX.
Dr. Thomas is Professor and Chairman, Department of Radiation Medicine, Oregon Health & Science University, Portland, OR.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 DIAGNOSIS AND STAGING
 TREATMENT
 EVOLVING THERAPIES
 CONCLUSION
 REFERENCES
 
The role of combined-modality therapy for pancreatic cancer is evolving with the recent development and completion of major, multi-institutional clinical trials. One of the challenges for the busy clinician is to appreciate the variation in staging, surgical expertise, and application of either definitive chemoradiotherapy or adjuvant chemoradiotherapy for local and/or regionally advanced disease. Our aim is to summarize the current state-of-the-art management and future directions regarding the multimodality approach to pancreatic cancer.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
DIAGNOSIS AND STAGING
 TREATMENT
 EVOLVING THERAPIES
 CONCLUSION
 REFERENCES
 
Pancreatic cancer has the poorest prognosis of any common gastrointestinal malignancy, with a 5-year overall survival of less than 5%.1 In 2005, it is estimated that 32,180 people will be diagnosed with and 31,800 deaths will be attributed to pancreatic cancer in the United States. It represents the second leading cause of death among gastrointestinal malignancies and the fourth leading cause of cancer death overall in the United States.2 Although the incidence has stabilized nationally over the last 25 years at approximately 11 cases per 100,000 people per year, there has been very little improvement in death-to-incidence ratio, which continues to approach 0.95.3

Certain prognostic factors, both positive and negative, will help guide the appropriate therapy. Historically, those patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, early (T1-T2) lesions with no preoperative evidence of lymph node involvement, or tumor encasement of the superior mesenteric vessels and portal vein have a more favorable outcome. In addition, those lesions located toward the head of the pancreas are more likely to be surgically resectable. Factors predicting a poorer outcome include the presence of gross or microscopic residual disease following an attempted curative resection, invasion of the major vessels, and perineural and/or lymphatic invasion. The presence of metastasis to local lymph nodes and distant metastasis are both negative prognostic factors for overall survival.1,4–6

The poor survival associated with pancreatic cancer stems from the advanced stage at diagnosis for the majority of cases. In many instances, even in patients with apparently localized resectable tumors, distant micrometastases already exist. So although surgery remains at the center of any potentially curable case, the need for other treatment modalities is paramount to maximize survival. Chemotherapy and radiation have each been widely used, both as an adjunct to surgery and as definitive treatment for unresectable locally advanced disease. Although overall survival has not dramatically changed in recent years, with better understanding of the molecular biology of this disease and with evolving technologies, there is hope that patient outcomes can be improved.


   DIAGNOSIS AND STAGING
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSIS AND STAGING
TREATMENT
 EVOLVING THERAPIES
 CONCLUSION
 REFERENCES
 
    Presenting Symptoms
Initial symptoms of pancreatic cancer include abdominal discomfort, nausea, loss of appetite, and weight loss. These vague, nonspecific complaints pose a clinical challenge and often lead to a delay in diagnosis.7 Pain associated with pancreatic cancer is usually dull and in an epigastric distribution, typically affecting the back. It can be caused by invasion of the splanchnic plexus and retroperitoneum and typically is worse while lying supine. Jaundice is also a common presenting symptom caused by extrahepatic biliary duct obstruction. Lesions arising along the common bile duct and at the ampulla of Vater often cause early biliary obstruction, lead to a more prompt diagnosis, and tend to carry a better prognosis than tumors originating elsewhere in the pancreas. In the absence of biliary obstruction, most pancreatic tumors are not diagnosed until the disease is locally advanced or metastatic.1

    Diagnostic Imaging and Procedures
In evaluating a patient with vague abdominal symptoms, diagnostic imaging often becomes part of the early workup. In patients presenting with jaundice, abdominal computed tomography (CT) or transabdominal ultrasonography should be performed. Historically, if either of these studies detects a pancreatic mass with no evidence of distant metastasis, the patient went on to surgical exploration. At the time of surgery, the tumor was either deemed resectable and removed during the same procedure or considered unresectable. Many centers have recently adopted more rigorous diagnostic evaluation before surgical manipulation. This approach has the advantage of limiting surgery to those patients who are likely to have successful resection, as well as allowing those patients suitable for neoadjuvant therapy to begin treatment before surgical exploration. It also identifies complex cases requiring preoperative preparation, such as those requiring vessel reconstruction.8

    Multiphase Spiral CT
Multiphase spiral or helical CT with intravenous contrast is the preferred diagnostic test for diagnosing and staging suspected pancreatic lesions. The resulting images capture thin cuts through the pancreas during the arterial, venous, and parenchymal phases of enhancement. Visualization of these different phases allows for detection of tumor invasion into the surrounding arteries, veins, and adjacent structures, as well as evaluation for local lymphadenopathy and distant metastases.9 It also allows for three-dimensional (3D) reconstruction of images to better analyze the patency of the nearby major vessels. Single-institution studies have shown that pancreatic tumors predicted to be resectable by multiphase CT are actually resectable in 64% to 80% of cases.10–12

    Endoscopic Ultrasound
Endoscopic ultrasound (EUS) has also been proven to be a useful diagnostic tool in pancreatic cancer. It has been used to further describe the local extent of disease, especially in cases where spiral CT has not definitively identified a mass. In these cases, ultrasound through the wall of the stomach can detect lesions in the body and tail of the pancreas, while imaging through the wall of the duodenum can visualize masses in the pancreatic head. EUS is effective in detection and fine-needle aspiration (FNA) of regional lymph nodes.13 When cytologic diagnosis is sought in cases of unresectable disease or consideration of neoadjuvant treatment, EUS with FNA has been shown to be highly reliable when utilized in high-volume centers.14

    Endoscopic Retrograde Cholangiopancreatography
Endoscopic retrograde cholangiopancreatography (ERCP) is very useful for visualizing the ducts that traverse the pancreas. Because most pancreatic cancers are of ductal origin, ERCP is a very sensitive and specific procedure for detecting pancreatic malignancies.15 It is not, however, considered the diagnostic study of choice because it is associated with potential complications (bowel perforation, bleeding, and pancreatitis) not encountered with CT or EUS.16 ERCP is usually reserved for cases in which endoscopic stenting is needed for symptom management or in cases where histologic diagnosis is needed for neoadjuvant treatment or treatment of unresectable disease and EUS-guided FNA has failed.

    Magnetic Resonance Imaging
The role of magnetic resonance imaging (MRI) in the clinical setting is expanding. Initial use of MRI had been limited secondary to motion artifacts, but by using techniques such as dynamic contrast-enhanced MRI, sensitivity has greatly improved.17 When compared with multiphase helical CT, MRI more accurately predicted resectability (96% to 81%, P = 0.01).18 These findings suggest that MRI has the potential to save a significant percentage of patients with unresectable disease from having attempted surgical resection. MRI also compares favorably to EUS in determining resectability and has been found to have a greater sensitivity than CT in detecting liver metastases.19 MRI can provide both anatomic and functional information and has a diverse range of applications from pancreatography via magnetic resonance cholangiopancreatography (MRCP) to angiography via dynamic MRI.17

    Positron Emission Tomography
Positron emission tomography (PET) offers another sensitive imaging modality with which to evaluate suspected pancreatic lesions (Figure 1). Although the reported sensitivity and specificity of PET varies considerably, the premise of using metabolic information to detect tumor is promising.20 It also offers a unique way to detect metastatic disease and to help differentiate questionable lesions detected by CT.21,22 Although PET has relatively poor anatomic accuracy, PET-CT scanners provide a means to overcome that limitation. Recent interest in the utility of PET for diagnosis and staging of pancreatic cancer is also fueled by findings indicating the prognostic relevance of high standardized uptake values (SUV) in 18-fluoro-deoxyglucose PET.23


Figure 1
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  		Figure 1 Positron Emission Tomography with Computed Tomography Fusion in Evaluating Pancreatic Lesions.

 

    Diagnostic Laparoscopy
By performing a diagnostic laparoscopy, the surgeon has direct visualization of the liver and peritoneum and can discover small metastases (1 to 2 mm) that have escaped detection by other diagnostic tests. Detection of metastases by laparoscopy allows laparotomy and its potential morbidity to be avoided. Studies have shown that new metastases are discovered on diagnostic laparoscopy in 8% to 24% of cases.24,25 When combined with laparoscopic sonogram to evaluate for vascular invasion and extent of local disease, this technique is highly effective in determining resectablility.


   TREATMENT
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSIS AND STAGING
 TREATMENT
EVOLVING THERAPIES
 CONCLUSION
 REFERENCES
 
    General Treatment Principles
Surgical resection of the tumor and first-echelon draining lymph nodes is essential for any realistic chance of cure. Unfortunately, in about four out of every five patients, the primary tumor is deemed unresectable at diagnosis,26 meaning that roughly 80% of patients need another form of primary management. Depending on the stage of disease, treatment generally consists of some combination of chemotherapy, radiation, and/or palliative surgery. Even among those patients who undergo surgery with curative intent, the 5-year survival rate is still only around 20%, highlighting the need for effective adjuvant treatment. Thus, nearly every case of pancreatic cancer requires a multidisciplinary approach.

    Surgery
    Curative Surgery
A large part of the diagnostic workup and staging is centered on determining the potential resectability of the primary mass. Tumors encasing the superior mesenteric or hepatic artery are not typically amenable to curative resection. Also, major disturbance of venous flow through the superior mesenteric-portal vein confluence on pre-operative imaging is a good predictor of unresectability. Roughly 50% of patients undergoing curative resection actually have complete tumor removal, with metastases, extension to the major vessels discovered, or incomplete resection at the time of surgery in the other half of cases.27,28 Patients with a positive surgical margin after tumor resection have no better overall survival than unresectable patients treated with systemic chemotherapy and localized radiation.27,29,30 It should be noted that the mortality associated with curative pancreatic cancer surgery in major referral centers is as low as 2% and is inversely proportional to patient volume.31–33

During the initial part of the procedure, there is assessment of tumor resectability, specifically evaluating the major vessels and searching for any metastatic disease. Direct extension into or encasement of a major artery is a contraindication to definitive surgery. Tumors metastasizing to the celiac lymph nodes are typically out of the standard resection and represent unresectable disease.34 Once the abdominal cavity has been found clear of metastasis and the tumor is determined to be resectable, an en bloc resection with pancreaticoduodenectomy can be performed.35 A form of the Whipple procedure is generally the recommended operative procedure for most resectable lesions found in the head of the pancreas.

Location of the tumor impacts heavily on postoperative survival. Past series have suggested a 5-year survival rate greater than 30% in patients with lesions resected from around the ampulla and duodenum.32 Conversely, patients with lesions resected from the head of the pancreas have historically poor 5-year survival rate of roughly 5%.36–38 Although these survival numbers have been improving in recent years (with Johns Hopkins reporting a 17% 5-year survival in patients with adenocarcinoma resected from the head, neck, uncinate process, body, or tail of the pancreas), location remains an important prognostic factor.39 Other indicators found to be significantly predictive of shorter survival include tumor size greater than 3 cm in diameter, lymph node involvement, poorly differentiated histology, and positive margin status.34

    Invasive Palliation
Patients with significant symptoms related to an unresectable malignancy may benefit from some form of invasive palliation. Complications potentially requiring invasive intervention include documented duodenal obstruction, as well as jaundice-associated symptoms such as pruritus.1 In these cases, symptoms may be relieved by a surgical bypass of the tumor, including rerouting of the obstructed biliary and/or gastric outflow tract. A choledochojejunostomy is the procedure of choice for patients with obstructive jaundice. In addition, a gastrojejunostomy effectively addresses gastric outlet obstruction secondary to tumor compression on the duodenum. For patients with significant malignancy-related pain, administration of 50% alcohol into the celiac nerve plexus, either percutaneously under image guidance or during surgical intervention, can provide effective analgesia from pancreatic cancer.40 Placement of stents into the compromised biliary system can be performed as part of ERCP, by percutaneous transhepatic biliary drainage, or laparoscopically. The overall rate of jaundice relief with stent placement is between 75% and 85%. Although the jaundice relief rate is equivalent to surgical biliary bypass, complications such as ascending cholangitis, biliary leaks, bleeding, and stent occlusion resulting in recurrent jaundice are significantly more common with the placement of stents.41,42 Therefore, stents are typically recommended only for patients who are poor operative candidates with an expected survival of less than 6 months.43

    Adjuvant Therapy
    Rationale of Adjuvant Treatment
Treatment with definitive surgery alone in Phase III trials conducted over the last decade has yielded 5-year survival rates of 8% to 11%.44–46 Based on these numbers, it is clear that although surgery is a necessary component of curative treatment, adjuvant therapies must be employed to maximize survival. Compared with other malignancies, pancreatic cancer metastasizes early in its course. Thus, it can be assumed that the vast majority of these patients have occult metastases at the time of curative surgery. In several small studies, the risk of peritoneal or hepatic metastases following definitive surgery was 75% or greater, hence the need for systemic therapy.47–49 As described, pancreaticoduodenectomy is a complicated surgery and adequate dissection along the superior mesenteric artery and other major vessels in the field and deep into the retroperioneum can be challenging. Pathologic assessment of surgical margins of the specimen can also be quite difficult. To better ensure locoregional control in this setting, radiation therapy to the postoperative bed and draining lymph nodes is often employed. Local failure rates with surgery alone can range anywhere from 50% to 86% in some series.47–50 In the United States, standard therapy in most adjuvant cases involves a combination of radiation and chemotherapy, in an attempt to improve local control while preventing early metastatic disease.

    Chemoradiation
In 1974, the Gastrointestinal Tumor Study Group (GITSG) began a prospective randomized trial testing the effect of adjuvant combined modality therapy (CMT) for patients with surgically resected pancreatic cancer.51 Patients treated with adjuvant chemoradiation had a significantly higher overall survival than those patients randomized to observation (20 months versus 11 months, P = 0.03), with a superior 2-year survival of 42% versus 15%.51 This paper has been criticized for many reasons, including the long accrual time, early termination, poor compliance and quality assurance, and inclusion of many patients with a poor ECOG performance status. In response to this criticism, the GITSG released the results of another 30 patients treated according to the adjuvant arm of the protocol. The results were similar, with a median survival time of 18 months and a 2-year actuarial survival of 46% (95% confidence interval [CI], 28% to 65%).52 Even with the recognized shortcomings of the GITSG trial, it represented the only prospective randomized trial of adjuvant therapy for pancreatic cancer in the United States. As seen in Table 1, the relatively favorable results of chemoradiation have been confirmed by other single institution retrospective series.


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  		TABLE 1 Adjuvant 5-Fluorouracil-based Chemoradiation Versus Surgery Alone for Pancreatic Cancer
 

When compared with today’s standards, many of the earlier trials, like those from the GITSG and the European Organization for Research and Treatment of Cancer (EORTC), used suboptimal radiation doses, schedules, and equipment as well as inadequate chemotherapy regimens. Despite the limitations of these studies, the evidence that some form of adjuvant therapy is needed cannot be ignored. Optimizing that therapy is the goal of the Radiation Therapy Oncology Group’s (RTOG) recently completed Phase III trial, RTOG 97-04. It is the first Phase III trial of adjuvant treatment for pancreatic cancer in the United States since the results of the GITSG trial were published two decades ago.57 In this study, 518 patients were randomized after surgery to receive either: 1) gemcitabine followed by concurrent radiation and 5-fluorouracil (5-FU), then three more cycles of gemcitabine; or 2) 5-FU followed by concurrent radiation and 5-FU, then two more cycles of 5-FU. The aims of the trial are to assess whether gemcitabine offers an advantage over 5-FU in improving overall survival, disease-free survival, local control, and metastatic disease. Although the concurrent chemoradiation will be standardized in both arms, analysis of the rate of local recurrence can be compared with studies with similar patient cohorts, especially those from Europe, where care is shifting away from radiation in the adjuvant setting.

    Chemotherapy Alone Versus Chemoradiation
The European Study Group for Pancreatic Cancer (ESPAC) recently published mature data from the ESPAC-1 trial.46 This is the largest Phase III trial to date evaluating various adjuvant therapy options for patients with surgically resected pancreatic cancer, enrolling a total of 541 postoperative patients.59 There was no survival benefit to adjuvant chemoradiation, with the 175 patients receiving postoperative chemoradiation having a median survival of 15.5 months compared with 16.1 months among those patients observed. There was, however, a significant survival benefit associated with those patients receiving adjuvant chemotherapy compared with those who did not (19.7 months versus 14 months, P = 0.005).

Both the initial results of this trial and the recent update have been associated with several criticisms. One major concern is that physicians and patients could decide between randomization groups (chemoradiation versus observation or chemotherapy alone versus observation), thus introducing selection bias. Secondly, patients randomly assigned to receive adjuvant chemoradiation were allowed to have "background" chemotherapy, and those patients randomized to receive chemotherapy alone were allowed to receive "background" radiation. There are 82 patients (15% of the entire cohort) for whom the background treatment is unknown. This additional therapy was not controlled in this study, likely skewing the results.60,61 An additional 50 patients (9.2% of total) either refused their randomization or withdrew from the trial secondary to toxicity. Also, by pooling the results from the different randomizations, about 30% of patients in the no-chemotherapy arm and chemotherapy-alone arm received adjuvant chemoradiation, further confounding the results. It should be noted that commencement of chemotherapy was 48 days following surgery compared with 61 days postoperatively for chemoradiation, suggesting a worse performance status among those undergoing chemoradiation.62 Although those patients with microscopically positive surgical margins were allowed on the trial, there was no standardized pathologic review and no reported quality control. Among the 289 patients included in the original 2 x 2 factorial design, 158 developed disease recurrence, with 63% of these having a component of local recurrence. This large number suggests residual tumor was present at a rate higher than the 18% of patients listed with microscopically positive disease. Among similar series published by MD Anderson Cancer Center with clearly defined quality control criteria for surgery and pathologic assessment, local recurrence rates accounted for 10% of all recurrences.63

There have been several concerns with the delivery of the radiation component of treatment in this trial. To reach therapeutic doses of radiation to the pancreatic bed and draining lymph nodes, careful planning and decision making need to take place before treatment is initiated. As pointed out in a recent editorial, the final manuscript of this trial lacked details regarding the size of radiation fields used, types of equipment, dosimetric parameters employed, and overall quality assurance measures employed.63

    Neoadjuvant Therapy
In many patients, micrometastases are present locally and systemically by the time intervention is planned and neoadjuvant therapy has the theoretical advantage of providing immediate systemic treatment. Additionally, patients with advanced disease on restaging after neoadjuvant therapy can be spared the radical surgery reserved for curative cases. Including those patients with progression not having curative surgery, Wayne, et al. theorized that more patients will receive a full course of treatment with curative intent if the adjuvant therapy is given preoperatively.64 By receiving adjuvant therapy upfront, patients avoid delays secondary to postoperative complications. With respect to radiation, preoperative treatment is thought to be more effective with the treated tissues being fully vasularized and oxygenated. Additionally, preoperative treatment can theoretically reduce tumor seeding in the peritoneum at the time of surgery.1 Although this provides a practical advantage for physicians and patients, selecting out patients with progression after neoadjuvant therapy makes direct comparisons between neoadjuvant and postoperative therapy difficult.

The ECOG has been investigating the role of preoperative chemoradiation schemes in patients with potentially resectable tumors. They have published data on a prospective, multi-institutional trial of 53 patients treated preoperatively with a regimen of external beam radiation therapy (EBRT) combined with mitomycin C and 5-FU. Twenty-four patients (45% of total) had tumor resection with a median survival of 15.7 months compared with 9.7 months for the entire group.65 Other investigators have also examined the possibility of neoadjuvant chemoradiation in potentially resectable cases, with similar results.66–71 At present, neoadjuvant therapy is a feasible alternative at centers with experience in neoadjuvant treatment, but retrospective comparisons of preoperative and postoperative chemoradiation have not yielded any significant difference in long-term outcome.72,73

    Treatment of Unresectable Disease
In many cases, diagnostic evaluation reveals pancreatic lesions that are associated with widespread lymphadenopathy or directly involve or completely encase the local major vessels. If metastatic workup reveals no distant disease, these patients have locally advanced, unresectable disease. Combined modality management has been studied in these patients for many decades. GITSG conducted a trial with unresectable patients randomized to one of three arms: 1) 60 Gy of EBRT over 10 weeks; 2) 40 Gy of EBRT over 6 weeks plus 5-FU followed by maintenance 5-FU; or 3) 60 Gy of EBRT over 10 weeks plus 5-FU followed by maintenance 5-FU.74 In this series, both CMT arms had superior survival when compared with EBRT alone (10 months for all patients receiving CMT versus 5.5 months for patients receiving EBRT only, P < 0.05). In 1988, GITSG published another trial comparing CMT to chemotherapy alone.75 The group receiving CMT had a superior 1-year survival rate of 41% compared with 19% for the group receiving chemotherapy alone (P < 0.05). Combined therapy seems to provide a survival benefit over either radiation or chemotherapy alone (Table 2).


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  		TABLE 2 Phase III Trials of Chemoradiation Versus Radiation Alone and Chemoradiation Versus Chemotherapy Alone in Locally Advanced Unresectable Pancreatic Cancer
 


   EVOLVING THERAPIES
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSIS AND STAGING
 TREATMENT
 EVOLVING THERAPIES
CONCLUSION
 REFERENCES
 
    Advances in Chemotherapy
Although 5-FU continues to be regarded as an effective radiosensitizer, investigators have searched to improve the rates of local and distant recurrence. Over the last several years, there have been many developments in systemic management of pancreatic cancer. With its radiosensitizing properties and systemic antitumor qualities, gemcitabine is an agent that has been the focus of innumerable studies in all stages of pancreatic cancer. Early studies using gemcitabine suggested that patients with pancreatic cancer experienced an improvement in disease-related symptoms like weight loss, pain, and performance status.78,79 Based on those findings, a Phase III trial was performed to compare the use of gemcitabine and 5-FU in patients with newly diagnosed advanced pancreatic cancer.80 Clinical benefit response was seen in 23.8% of patients treated with gemcitabine compared with 4.8% of patients receiving 5-FU (P = 0.022). Additionally, the median survival for gemcitabine-treated patients was 5.65 months compared with 4.41 months for 5-FU-treated patients (P = 0.025). This study showed that for palliative cases, gemcitabine is more effective than 5-FU in improving disease-related symptoms and offers a significant improvement in survival. Although gemcitabine has shown promise as a radiosensitizer in the setting of local-regional disease, its superiority over 5-FU-based therapy has not yet been demonstrated in prospective randomized trials. The RTOG recently completed a Phase III study of pre- and postchemoradiation 5-FU versus pre- and postchemoradiation gemcitabine for adjuvant treatment of resected pancreatic adenocarcinoma; this study should provide some insight of gemcitabine’s effectiveness in the adjuvant setting.

Another emerging therapy is the use of locoregional chemoimmunotherapy in the treatment of node-positive pancreatic cancer. In a Phase III trial out of Greece, 128 patients were prospectively randomized intraoperatively to one of three arms: surgical resection alone, surgical resection with intra-arterial chemotherapy followed by systemic chemotherapy, or surgical resection plus intra-arterial chemotherapy and intra-arterial interleukin-2 followed by adjuvant systemic chemoimmunotherapy.81 Five-year survival rates for these three groups were 0%, 10%, and 18%, respectively. The overall survival of patients receiving intra-arterial chemotherapy and interleukin-2 followed by systemic chemoimmunotherapy was significantly improved over surgical resection alone (P = 0.02).

The group at the Virginia Mason Medical Center has pioneered the use of interferon-{alpha} in its adjuvant treatment scheme for patients with surgically resected disease. In a Phase II trial, 33 patients received GITSG-type adjuvant therapy or interferon-{alpha} adjuvant therapy.82 Patients in the interferon-{alpha} group received EBRT of 45 to 54 Gy with 5-FU by continuous infusion, weekly intravenous bolus cisplatin, and interferon-{alpha} during the 5 weeks of radiation. CMT was followed by two 6-week courses of 5-FU by continuous infusion. It should be noted that more advanced tumor stage was observed in patients treated with interferon-{alpha} (13/17 patients with positive lymph nodes) when compared with the GITSG group (7/16) (P = 0.052). The 2-year overall survival was superior in the interferon-{alpha} cohort (84%) versus the GITSG group (54%), with actuarial survival curves significantly favoring the interferon-{alpha} group (P = 0.04). The authors concluded that this interferon-{alpha} regimen, although producing significant toxicity, was a highly effective adjuvant therapy and is associated with greater long-term overall survival than seen in previous adjuvant trials for pancreatic cancer. These favorable results in a relatively high-risk group of patients have prompted the American College of Surgeons Oncology Group to open a Phase II study (ACOSOG-Z0,5031) to evaluate the use of adjuvant interferon-{alpha} in a multicenter setting.

    Evolving Radiation Technologies
With improving technologies and conformal treatments, tolerable radiation doses continue to escalate. Ceha, et al. demonstrated in a Phase II study that high-dose conformal radiotherapy for patients with locally advanced pancreatic carcinoma is feasible.83 In this study, 41 patients received 70 to 72 Gy in standard fractionation, with acute Grade 3 toxicity limited to 9.7% (4/41) of patients, and late Grade 4 or 5 toxicity observed in 12% (5/41) patients. Dose escalation is possible, in part, by reducing overall field size. It is, however, important to recognize that the pancreas and surrounding tissues are not static targets. Horst, et al. conducted a study to measure the nonrespiratory organ motion in the pancreatic region and how that affects the target volume.84 In 20 patients, the position of the pancreatic head, body, tail, the kidneys, and the superior mesenteric artery were analyzed. Three spiral CT studies were performed at static exhalation following oral administration of 500 mL dilute barium sulfate, 750 to 900 mL of water, or no oral contrast for representation of differential gastrointestinal distention. Analysis revealed significant movement in the volumes of interest. The most mobile parts of the target organs were the pancreatic tail (P = 0.001) and the superior mesenteric artery (P = 0.01). Although the median displacements clustered around relatively small 3- to 4-mm changes, maximum organ movements of 15.6 to 17.6 mm were observed. The authors concluded that this data could provide a basis for further organ motion studies to allow for more accurate determination of treatment margins.84

The concept of image-guided radiation therapy (IGRT) acknowledges the challenges of organ motion occurring between treatment simulation and each day of radiation treatment delivery. IGRT defines the concept of assessing a tumor or target location before radiation delivery and a workflow allowing for positional corrections when necessary. Thus, in the case of pancreatic cancers, setup variations caused by (among other reasons) changes in hollow organ filling can be quantified and compensated with resulting reductions in necessary planning target volume safety margins and, thus, field size. Image guidance is not an entirely new concept associated with EBRT for pancreatic cancer but was in the past most often executed as an indirect assessment of the organ’s location relative to bony landmarks of the spinal column. Fuss, et al. have recently introduced a technique to assess the location of upper abdominal and retroperitoneal tumors by use of daily ultrasound-based image guidance.85 For positional assessment of 20 pancreatic cancers, the organ’s location was derived by direct visualization or indirectly by the individual relationship of the organ with major named vessels such as the aorta, celiac trunk, and superior mesenteric artery. This approach has allowed for narrow planning target volume safety margins of 6 to 10 mm, and moderate radiation dose escalation to median 60 Gy. A recent presentation of clinical outcomes in abstract form indicates that this treatment concept was well tolerated with 19 of 25 patients expressing low acute toxicity and only four patients requiring treatment cessation or interruption.86 A Phase I radiation dose escalation study published by Koong, et al. employed x-ray tracking of gold fiducials (small gold markers) implanted into pancreatic tumors for radiosurgery (single-dose radiation of 15 to 25 Gy) of locally advanced pancreatic cancer. Despite the fact that the time to local tumor progression was only 2 months, the data from this small study suggest that image guidance in conjunction with breath-hold radiation delivery techniques allows for high-dose radiation administration with a favorable toxicity profile.87 Image guidance may thus enable safe radiation dose escalation or chemoradiation intensification and allow for the full exploitation of the capabilities of modern radiation treatment planning and delivery techniques, such as intensity-modulated radiation therapy (IMRT) or charged particle radiation therapy, to tightly conform radiation doses to a pancreatic cancer target volume.88

For the last several years, radiation oncologists have been utilizing IMRT for many disease sites to allow for more precise delivery of radiation (Figure 2).89 By breaking the large radiation ports used in conventional and 3D conformal radiation therapy into a number of smaller field segments or pencil beams, the conformality of a computed radiation dose distribution to the outline of a target volume can be improved.


Figure 2
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  		Figure 2 Intensity-modulated Radiation Therapy in the Treatment of Pancreatic Cancer.

 

Simultaneously, the radiation exposure to surrounding structures and organs at risk for radiation-induced damage can be effectively reduced. Inverse IMRT treatment planning is based on a numerical specification of dose requirements for the target volume and radiation dose limits placed on the organs at risk. A computer-based optimization procedure subsequently derives a treatment plan that complies with those requirements and stipulations. Theoretically, the optimizers employed during inverse IMRT planning identify the best radiation plan, from a set of literally millions of alternatives in a so-called solution space. Today, IMRT is routinely used for many disease sites like prostate cancer, head and neck cancer, and intracranial tumors.90–92 In diseases like prostate cancer, IMRT has improved the therapeutic ratio by allowing for dose escalation to doses previous thought to be associated with unacceptable morbidity.

In a study from Emory University, Landry, et al. randomly selected 10 patients with adenocarcinoma of the pancreatic head to undergo simultaneous planning with 3D conformal EBRT and inverse-planned IMRT.93 The aim of this simulation was to deliver 61.2 Gy to the gross tumor volume (GTV). In this study, the average dose delivered to one-third of the small bowel was significantly lower with the IMRT plan compared with 3D conformal EBRT (P = 0.006). Additionally, the median volume of small bowel that received significantly greater than either 50 or 60 Gy was reduced with IMRT (P = 0.048 and P = 0.034, respectively). Using a normal-tissue complication probability model, the risk of small-bowel complications was 9.3% with IMRT compared with 24.4% with 3D conformal EBRT (P = 0.021). The authors concluded that IMRT with inverse treatment planning can significantly improve radiation to the pancreas by reducing normal tissue dose while allowing for dose escalation to further enhance locoregional control. A cohort of 25 patients treated by IMRT in combination with various chemotherapy regimens was reported by investigators from the University of Texas at San Antonio. In this study, 76% of patients experienced Grade 2 or less toxicity following administration of median doses of 60 Gy.86 At a median follow up of 20 months, 14 of 25 patients treated were alive. Another recent study evaluated the use of IMRT with concurrent capecitabine. Seven patients received it as adjuvant therapy following curative resection, and eight patients were treated for unresectable disease. Treatment was tolerated well. Only one patient (7%) developed Grade 3 toxicity, and with a median follow- up of 8.5 months, there had been no deaths in the resectable group and only one (14%) local recurrence.94

    Targeted Therapies
Over the last several years, investigators have gained a better understanding of the molecular biology and events that lead to the development of malignancies. For solid tumors to grow and metastasize, multiple tumor suppressor genes must be inactivated while other oncogenes and proto-oncogenes are overexpressed. Recently, many tumor-specific alterations have been discovered and evaluated. These alterations create a tumor-specific environment with many potential targets for therapy. Although these targeted therapies are used for many solid malignancies, there is particular interest in their investigation for use in pancreatic cancer, given its generally poor prognosis and the feeling that survival benefits associated with conventional therapy have nearly maximized.1

    Matrix Metalloproteinase Inhibition
Matrix metalloproteinases (MMPs) are a collection of proteases normally used for tissue remodeling that have been found to be upregulated in the setting of many tumors, including pancreatic cancer. In patients with pancreatic cancer, MMPs have been related to tumor invasion, growth, and metastasis.95 MMP inhibition in pancreatic cancer has been thoroughly investigated given the rapid local progression and development of metastasis associated with this disease.96

Marimastat is an inhibitor of many MMPs, and different dosages of the drug have been compared with gemcitabine in a large Phase III trial of patients with advanced disease.97 In this study, patients treated with gemcitabine were found to have a superior overall survival compared with the group treated with marimastat (3.8 months versus 1.9 to 2.0 months, P = 0.001). A subset analysis of patients receiving marimastat showed a survival benefit in those patients with locally advanced disease compared with metastatic disease, a trend not seen in the group treated with gemcitabine. These findings suggest promise for the use of MMP inhibitors in the adjuvant and locally advanced setting because of their ability to limit tumor invasion to surrounding structures. Although their efficacy in the advanced setting has not been proven, future trials evaluating patients with nonmetastatic disease may show value in their use.98

    Angiogenesis Inhibition
When tumors reach a volume of 1 to 2 mm3, they need new blood vessel growth to continue to increase in size.99 When tumors begin to neovascularize, they progress rapidly and have been shown to have an increased rate of metastasis. The number of blood vessels in a tumor has been shown to predict behavior in pancreatic cancer.100 Vascular endothelial growth factor (VEGF) has been shown to be a potent regulator of both normal and pathological angiogenesis.101 It works by enabling endothelial cell mitogenesis and migration, inducing proteinases that remodel the extracellular matrix, and increasing vascular permeability. Levels of VEGF expression have been found to be elevated in pancreatic cancer, making it an attractive target for therapy.99

Bevacizumab is a recombinant humanized monoclonal antibody to VEGF, and it has been the most widely studied antiangiogenic agent. In a large Phase III study of patients with metastatic colon cancer, bevacizumab was shown to increase survival when added to irinotecan and 5-FU, compared with irinotecan and 5-FU alone (20.3 months versus 15.6 months, P < 0.001).102 This trial was the first Phase III study showing efficacy of antiangiogenic therapy in treating human cancer.

The group at MD Anderson Cancer Center has been conducting a Phase I study of patients with locally advanced pancreatic cancer treated with a combination of bevacizumab and capecitabine and concurrent EBRT. At the 2005 American Society of Clinical Oncology Meeting, the group presented analysis of 48 patients.103 The median and 1-year actuarial survival estimates were 15.7 months and 65%, respectively, and the addition of bevacizumab did not significantly increase the acute toxicity. These encouraging results have prompted the RTOG to further investigate bevacizumab in combination with capecitabine and concurrent EBRT.

    Epidermal Growth Factor Receptor Inhibition
Overexpression of epidermal growth factor receptor (EGFR) in combination with at least one of its ligands is associated with aggressive tumors and is a negative predictor of survival.104 Cetuximab is a monoclonal antibody designed to inhibit ligand binding that has been shown to have a high affinity for EGFR.105 After binding, cetuximab induces antibody-dependent cellular toxicity.106 It has shown activity in patients with metastatic colon cancer whose disease has become refractory to irinotecan.107 Abbruzzese, et al. conducted a Phase II study of patients with advanced pancreatic cancer who received cetuximab in combination with gemcitabine.108 In this study, a partial response was demonstrated in 13% of patients, with an overall survival of 7.1 months. The regimen was well tolerated, and the Southwestern Oncology Group is now conducting a Phase III trial in patients with advanced pancreatic cancer, comparing the combination of gemcitabine plus cetuximab versus gemcitabine alone.

Small-molecule tyrosine kinase inhibitors (TKIs) bind to the growth factor receptor on the cytoplasmic portion of the protein. Specifically, erlotinib has been used in trials for both locally advanced and metastatic pancreatic cancer. Moore, et al. recently presented the results of a Phase III trial in which 569 patients with advanced pancreatic adenocarcinoma received either gemcitabine plus erlotinib or gemcitabine plus placebo.109 There was a significant difference in overall survival (P = 0.025 favoring the combined treatment arm) as well as in the quality-of-life analysis.

    Immunotherapy
Immunotherapy has been investigated for use against several types of solid tumors. The aim of the therapy is to stimulate the immune system to act specifically against the tumor cells while limiting damage to the normal tissue. Gastrin has been shown to be a growth factor in gastrointestinal tumors, and the presence of gastrin receptor in pancreatic tumors has been described. The combination of the aminoterminal sequence of gastrin-17 linked to diphtheria toxoid is called G17DT, and it acts as an antigastrin immunogen. It works by raising antibodies that blockade gastrin-stimulated growth.110 In a randomized trial of 154 patients with advanced pancreatic cancer unable to take chemotherapy, patients received either G17DT or placebo. Overall survival was significantly improved in the group receiving G17DT compared with placebo (151 days versus 82 days, P = 0.03). The authors concluded that G17DT prolongs overall survival while maintaining performance and provides a well-tolerated option for patients with advanced pancreatic cancer. These results were confirmed by a Phase II study, which demonstrated that patients with advanced pancreatic cancer can mount an adequate antibody response to G17DT.111 Among these patients, antibody responders demonstrate significantly greater survival than antibody nonresponders. However, a recently presented Phase III trial comparing gemcitabine alone to gemcitabine plus G17DT showed no benefit for the addition of G17DT for overall survival, relapse rate, and time to progression in patients with locally advanced, recurrent, or metastatic pancreatic cancer.112 Other vaccine therapies have been developed that work by similar mechanisms to treat rather than prevent tumors, many of which are also being evaluated as monotherapy or in combination with chemotherapy for treatment of pancreatic cancer.113


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSIS AND STAGING
 TREATMENT
 EVOLVING THERAPIES
 CONCLUSION
REFERENCES
 
Despite technological advances, innovative treatments, and significant discoveries, treatment of pancreatic cancer remains a challenge. However, there have been many agents and treatment regimens that have shown promise. The level of understanding of pancreatic cancer at the molecular level continues to grow. In the coming years, the role for combined modality should become better elucidated when the results of the many large trials mature. As collaboration between investigators continues to grow, future trials can continue to rapidly accrue, with focus on the addition of promising targeted therapies to standard treatments.


   Footnotes
 
This article is available online at http://CAonline.Am CancerSoc.org


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSIS AND STAGING
 TREATMENT
 EVOLVING THERAPIES
 CONCLUSION
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