ABSTRACT: This year, approximately 40% of the 28,300 patients diagnosed with pancreatic carcinoma in the United States will present with locally advanced disease. Radiotherapeutic approaches are often employed, as these patients have unresectable tumors by virtue of local invasion into the retroperitoneal vessels in the absence of clinically detectable metastases. These treatments include external-beam irradiation with and without fluorouracil (5-FU)-based chemotherapy, intraoperative irradiation, and more recently, external-beam irradiation with new systemic agents, such as gemcitabine (Gemzar). [ONCOLOGY 14(11):1535-1545, 2000]
Pancreatic cancer remains one of the most formidable challenges in oncology. In the year 2000, there will be an estimated 28,300 new cases of pancreatic cancer in the United States and 28,200 estimated deaths from the disease. Thus, pancreatic cancer is expected to be the fourth leading cause of cancer-related death, with less than 5% survival at 5 years after diagnosis.
The disturbing mortality rate of pancreatic cancer is due to the high incidence of metastases at the time of diagnosis, its fulminant clinical course, and the lack of adequate systemic therapies. At present, surgery offers the only therapeutic means of cure. Unfortunately, only 5% to 25% of patients present with tumors amenable to resection. Patients who undergo resection for localized pancreatic carcinoma have a long-term survival of approximately 20% and a median survival of 13 to 20 months.[2,3] At the other end of the clinical spectrum, a high percentage (40% to 45%) of patients present with metastatic disease, with a short survival of only 3 to 6 months.
Patients with locally advanced carcinoma of the pancreas comprise an intermediate group. Radiotherapeutic approaches are frequently employed, as these patients have unresectable tumors by virtue of local invasion of the portal, mesenteric, or celiac vessels in the absence of clinically detectable metastases. Combined treatment with radiation and chemotherapy increases median survival for patients with locally advanced cancers to approximately 9 to 13 months but rarely results in long-term survival. Clinical research efforts are currently focused on improved staging to better select patients for therapy, as well as the evaluation of new systemic agents with radiation therapy.
In the past several years, significant advances have been achieved in the imaging and staging of pancreatic cancer. Currently, the principal diagnostic tools are helical computed tomography (CT) scan, endoscopic ultrasound, and laparoscopy. These tools have facilitated the characterization of the primary tumor (resectable vs unresectable) as well as the identification of metastatic disease. Importantly, patients can be appropriately and reliably triaged to operative and nonoperative therapies. With contemporary staging, the vast majority of patients with locally advanced pancreatic cancer can be spared the morbidity of laparotomy.
The most commonly used diagnostic and staging examination is an abdominal CT scan. Newer generation high-speed helical CT performed with contrast enhancement and thin-section imaging allows high resolution, motion-free images of the pancreas and its surrounding structures to be obtained at varying phases of enhancement.
In general, a tumor is considered unresectable if there is (1) extrapancreatic involvement by tumor, including extensive parapancreatic lymph node involvement and/or distant metastases (typically to the liver or peritoneum) (2) encasement or occlusion of the superior mesenteric vein (SMV) or SMV–portal vein confluence, or (3) direct involvement of the superior mesenteric artery, inferior vena cava, aorta, or celiac axis. By these criteria, over 90% of patients deemed unresectable by CT are actually unresectable at operation, thereby sparing these patients potential operative morbidity. In addition, because tissue confirmation of malignancy is a necessary step prior to initiating therapy for patients with locally advanced tumors, CT can be utilized to facilitate fine-needle aspiration. Figures 1A, 1B, and 1C illustrate examples of locally advanced pancreatic cancers.
Another promising tool for staging and diagnosis is endoscopic ultrasound. In this procedure, an endoscope with an ultrasound transducer at its tip is passed into the stomach and duodenum, where it provides high-resolution images of the pancreas and surrounding vessels and facilitates needle biopsies. The endoscopic ultrasound image in Figure 2 shows a pancreatic head tumor invading the portal vein.
Frequently, endoscopic ultrasound is performed in conjunction with endoscopic retrograde cholangiopancreatography (ERCP) when assessing pancreatic neoplasms. This combined diagnostic approach allows for staging, therapeutic stenting of the common bile duct when indicated, and retrieval of tumor cells by fine-needle aspiration without exposing the peritoneum to potential tumor seeding.
Magnetic Resonance Imaging
Conventional magnetic resonance imaging (MRI) has not been shown to offer significant benefit over high-quality CT scan for establishing resectability of pancreatic cancer. Dynamic, contrast-enhanced MRI is a newer imaging modality that permits high-definition imaging of the pancreas without motion artifact, although currently this technique is not widely available. It is not yet clear whether MRI will be an improvement over CT scan imaging for determining resectability, as both imaging modalities undergo continued improvement.
Because current imaging techniques cannot visualize small (1- to 2-mm) liver and peritoneal implants, staging laparoscopy has been used preoperatively to exclude intraperitoneal metastases. This technique can detect intraperitoneal metastases in up to 25% of patients with apparent localized disease by CT. Additionally, peritoneal washings can be obtained at the time of the procedure for cytologic evaluation. If visual inspection or washings confirm extrapancreatic involvement, patients with locally advanced pancreatic cancer have the same prognosis as those with metastatic disease. These patients are more appropriately treated with systemic therapies.
The therapeutic options of patients with locally advanced pancreatic cancer include external-beam radiation therapy (EBRT) with fluorouracil (5-FU) chemotherapy, intraoperative radiation therapy (ie, brachytherapy or electron beam), and more recently, EBRT with novel chemotherapeutic agents. In evaluating the results of these therapies, it is useful to remember that a median survival of 3 to 6 months has been reported for this subset of patients undergoing palliative gastric or biliary bypass only.
EBRT With or Without 5-FU
With the exception of one trial, conventional EBRT for locally advanced pancreatic cancer has been shown to improve survival when combined with 5-FU, compared to EBRT alone or chemotherapy alone (Table 1).[10-14]
The Mayo Clinic undertook an early randomized trial in which 64 patients with locally unresectable, nonmetastatic pancreatic adenocarcinoma received 35 to 40 Gy of EBRT with concurrent 5-FU vs the same EBRT schedule plus placebo. A significant survival advantage was seen for patients receiving EBRT with 5-FU vs EBRT only (10.4 vs 6.3 months).
The Gastrointestinal Tumor Study Group (GITSG) followed with a similar study comparing EBRT alone to EBRT with concurrent and maintenance 5-FU. In this trial, 194 eligible patients with surgically confirmed unresectable and nonmetastatic pancreatic adenocarcinoma were randomized to receive 60 Gy of split-course EBRT alone, 40 Gy of split-course EBRT with two to three cycles of concurrent bolus 5-FU chemotherapy, or 60 Gy of split-course EBRT using a similar chemotherapy regimen. Patients in the latter groups received maintenance 5-FU after EBRT completion. The EBRT-alone arm was closed early as a result of an inferior survival rate. The 1-year survival rate in the two combined-modality therapy arms was 40%, compared with 10% in the EBRT-alone arm.
The second GITSG trial of this series randomized 143 eligible patients with unresectable disease to 60 Gy of split-course EBRT with concurrent and maintenance 5-FU from the previous trial or 40 Gy of continuous-course radiation with weekly concurrent doxorubicin chemotherapy, followed by maintenance doxorubicin and 5-FU. A significant increase in treatment-related toxicity was seen in the doxorubicin arm. However, no survival difference was observed between the two groups (median survival: 37 vs 33 weeks).
A follow-up GITSG trial compared chemotherapy alone to chemoradiation, again in surgically confirmed unresectable tumors. A total of 43 patients were randomized to receive the combination chemotherapy regimen SMF (streptozocin [Zanosar], mitomycin-C [Mutamycin], and 5-FU) or 54 Gy of EBRT with two cycles of concurrent bolus 5-FU chemotherapy, followed by adjuvant SMF chemotherapy. The chemoradiation arm demonstrated a significant survival advantage over the chemotherapy-alone arm (1-year survival of 41% vs 19%).
In contrast to the results of the prior studies, the Eastern Cooperative Oncology Group (ECOG) reported no benefit to chemoradiation vs chemotherapy only. In this study, patients with unresectable, nonmetastatic pancreatic or gastric adenocarcinoma were randomized to receive either 5-FU chemotherapy alone or 40 Gy of EBRT with concurrent bolus 5-FU during week 1. Patients with locally recurrent disease as well as patients undergoing surgery with residual disease were eligible for this trial. In the 91 analyzable pancreatic patients, no survival difference was observed between the two groups (median survival: 8.2 vs 8.3 months).
In summary, with the exception of one study, conventional EBRT combined with 5-FU chemotherapy has been shown to offer a modest survival benefit for patients with locally advanced unresectable pancreatic cancer, compared to irradiation alone or chemotherapy alone. The most favorable median survival duration and 2-year survival rate for EBRT plus 5-FU are approximately 11 months and 12%, respectively. Because of these results, EBRT with 5-FU–based chemotherapy has become a frequently employed therapy for these patients.
Preoperative 5-FU–Based Chemoradiation
Because of the limited tolerance of normal tissue in the upper abdomen (liver, kidney, spinal cord, and bowel) to EBRT, total doses of only 45 to 54 Gy, in 25 to 30 fractions, have usually been given. For an unresectable tumor, this dose of radiation is inadequate, as demonstrated by the high rates of tumor progression and poor survival seen in both prospective and retrospective studies.
For example, local progression occurred as the first site of failure in 58% of patients treated to 60 Gy with concurrent 5-FU in the second GITSG trial. Similarly, the Mayo Clinic reported a local failure rate of 72% for 122 patients with unresectable pancreatic cancer treated with an EBRT dose of 40 to 60 Gy. In a report from Thomas Jefferson University Hospital, 46 evaluable patients with unresectable disease by laparotomy were treated with 63 to 70 Gy of EBRT with or without chemotherapy. Despite high-dose EBRT, the local failure rate was 78%.
Because surgical resection of the primary tumor remains the only potentially curative treatment for pancreatic cancer, preoperative irradiation has been studied to assess its ability to convert locally unresectable pancreatic cancer to resectable disease. In a study from New England Deaconess Hospital, 16 patients with locally advanced unresectable pancreatic cancer were treated neoadjuvantly with 45 Gy of EBRT and infusional 5-FU. Of these 16 patients, only two (13%) were able to undergo resection. Similarly, investigators from Duke University reported that only 2 (8%) of 25 patients with locally advanced pancreatic cancer treated with 45 Gy of EBRT and 5-FU (with or without cisplatin [Platinol] or mitomycin-C) subsequently underwent complete resection with negative margins.
These and other studies indicate that it is unlikely that currently utilized neoadjuvant chemoradiation can convert unresectable lesions to resectable ones and thereby increase the number of patients potentially cured with combined-modality therapy (Table 2).[17-22] It is important to remember that broadening the definition of a locally advanced pancreatic cancer will give the appearance of more optimistic results. If, however, one maintains a stringent CT definition of locally advanced pancreatic cancer that includes only arterial involvement (superior mesenteric artery or celiac axis invasion) or superior mesenteric or portal vein encasement or occlusion, successful downstaging to allow complete surgical resection will be an uncommon event with contemporary chemoradiation approaches.
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