George P. Kim*
James L. Gulley†
Chris H. Takimoto‡
*Gastrointestinal Cancer Section, Mayo Clinic Cancer Center, Jacksonville, Florida
†Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
‡Institute for Drug Development, Cancer Therapy & Research Center, San Antonio, Texas
TABLE 9.1. Risk factors
The pancreas performs both endocrine and exocrine functions; however, approximately 80% of the cells in the pancreas are acinar cells and 10% to 15% are ductal cells. Approximately 95% of malignant pancreatic cancer arises in the exocrine pancreas, with two-thirds arising in the head of the pancreas. The sites where the cancer arises determine the symptoms: lesions arising in the head of the pancreas causing duct obstruction, jaundice, and pain, whereas tumors arising in the body or tail of the pancreas are less likely to cause symptoms before metastasis.
FIG. 9.1. Neoplastic progression model—pancreatic intraepithelial neoplasia (PanIN-1 through PanIN-3). (From Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Can Res 2000;6:2969–2972, with permission.)
The American Joint Committee for Cancer/International Union Against Cancer (AJCC/UICC) staging classification of pancreatic cancer is done using the TNM classification, as shown in Table 9.2 (1).
TABLE 9.2. American Joint Committee for Cancer/International Union Against Cancer (AJCC/UICC) staging classification (2002)
Tumor size, presence of lymph node metastasis, and histologic differentiation each have independent prognostic values, with larger tumors, lymph node metastasis, and poor differentiation having worse prognoses. The 36-month survival for node-negative patients is between 25% and 30%, whereas there is only a 6- to 8-month median survival for node-positive patients. Long-term survival is seen in about 20% of patients who successfully undergo a potentially curative surgical resection (Fig. 9.2).
FIG. 9.2. Resectable disease, locally advanced disease, metastatic disease.
For management considerations, pancreatic cancer can be divided into resectable disease (potentially curable), locally advanced disease, and metastatic disease (see Fig. 9.3).
FIG. 9.3. Staging studies should include computerized tomography (CT) (spiral with contrast preferred) or magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), as well as laparoscopy for potentially resectable cancers. * indicates that for CT-guided FNA, there is a controversy about tumor seeding in potentially curable (i.e., resectable) disease, and in some centers, patients undergo a planned Whipple procedure to obtain tissue at the time of surgery. Adj CRT, adjuvant chemoradiation; FNA, fine needle aspiration; ERCP, endoscopic retrograde cholangiopancreatography.
Less than 10% of patients with pancreatic cancer have resectable disease at diagnosis. Resectable disease is confined to the pancreas without encasement of the celiac axis or superior mesenteric artery and with a patent superior mesenteric–portal vein confluence. However, patients may have isolated involvement of the superior mesenteric vein, portal vein, or hepatic artery. A Whipple or modified, pylorus-sparing procedure is the surgical procedure of choice. The stomach (distal third), gallbladder, cystic and common bile ducts, duodenum, and proximal jejunum are resected, with resultant pancreatico-, choledocho-, and gastrojejunostomy. The peripancreatic, superior mesenteric, and hepatoduodenal lymph nodes are also staged. Even after complete resection, the risk of locoregional recurrence is greater than 70%. This risk has led to numerous studies of adjuvant chemotherapy and radiation therapy after surgical resection. The original Gastrointestinal Study Group (GITSG) trial (2) randomized 21 patients to chemoradiation versus 22 patients to surgery alone. The chemoradiation arm consisted of split-course administration of 4,000 cGy radiation in 200-cGy fractions concomitantly with bolus 5-fluorouracil
(5-FU; 500 mg/m2/day for the first 3 days of each 2,000-cGy segment of radiotherapy). 5-FU alone (500 mg/m2/week) was administered for up to two additional years. A significantly prolonged median survival of 20 months for the patients on chemoradiation versus 11 months for controls was observed. In addition, 43% 2-year actuarial survival (versus 18% for the control arm) and 25% 5-year overall survival were observed.
This relatively small trial established the benefit from postoperative combined-modality therapy. More recent approaches include: (a) administration of up to 5,040 cGy radiation as a continuous-course schedule instead of the split-course schedule; (b) combination with 5-FU at a dose of 500 mg/m2/day daily for the first 3 days and the last 3 days of radiation therapy or administration of continuous infusion 5-FU at a dose of 225 to 250 mg/m2/day during the entire radiation portion (3); and (c) the postradiation treatment of weekly 5-FU has also been shortened from 2 years to 4–6 months, and weekly gemcitabine at a dose of 1,000 mg per m2 for 3 of every 4 weeks has been used instead of 5-FU.
Several randomized trials have also provided additional information about the effectiveness of conventional adjuvant therapy. A European Organization for Research and Treatment of Cancer trial (4) treated 114 patients with a combined-modality approach similar to that of the GITSG trial except for the maintenance 5-FU versus no adjuvant treatment. The median survival was 17.1 months in the experimental arm versus 12.6 months in surgery-alone patients (p = 0.099), and 2-year survival (37% versus 23%) also suggested benefit. The study was considered negative but may more accurately be described as being underpowered. A recent trial from the European Study Group for Pancreatic Cancer (ESPAC-1) used a 2 × 2 factorial randomization design and suggested that chemotherapy alone in the adjuvant setting was more effective than chemotherapy–radiation (5). Unfortunately, the conclusion from this study is limited by selection bias and considerable treatment variability. The results, nonetheless, are intriguing. Finally, the recently completed Radiation Therapy Oncology Group trial 97-04 compared gemcitabine to 5-FU alone prior to combined-modality therapy (5,040 cGy external beam radiation and continuous infusion 5-FU at a dose of 225 mg per m2) followed by
three additional months of gemcitabine or 5-FU. The study represents the first pancreatic adjuvant trial in several decades and serves as the foundation for further studies with contemporary radiation and chemotherapeutic approaches.
Locally Advanced Disease
Approximately 25% of patients have regional involvement at diagnosis, and treatment with combined chemotherapy and radiation has been shown to improve survival more significantly than treatment with either modality alone. In locally advanced, unresectable patients with good performance status, one commonly administered regimen is 4,500 to 5,400 cGy radiation with 5-FU at a dose of 500 mg/m2/day daily on the first and last 3 days of radiation (6). The treatment schema is identical to that used for adjuvant treatment of resectable disease. Median survival is approximately 10 months with treatment. Administration of non–split-course radiation and continuous infusion of 5-FU (maximum tolerated dose is 250 g/m2/day) are acceptable approaches.
Use of gemcitabine as a radiation-sensitizing agent is undergoing evaluation in patients with locally advanced disease. Initial studies of gemcitabine at a dose of 400 to 600 mg/m2/week and 5,040 cGy irradiation reported tolerability (mainly gastrointestinal toxicity and myelosuppresion) and objective responses in patients. Alternatively, in an effort to maximize the systemic effects of gemcitabine, a full dose of 1,000 mg per m2 every week has been combined with a maximally tolerated 4,200 cGy radiation (administered as 280-cGy fractions over 3 weeks). The 8- to 11-month median survival with gemcitabine radiosensitization is similar to that observed with 5-FU.
Several studies have evaluated the use of preoperative chemotherapy–radiation in an effort to convert unresectable to resectable disease. Despite reports of improvements, this approach is of limited benefit, and only 8% to 13% of patients will achieve a complete resection.
Approximately 50% of newly diagnosed pancreatic cancer patients have metastasis, and palliative treatment with systemic chemotherapy should be offered to patients with a good performance status [Eastern Cooperative Oncology Group (ECOG) 0–2]. Gemcitabine is the first-line standard treatment in patients with metastatic pancreatic cancer (7). This is based on a study in which 126 untreated patients were randomized to receive gemcitabine, 1,000 mg per m2 intravenously weekly for 3 of 4 weeks, or single-agent 5-FU, 600 mg per m2intravenous bolus weekly. Despite an objective response rate of less than 10%, a benefit in quality-of-life scores (clinical benefit response 23.8% versus 4.8%, [p = 0.0022) and median survival (5.7 versus 4.4 months, p = 0.0025) was observed with the gemcitabine therapy. The 1-year survival also favored the gemcitabine arm (18% versus 2%).
Several clinical trials studies attempting to surpass survival outcomes with gemcitabine alone have been performed. These two- and three-drug combination studies report median survival of 6 to 10 months and 1-year survival of approximately 20% to 35%. To overcome saturation of intracellular drug accumulation, prolonged
infusion of gemcitabine at a fixed-dose rate of 10 mg/m2/minute has also been evaluated in a phase II study by Tempero et al. (8). Gemcitabine at a dose of 1,500 mg per m2 given over 150 minutes resulted in a response rate of 11.6%, median survival of 8.0 months, and 1-year survival of 23.8%.
The combination of gemcitabine and oxaliplatin (GEMOX) is promising, as reported by Louvet et al. (9,10). In the initial study, 64 patients with pancreatic cancer (45% locally advanced, 55% metastatic) were treated with gemcitabine (1,000 mg per m2 at a fixed dose rate of 10 mg/m2/minute on day 1) followed by oxaliplatin (100 mg per m2 on day 2) on an every 2-week schedule. The objective response rate was 30.6% and the clinical benefit response was 40%. The median survival was 9.2 months and the 1-year survival was reported as 36%. Louvet recently reported results from a larger phase III study comparing 30-minute infusion of gemcitabine to the GEMOX regimen. Although response rate and progression-free survival favored GEMOX, no statistically significant improvement in 6-month and 1-year survival was observed. Possible explanations for the lack of survival benefit include the better-than-expected survival observed in the control arm and the use of second-line, platinum-containing regimens. Nonetheless, an ongoing Eastern Cooperative Group Study comparing standard 30-minute gemcitabine to fixed–dose-rate gemcitabine and to GEMOX will determine the impact of the fixed–dose-rate approach and the contribution of oxaliplatin.
Novel agents such as bevacizumab (Avastin) and cetuximab (Erbitux) are also being evaluated.
Pain remains a significant problem with pancreatic cancer and can be palliated with narcotics, external beam radiation, and, if indicated, a nerve block to an involved plexus. Biliary and intestinal obstruction is also a common local issue and can be relieved with stents or surgical bypass.
Whipple procedure followed by adjuvant chemoradiation with a continuous course of 45- to 50.4-Gy external beam radiation in 1.8-Gy fractions split course can be considered in older patients (allowing greater dosage adjustment secondary to toxicity) with
Locally Advanced Disease
For those patients with good performance status (PS 0–2), clinical trials are the preferred mode of treatment, with chemoradiation or gemcitabine available as standard treatments. The chemoradiation is given as described earlier, and chemotherapy after chemoradiation consists of
For those patients with poor performance status, supportive care is recommended. The goal of treatment for locally advanced disease is to prolong survival.
For patients with good performance status, clinical trials are the preferred mode of treatment, with gemcitabine or supportive care available as standard approaches.
The goal of treatment for metastatic disease is to decrease symptoms.