Bethesda Handbook of Clinical Oncology, 2nd Edition

Digestive System

9

Pancreatic Cancer

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

EPIDEMIOLOGY

• In 2004, it was estimated that 31,860 new cases of pancreatic cancer would have been diagnosed and 31,270 patients would have died from this malignancy.
• It is the fourth leading cause of death from cancer in the United States.
• The 5-year survival of patients with pancreatic cancer remains less than 5%.
• Men and African Americans are at a higher risk for developing pancreatic cancer and thus exhibit higher mortality rates.
• Incidence of pancreatic cancer increases at the age of 50 and peaks in the seventh decade (Table 9.1).

Pathophysiology

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.

• Pain caused by localized disease is usually described as mid to upper back pain resulting from tumor invasion of the celiac and mesenteric plexi.
• Most patients develop glucose intolerance and some degree of pancreatic insufficiency.
• K-rasmutations are associated with most cases of pancreatic cancer (see Fig. 9.1).
• Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm are relatively benign lesions, but the presence of severe dysplasia or invasion warrant further investigation and probable resection. Despite the evolution of malignant clones within these lesions, the overall survival is better than with ductal adenocarcinoma.

STAGING

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).

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PROGNOSIS

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).

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DIAGNOSIS

• Screening tests:There are no good screening tests for pancreatic cancer. CA 19-9, a sialated Lewis antigen, is elevated in 70% to 90% of patients with pancreatic cancer; however, it is not useful as a screening test because of low specificity. The CA 19-9 may have greater utility in monitoring recurrent or advanced disease.
• Imaging techniques:Imaging techniques include chest radiographs, abdominal computerized tomography (CT), ultrasound, endoscopic retrograde cholepancreatography (ERCP), and endoscopic ultrasound (EUS):
• –Dual-phase contrast, helical CT—its sensitivity is 67% for lesions <1.5 cm and almost 100% for tumors >1.5 cm; it has a 95% positive predictive value in defining resectability if major vessel tumor encasement is present.
• –Endoscopic ultrasound—it is excellent for tumor and nodal staging, and also for detecting the presence of portal vein invasion; fine needle aspiration (FNA) is used for diagnosing tumor with minimal risk; it is also used for visualizing and sampling hepatic lesions; limitations include assessment of blood vessel encasement or superior mesenteric artery (SMA) invasion.
• –Pathologic diagnosis may be achieved with ERCP, laparoscopy, peritoneal cytology, or CT-guided biopsy.
• Most common metastasis to pancreas is from renal cell cancers.

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MANAGEMENT

For management considerations, pancreatic cancer can be divided into resectable disease (potentially curable), locally advanced disease, and metastatic disease (see Fig. 9.3).

Resectable Disease

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

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(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

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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.

Metastatic Disease

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

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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.

• Abbruzzese (11) evaluated gemcitabine and cetuximab (initial dose of 400 mg per m²followed by 250 mg per m² weekly) in a trial with 41 patients and observed a partial response rate of 12.5%, median survival of 6.7 months, and 1-year survival of 33%.
• Kindler et al. (12) evaluated gemcitabine and Avastin (10 mg per kg every 2 weeks) in a trial with 19% partial response rate and with 48% of patients exhibiting stabilized disease symptoms; median survival was 8.7 months, time to progression was 5.8 months, and 1-year survival was 29%.

Palliation

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.

TREATMENT OPTIONS

Localized Disease

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

• 5-FU, 500 mg/m²/day by intravenous bolus for the first 3 days of each 20-Gy segment of radiotherapy (total dose per 3-day course of fluorouracil, 1,500 mg per m²), or alternatively, 5-FU, 225 to 250 mg/m²/day continuous infusion concomitantly with radiation followed by

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• gemcitabine, 1,000 mg/m²/week intravenously weekly for 3 weeks (days 1, 8, and 15) followed by 1 week without gemcitabine for 4 to 6 months.

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

• gemcitabine, 1,000 mg/m²/week intravenously weekly for 3 weeks (days 1, 8, and 15) followed by 1 week without gemcitabine. Treatment cycles are repeated every 28 days for 4 to 6 months.

For those patients with poor performance status, supportive care is recommended. The goal of treatment for locally advanced disease is to prolong survival.

Metastatic Disease

For patients with good performance status, clinical trials are the preferred mode of treatment, with gemcitabine or supportive care available as standard approaches.

• Gemcitabine, 1,000 mg/m²/week intravenous weekly for 3 weeks (days 1, 8, and 15), followed by 1 week without gemcitabine (total dose per cycle: 3,000 mg per m²). Treatment cycles are repeated every 28 days.

The goal of treatment for metastatic disease is to decrease symptoms.

References

1. American Joint Committee on Cancer. AJCC cancer staging manual, 6th ed. New York: Springer, 2002:157–164.
2. Gastrointestinal Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59:2006–2010.
3. Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. Ann Surg1997;225:621–636.
4. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg1999;230:776–784.
5. Neoptolemos JP, Stocken DD, Friess H, et al. European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med2004;350:1200–1210.
6. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic carcinoma: a randomised comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads) + 5-fluorouracil, and high dose radiation + 5-fluorouracil. Cancer1981;48:1705–1710.
7. Burris HA III, Moore MJ, Andersen J, et al. Improvements in clinical survival and clinical benefit with gemcitabine as first line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol1997;15:2403–2413.
8. Tempero M, Plunkett W, Ruiz Van Haperen V, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol2003;21:3402–3408.
9. Louvet C, Andre T, et al. Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study. J Clin Oncol2002;20:1512–1518.
10. Louvet C. GemOx (gemcitabine + oxaliplatin) versus Gem (gemcitabine) in non resectable pancreatic adenocarcinoma: final results of the GERCOR /GISCAD intergroup phase III. Proc Am Soc Clin Oncol2004;Abstract 4008.
11. Xiong HQ, Rosenberg A, LoBuglio A, et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol2004;22:2610–2616.
12. Kindler HL, Friberg G, Stadler WM, et al. Bevacizumab plus gemcitabine in patients with advanced pancreatic cancer: updated results of a multi-center phase II trial. Proc Am Soc Clin Oncol2004;23:314, Abstract 4009.