Adjuvant Concurrent Chemoradiation for Node-Positive Adenocarcinoma of the Duodenum FREE

Primary malignancy of the small bowel is uncommon. As a result, our knowledge of the natural history, ideal management, and prognosis of patients with tumors of the small bowel is limited compared with other gastrointestinal malignancies. The American Cancer Society estimates that 2840 men and 2580 women will be diagnosed with cancer of the small bowel, and 1070 men and women will die of the disease in 2005.¹ Of newly diagnosed small-bowel cancers, approximately 40% are adenocarcinomas. Another 40% are carcinoids, 15% are sarcomas, and less than 5% are lymphomas.²

Adenocarcinoma of the small bowel most commonly arises in the duodenum. For these tumors, surgery has been the mainstay of definitive treatment. A variety of surgical options exist, including segmental resection, pancreaticoduodenectomy, and pancreas-preserving duodenal resection. Previously published data suggest that patients undergoing pancreaticoduodenectomy experience improved overall survival compared with those undergoing segmental resection.³ Because of the rare nature of adenocarcinomas arising in the duodenum, little information exists in the literature regarding adjuvant chemotherapy and radiation therapy. In the largest retrospective series of small-bowel adenocarcinoma from the National Cancer Data Base, only 15% of patients with duodenal adenocarcinoma received radiotherapy, while 21% received chemotherapy.⁴

Overall 5-year survival with surgery alone has been reported as 38% to 83% for node-negative patients and 15% to 53% for node- positive patients. The difference in 5-year survival between node-negative and node-positive patients appears to be especially pronounced in patients who undergo histologic examination of 15 or more regional lymph nodes.⁵ Barnes et al⁶ reported that lymph node metastases were significantly related to the occurrence of distant metastases in duodenal adenocarcinomas and suggested that patients with stage III disease should receive adjuvant therapy. It has been our policy to offer adjuvant chemoradiation therapy to all patients with node-positive disease. The purpose of this retrospective review is to report the results of patients with node-positive duodenal adenocarcinoma treated with pancreaticoduodenectomy and adjuvant chemoradiation therapy at a single, high-volume institution.

After receiving approval from our institutional review board, we reviewed all cases of patients with duodenal adenocarcinoma who were treated with adjuvant chemotherapy and concurrent external beam radiation therapy at The Johns Hopkins Hospital between 1994 and 2003. We identified a total of 14 patients who met inclusion criteria, which included the presence of histologically confirmed nonmetastatic adenocarcinoma arising in the duodenum, resected by pancreaticoduodenectomy, and treated with adjuvant therapy at our institution. All patients in this study had pN1 disease.

All patients underwent pancreaticoduodenectomy. The standard surgical approach at our institution is as follows: a standard pancreaticoduodenal resection without extended retroperitoneal lymph node dissection is performed with a partial pancreatectomy, leaving the body and tail of the pancreas intact. A pylorus-preserving approach is standard with distal gastric resection added for cancers involving the distal stomach or first portion of the duodenum. Pancreaticenteric reconstruction is accomplished by pancreaticojejunostomy or pancreaticogastrostomy.^7- 8

All pathology specimens were reviewed to determine the primary pathologic diagnosis and extent of the disease. Lymph nodes were considered positive if any lymph node in the re section specimen contained a tumor, whether it was involved by direct extension or was not contiguous with the primary tumor. Resection margins were considered positive if the adenocarcinoma was present at the final pancreatic neck, uncinate process, bile duct, or duodenal or retroperitoneal soft tissue margin.

All patients received adjuvant external beam radiation therapy, and all were offered fluorouracil-based concurrent and maintenance chemotherapy. Eight patients received concurrent fluorouracil, leukovorin, dipyridamole, and mitomycin C, followed by maintenance chemotherapy with the same agents as part of an institutional study investigating those agents in periampullary carcinomas. Two patients received concurrent fluorouracil with no maintenance therapy; 2 received concurrent fluorouracil and leucovorin, followed by maintenance with the same agents; 1 patient received concurrent fluourouracil and cisplatin; and 1 patient refused chemotherapy.

All patients received external beam radiation therapy using a computed tomography–based treatment plan employing 3 or 4 fields. The median dose was 5000 cGy (range, 4000-5760 cGy). Median dose per fraction was 180 cGy (range, 180-250 cGy). Patients were treated with 1 fraction per day, 5 days per week.

Patient follow-up was obtained from paper and electronic hospital charts. Survival was determined and cross-checked by review of clinical follow-up, a cancer center abstracting service, the Social Security Death Index, and an Internet obituary index.⁹ Statistical analysis was performed using MedCalc statistical software (Mariakerke, Belgium).

A total of 14 patients met inclusion criteria: 10 men and 4 women. The median age at diagnosis was 54.5 years (range, 36-66 years). Symptoms at presentation included abdominal pain,¹⁰ jaundice,⁶ weight loss,⁶ pruritis,² and nausea and vomiting³ (Table 1).

All patients in this study underwent pancreaticoduodenectomy. Median tumor size was 3.2 cm in diameter. All patients included in this analysis had lymph node involvement. Half of the patients had moderately differentiated tumors, and half had poorly differentiated tumors. According to the 2002 American Joint Committee on Cancer TNM staging system, 9 patients had T3 tumors, while 5 patients had T4 tumors. All patients had N1 disease, and all were classified as stage III.

Median follow-up was 12 months for patients who died and 42 months for those who survived. The median survival for all patients was 41 months, with a 5-year survival rate of 44% (Figure 1).

Seven out of the 14 patients in this analysis experienced recurrent disease; all of those patients died of their disease. One of these 7 patients failed both locally and distantly with abdominal carcinomatosis, while the other 6 failed with distant metastatic disease. Of those 6 patients, 3 patients had abdominal carcinomatosis, 2 had lung metastases, and 1 had liver metastases. Local control for all patients in the study was 93%.

Survival data for a series of patients with adenocarcinoma of the duodenum treated by surgery alone at The Johns Hopkins Hospital was reported by Yeo et al.¹⁰ A total of 17 patients were included in that report. Table 2 presents differences between that group of patients and our patient group. The 5-year survival rate in the group of patients reported by Yeo et al¹⁰ was 59%, compared with 44% in this analysis. The percentage of patients with positive nodes, however, was only 65% in the previous report and is 100% in this analysis. Rates of positive margins and degree of differentiation were similar between the 2 groups of patients. A separate comparison was made between 11 patients included in the previous report with lymph node involvement treated with surgery alone, and the 14 patients included in this study with lymph node involvement treated with adjuvant therapy. Median survival appears to be improved with the use of adjuvant therapy (41 months vs 21 months). Overall survival at 5 years, however, was not different between the 2 groups (Figure 2).

This report represents the largest single-institution retrospective series of adjuvant chemoradiation after pancreaticoduodenectomy for node-positive adenocarcinoma of the duodenum. The median survival was 41 months, with a 5-year survival of 44%.

Compared with historical controls from our own institution, the use of adjuvant chemoradiation therapy in such patients seems to improve median survival, but does not improve overall survival at 5 years. This finding is consistent with a previously published retrospective analysis of 48 patients treated at our institution from 1984 to 1996. In that study, Sohn et al³ found that pancreaticoduodenectomy, negative resection margins, and tumors in the first and second portions of the duodenum were favorable predictors of long-term survival by univariate analysis, while use of adjuvant chemoradiation was not; the 5-year survival rate in patients treated with adjuvant chemoradiation therapy was 39%.

The use of adjuvant chemoradiation therapy in node-positive adenocarcinoma of the duodenum may improve local control. Local control for patients treated with adjuvant chemoradiation therapy in this study was 93%. Barnes et al⁶ published a single-institution retrospective series of 36 patients with duodenal adenocarcinoma treated with surgery alone. They reported a 50% disease recurrence rate, identical to the results of this study. The reported local control with surgery alone, however, was only 67%.

There are a number of limitations to this study. Because of its retrospective nature, patients were not randomly assigned to receive certain types of therapy. The use of historical controls also introduces potential selection bias to this study. This study is small and may be underpowered to show a potentially significant benefit to adjuvant therapy. The chemotherapy administered in this study, while fluorouracil based, was not uniform among all patients. The radiation therapy dose and treatment fields, while similar, were also not identical. The effects of these potential biases on the outcome of this study are unknown.

In conclusion, adjuvant chemoradiotherapy for node-positive duodenal adenocarcinoma after pancreaticoduodenectomy may improve local control and median survival but does not appear to improve overall survival. All patients who had disease recurrence in this study died of distant metastatic disease, highlighting the need for improved systemic therapy for this disease. Given the rarity of this tumor, a multi-institutional trial is needed to further elucidate the role of adjuvant therapy in this disease.

Correspondence: Deborah A. Frassica, MD, Department of Radiation Oncology, 401 N Broadway, Suite 1440, Baltimore, MD 21231.

Accepted for Publication: January 28, 2006.

Author Contributions:Study concept and design: Swartz, Hughes, Yeo, Laheru, and Abrams. Acquisition of data: Swartz, Hughes, Riall, Lillemoe, and Abrams. Analysis and interpretation of data: Swartz, Hughes, Frassica, Herman, Cameron, Donehower, and Hruban. Drafting of the manuscript: Swartz and Hughes. Critical revision of the manuscript for important intellectual content: Swartz, Hughes, Frassica, Herman, Yeo, Riall, Lillemoe, Cameron, Donehower, Laheru, Hruban, and Abrams. Statistical analysis: Hughes. Administrative, technical, and material support: Swartz, Yeo, Lillemoe, Donehower, Laheru, and Hruban. Study supervision: Frassica, Herman, Cameron, and Laheru.

Financial Disclosure: None reported.