Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma

Authors: Vincent J. Picozzi, M.D., Richard A. Kozarek, M.D., L. William Traverso, M.D.
Affiliation: Virginia Mason Medical Center, Seattle, WA, USA
Source: Am J Surg. 2003 May; 185(5):476-80

Background

Historically, 5-year survival rates in patients with locally advanced pancreatic cancer have been dismal (<10%), even following a Whipple resection. Disease recurrence is typically both local and distant. Further advances in the management of pancreatic cancer led to the incorporation of chemotherapy and radiotherapy following surgery, with a subsequent improvement in 2-year survival from 18% to 43% according to the GITSG studies. In 2000, Nukui et al reported the results of a phase II study using more aggressive chemoradiation in addition to interferon for the treatment of locally advanced pancreatic cancer. The study employed continuous infusion 5-FU, weekly cisplatin, and subcutaneous interferon concurrent with radiation in the post-operative setting. The rationale for interferon was possible enhancement of tumoricidal effects of certain chemotherapeutic agents. The authors reported a 2-year survival rate of 84% with this aggressive treatment approach. This current article by Picozzi et al serves as an update to the results reported by Nukui et al in 2000.

Materials and Methods

• A cohort of 43 patients were evaluated, all with ductal adenocarcinoma of the pancreatic head and of pancreatic origin
• Primary tumors of the distal common bile duct, ampulla, and duodenum were excluded
• All patients underwent pancreaticoduodenal resection (Whipple)
• Approximately 6-8 weeks following resection, patients were begun on concurrent chemo-radiation as well as interferon therapy
• Radiation therapy was external beam, 45 Gray (Gy) – 54 Gy, given over 5 weeks in 25 daily fractions, delivered to the pancreatic bed
• Chemotherapy consisted of continuous infusion 5-FU (200mg/m2) on days 1-35 and weekly cisplatin (30mg/m2) on days 1, 8, 15, 22, and 29
• Interferon was given as a subcutaneous injection, 3 million units QOD for 5 weeks
• All patients received adjuvant chemotherapy in the form of 5-FU (200mg/m2) on days 64-105, then again on days 120-161
• Several factors were analyzed, including resection type, blood loss, nodal status, treatment toxicity, and survival
• Follow-up was obtained by telephone contact, and evidence of relapse was determined by physical examination, CXR, and CT scans
• Statistical evaluation was done using Kaplan-Meier analysis

Results

• Between 1995-2002, 43 patients were accrued, with a median patient age of 62 years
• Median patient follow-up was 21.8 months (range of 4-86 months)
• All but 7% of patients had pylorus-preserving surgery, and 2 had total pancreatectomies
• Two percent of patients had stage I disease, 12% had stage II, 72% had stage III, and 14% had stage IVa disease
• Eighty-four percent of patients had positive lymph nodes with an average of 2.2 nodes per patient
• With regard to histology, 26% were poorly differentiated, and there was perineural invasion in 68% of samples
• A total of 19% patients had gross or microscopic positive margins
• Ninety-five percent of patients completed their radiation course
• Ninety-three percent of patients received greater than 85% of the intended 5-FU dose, while the last dose of cisplatin was held in 28% of patients
• With regard to adjuvant chemotherapy, 56% of patients got 100% of the intended 5-FU dose, and 70% received >85% of the intended dose
• Treatment-related toxicity was mostly gastrointestinal, with grade 3 toxicity in 70% of the patients; 70% had some form of delay in their chemoradiotherapy, while 43% of patients were hospitalized for treatment-related toxicity
• Actuarial overall survival at 1, 2, and 5 years was 95%, 64%, and 55% respectively; disease-free survival was 67%, 52%, and 52% at 1, 2, and, 5 years respectively

Discussion

• When compared to other studies using adjuvant chemotherapy, the results of this study demonstrate the highest survival rates to date, and thus are very encouraging
• However, this improvement in survival comes at the cost of significantly increased treatment-related toxicity requiring hospitalization in 42% of patients
• Though toxicity was high, there was no treatment-related mortality
• There was no mention of the performance status of enrolled patients, but one should assume that patients were carefully selected for this aggressive treatment regimen
• All surgeries were performed at a single institution with one surgeon performing 91% of the resections; it will be interesting to see if the same results will hold when surgery is performed at other centers.