Preoperative Chemoradiation and Pancreaticoduodenectomy for Adenocarcinoma of the Pancreas

Douglas

B. Evans, MD;

Tyvin A. Rich, MD; David R. Byrd, MD;

Bernard Levin, MD;

Chusilp Charnsangavej, MD;

Chemoradiation prior to pancreaticoduodenectomy enthat all patients who undergo resection complete multimodality therapy, avoids resection in patients with rapidly progressive disease, and allows radiation therapy to be delivered to well-oxygenated cells before surgical devascularization. Twenty-eight patients with cytologic or histologic proof of localized adenocarcinoma of the pancreatic head received preoperative chemoradiation (fluorouracil, 300 mg/m2 per day, and 50.4 Gy) with the intent of proceeding to resection; all 28 completed this preoperative therapy. Hospital admission because of gastrointestinal toxic effects was required in nine patients, yet no patient experienced a delay in operation. Restaging was performed 4 to 5 weeks after completion of chemoradiation, and five patients were found to have metastatic disease; the 23 patients without evidence of progressive disease underwent laparotomy. At laparotomy, three patients were found to have unsuspected metastatic disease, three patients had unresectable locally advanced disease, and 17 patients were able to undergo pancreaticoduodenectomy. One perioperative death resulted from myocardial infarction, and perioperative complications occurred in three patients. Histologic evidence of tumor cell injury was present in all resected specimens. Our results suggest that ' coduodenectomy can be performed with a low incidence of complications after chemoradiation for localized adenocarcinoma of the pancreas. \s=b\

sures

(Arch Surg. 1992;127:1335-1339)

for pancreatic standard surgical The pancreaticoduodenectomy, 1935.1 al cribed treatment

cer

can¬

first des¬

remains the

Initially, high operative by Whipple et in morbidity and mortality rates led to technical modifications

of the operation that, combined with improvements in an-

Accepted for publication August 8,

1992. From the Departments of General Surgery (Drs Evans, and Ms Fenoglio), Clinical Radiotherapy (Dr Rich),

Byrd, and Ames, Pathology (Drs Cleary and Connelly), and Diagnostic Radiology (Dr Charnsangavej) and the Section of Gastrointestinal Oncology and Digestive Diseases (Dr Levin), The University of Texas

M. D. Anderson Cancer

Center,

Houston.

Presented at the 45th Annual Cancer Symposium of the Society of New York, NY, March 17, 1992. Reprint requests to the Department of General Surgery, Section of Endocrine Tumor Surgery, Box 106, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (Dr Evans).

Surgical Oncology,

Cleary, MD; John H. Connelly, Fenoglio, RN; Frederick C. Ames, MD

Karen R.

Claudia J.

MD;

esthesia and critical care, have resulted in current perioperative mortality rates of 2% or less.2"4 Surgery alone, however, has cured few patients with pancreatic adenocarcinoma, and controversy persists regarding the merits of resection

as a

palliative procedure.

External-beam radiation therapy and concomitant fluorouracil chemotherapy (chemoradiation) have been shown to be effective in local-regional control and in prolonging survival in patients with unresectable locally advanced pancreatic adenocarcinoma.5"7 Neither doxorubicin used as a radiation potentiator nor multidrug chemotherapy alone or continued after chemoradiation has been proven supe¬ rior to 5-fluorouracil chemoradiation.8-9 A prospective randomized study of adjuvant chemoradiation (5fluorouracil, 500 mg/m2 per day for 6 days, and 40 Gy of irradiation) following pancreaticoduodenectomy also demonstrated a survival advantage from multimodality therapy compared with resection alone.1011 However, five (24%) of the 21 patients in the adjuvant chemoradiation arm could not begin chemoradiation until more than 10 weeks after pancreaticoduodenectomy owing to a pro¬ longed recovery. This risk of delay in adjuvant therapy, combined with small published experiences of successful pancreatic resection following external-beam radiation therapy, prompted us to initiate a study in which chemo¬ radiation was given before pancreaticoduodenectomy for patients with potentially resectable adenocarcinoma of the

pancreas.1214 The use of preoperative chemoradiation is supported by the following considerations: (1) radiation therapy is more effective on well-oxygenated cells that have not been devascularized by surgery15; (2) radiation therapy before surgery may prevent implantation and dissemination of tumor cells at laparotomy, thereby decreasing subsequent peritoneal tumor recurrence1216; (3) potentially unresect¬ able tumors may be downstaged to enable surgical resec¬

patients with disseminated disease evident on restaging studies after chemoradiation will not be sub¬ jected to laparotomy; and (5) because radiation therapy and chemotherapy will be given first, delayed postopera¬ tive recovery will have no effect on the delivery of multimodality therapy, a frequent problem in adjuvant therapy tion12 -13; (4)

studies.10-17 However, surgeons have traditionally hesi¬ tated to perform pancreatic, biliary, and intestinal anasto¬ moses after external-beam radiation therapy because of the potential for anastomotic leak. Therefore, the objectives of this study were to determine the morbidity and mortality

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preoperative chemoradiation followed by pancreati¬ coduodenectomy in patients with adenocarcinoma of the pancreas and to document the radiologie and pathologic response to preoperative chemoradiation. of

Table

Treatment

Grade I

PATIENTS AND METHODS

Twenty-eight patients (15 men and 13 women) who were con¬ sidered by their attending surgeons to have potentially resectable disease were enrolled in our study between September 1988 and March 1991. All patients had cytologie or histologie proof of ad¬ enocarcinoma of the pancreatic head. Patients were required to have a Zubrod performance status of 2 or less (symptomatic; in bed less than 50% of the time) and no radiologie evidence of dis¬ tant metastatic disease. Symptomatic hyperbilirubinemia was corrected before treatment with endoscopie or percutaneous bil¬ iary drainage. Patients were also required to be able to maintain adequate oral nutrition with no significant nausea or vomiting before receiving chemoradiation. All patients had adequate bone marrow reserve as measured by a total white blood cell count of 3.0X109/L or greater, platelet count of 100xl09/L or greater, and adequate renal function as measured by a serum creatinine level of less than 130 u.mol/L with bilateral renal function. Pretreatment staging included chest roentgenography and computed to¬ mography (CT); angiography and laparoscopy were optional. Restaging with chest roentgenography and CT was performed 4 to 5 weeks following completion of chemoradiation; the attend¬ ing surgeon then decided whether to proceed with laparotomy. Patients received a full explanation of the purpose, procedures, and risks of the study and signed a statement of informed con¬ sent approved by the surveillance committee of The University of Texas M. D. Anderson Cancer Center, Houston.

Preoperative Chemoradiation Radiation therapy was delivered with 18-MeV photons to a to¬ tal dose (tumor minimum) of 50.4 Gy, prescribed to the 95% isodose, in 28 fractions over a period of 5Vi weeks (1.8 Gy/d, 5 d/wk). The radiation field included the primary tumor and a margin of 3 to 5 cm covering the pancreaticoduodenal, porta hepatis, and celiac axis lymph nodes. A 4-field "box" arrangement was used, with the anterior-posterior (AP) fields ranging from 10 to 15 cm2. The spinal cord dose was less than 40 Gy. Fluorouracil was given concurrently by continuous infusion at a dose of 300 mg/m2 per day, 5 d/wk, through a central venous catheter. The toxicity of chemoradiation was scored weekly using the toxicity scale (grade 1 to 4) described by Ajani et al.18 All treatment was initiated in an outpatient setting. If grade 3 toxicity was en¬ countered, chemotherapy was temporarily discontinued for 5 days and then resumed at a 25% reduced dose level. Patients were admitted to the hospital for intravenous hydration at the discre¬ tion of the attending surgeon and radiotherapist. No postopera¬ tive

chemotherapy was given.

Radiologie Assessment radiologically as an area of low density during a bolus phase of intravenous contrast-enhanced CT, performed at 1.5-, 5-, or 10-mm section thickness. The tumor size was measured along the AP and lateral Tumor was identified in the pancreatic head axes

before and after chemoradiation.

Surgery and Intraoperative Radiation Therapy All surgical resections were performed by surgical fellows or chief residents under the direction of two faculty members (D.B.E. and F.C.A.) using a standardized technique, as previously de¬ scribed.19 At resection, the common bile duct and pancreatic and retroperitoneal margins were submitted for frozen-section patho¬ logic evaluation, and the bile duct and pancreas were resected until negative margins were obtained. The pancreatic anastomo¬ sis was completed over a small Silastic stent (Dow Corning Corp, Midland, Mich) in two layers using either a duct-to-mucosa tech¬ nique or complete invagination of the pancreatic remnant. Two

for Chemoradiation 1.—Grading System Effect

II

Histologie Appearance cytologie changes of malignancy

Characteristic are present, but little (