Tara M. Breslin, Nora A. Janjan, Jeffrey E. Lee, Peter W. T. Pisters, Robert A. Wolff, James L. Abbruzzese, Douglas B. Evans

Pancreatic Tumor Study Group: Departments of Surgical Oncology (TMB, JEL, PWTP, DBE), Radiation Oncology (NAJ), and Gastrointestinal Oncology and Digestive Diseases (RAW, JLA), The University of Texas M. D. Anderson Cancer Center, Houston, TX

Received 6/4/98 Accepted 5/5/98

6. MULTIMODALITY TREATMENT STRATEGIES

External-beam radiation therapy (EBRT) and concomitant 5-fluorouracil (5-FU) chemotherapy (chemoradiation) have been shown to prolong survival in patients with locally advanced adenocarcinoma of the pancreas (27). Those data were the foundation for a prospective, randomized study of adjuvant chemoradiation (500 mg/m2/day of 5-FU for 6 days and 40 Gy of radiation) following pancreaticoduodenectomy conducted by the Gastrointestinal Tumor Study Group (GITSG); that trial also demonstrated a survival advantage from multimodality therapy compared with resection alone(3, 5). However, because of a prolonged recovery, 5 (24%) of the 21 patients in the adjuvant chemoradiation arm could not begin chemoradiation until more than 10 weeks after pancreaticoduodenectomy. This, despite the obvious selection bias in patient accrual; the patients likely to be considered for protocol entry were those who recovered rapidly from surgery and had a good performance status. Similar findings have recently been reported from the European Organization for Research and Treatment of Cancer (EORTC). The EORTC initiated a study in 1987 comparing adjuvant 5-FU–based chemoradiation following pancreatectomy with surgery alone ( 28).>Between 1987 and 1995, 218 patients were randomized to receive either chemoradiation or no further treatment following pancreaticoduodenectomy for adenocarcinoma of the pancreas (55%) or periampullary region (45%). Median survival duration, reported in abstract form, was 23.5 months for those who received adjuvant therapy and 19.1 months for those who received surgery alone; subset analysis for patients with adenocarcinoma of pancreatic origin has not been reported. Importantly, 22% of those randomized to receive chemoradiation did not receive intended therapy due to postoperative complications or patient refusal. A similar selection bias is likely in effect when attempts are made to retrospectively compare patients who received postoperative adjuvant chemoradiation with patients who were treated only with pancreaticoduodenectomy.

Recently reported data from Yeo and colleagues at Johns Hopkins University add further support to the use of multimodality therapy (8). Those investigators reviewed all patients who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreatic head during a 4-year period. One-hundred and twenty patients received adjuvant chemoradiation, and 53 underwent pancreaticoduodenectomy alone. Median survival for those receiving adjuvant therapy was 19.5 months compared with 13.5 months for the group who received surgery alone.

The primary disadvantage of postoperative chemoradiation is the inability to deliver postoperative therapy to all patients in a timely manner because of perioperative complications or delayed recovery following pancreaticoduodenectomy. In contrast, if radiation therapy and chemotherapy are given first, delayed postoperative recovery will have no effect on the delivery of multimodality therapy. The first report of preoperative chemoradiaiton and pancreaticoduodenectomy from MDACC used a standard-fractionation treatment schema (19). Radiation therapy was delivered over 5.5 weeks with 18-MeV photons using a four-field technique to a total dose of 50.4 Gy, prescribed to the 95% isodose, at 1.8 Gy/fraction (28 fractions), 5 days/week. 5-fluorouracil (5-FU) was given concurrently by continuous infusion at a dosage of 300 mg/m2/day, 5 days/week, through a central venous catheter. The recently reported multicenter Eastern Cooperative Oncology Group (ECOG) trial documented the need for hospital admission in 51% of patients during or within four weeks of completing chemoradiation (4). This finding caused us to change the delivery of radiation therapy and 5-FU to a rapid-fractionation program of chemoradiation designed to avoid the gastrointestinal toxicity seen with our standard 5.5 week program while attempting to maintain the excellent local tumor control achieved with multimodality therapy (29). Rapid-fractionation chemoradiation was delivered over 2 weeks with 18-MeV photons using a four-field technique to a total dose of 30 Gy, prescribed to the 95% isodose, at 3 Gy/fraction (10 fractions), 5 days/week. 5-FU was given concurrently by continuous infusion at a dosage of 300 mg/m2/day, 5 days/week. This program was based on the principle that the total radiation dose required to obtain a given biological effect decreases as the dose per fraction increases. Restaging with chest roentgenography and abdominal CT was performed 4 weeks following completion of chemoradiation in preparation for pancreaticoduodenectomy. Thirty-five patients received this treatment, 27 were taken to surgery and 20 (74%) underwent successful pancreaticoduodenectomy. Local tumor control and patient survival were equal to our results with standard-fractionation (5.5 wks) chemoradiation (30).

In patients who receive chemoradiation prior to planned pancreaticoduodenectomy, a repeat staging CT scan after chemoradiation reveals liver metastases in approximately 25% (9). If these patients had undergone pancreaticoduodenectomy at the time of diagnosis, it is probable that the liver metastases would have been subclinical; these patients would therefore have undergone a major surgical procedure only to have liver metastases discovered soon after surgery. In the MDACC trials, patients who were found to have disease progression at the time of restaging had a median survival of only 7 months (9). The avoidance of a lengthy recovery period and the potential morbidity of pancreaticoduodenectomy in patients with such a short expected survival duration represents a distinct advantage of preoperative over postoperative chemoradiation. When delivering multimodality therapy for any disease, it is beneficial, when possible, to deliver the most toxic therapy last, thereby avoiding morbidity in patients who experience rapid disease progression not amenable to currently available therapies.

The survival advantage for the combination of chemoradiation and surgery compared with surgery alone (table 1) likely results from improved local-regional tumor control. Because of the poor rates of response to 5-FU–based systemic therapy in patients with measurable metastatic disease, it is unlikely that current chemoradiation regimens significantly impact the development of distant metastatic disease. Recent data from MDACC support this belief (6). Thirty-nine patients with biopsy-proven adenocarcinoma of the pancreatic head received preoperative infusional 5-FU (300 mg/m2/day, M-F) and external-beam irradiation (50.4 Gy) followed by pancreaticoduodenectomy and electron-beam intraoperative radiation therapy (10 Gy). Thirty-eight patients were evaluable for analysis of patterns of treatment failure; there was one perioperative death. Overall, there were 38 recurrences in 29 patients: 8 (21%) recurrences were local-regional (pancreatic bed and/or peritoneal cavity), and 30 (79%) were distant (lung, liver, and/or bone). The liver was the most frequent site of tumor recurrence, and liver metastases were a component of treatment failure in 53% of patients (69% of all patients who had recurrences). Fourteen patients (37% of all patients; 48% of patients who had recurrences) had liver metastases as their only site of recurrence. Isolated local or peritoneal recurrences were documented in only four patients (11%). In contrast, previous reports of pancreaticoduodenectomy for adenocarcinoma of the pancreas have documented local recurrence in 50% to 80% of patients (1). This improvement in local-regional control was seen despite the fact that 14 of 38 evaluable patients had undergone laparotomy with tumor manipulation and biopsy prior to referral for chemoradiation and reoperation. If these 14 patients were excluded, only two patients (8%) would have experienced local or peritoneal recurrence as any component of treatment failure. However, because of the large percentage of patients who developed distant metastatic disease, predominantly in the liver, improved local-regional tumor control translated into only a small improvement in median survival compared with that in other recently published studies. Therefore, in the absence of more effective systemic therapy, the goal of chemoradiation (preoperative or postoperative) and pancreatectomy should be to maximize local-regional tumor control while minimizing treatment time, treatment-related toxicity, and cost.

In an effort to compare preoperative and postoperative chemoradiation strategies we recently reported on the multimodality treatment of 142 consecutive patients with localized adenocarcinoma of the pancreatic head deemed resectable on the basis of pretreatment radiographic images (9). The subset of 41 patients who completed protocol-based preoperative chemoradiation and pancreaticoduodenectomy (27 patients received standard-fractionation chemoradiation (50.4 Gy) and 14 patients received rapid-fractionation chemoradiation (30 Gy) were compared to 19 patients who received pancreaticoduodenectomy and postoperative adjuvant chemoradiation. Overall median follow-up for these 60 patients was 19 months. No patient who received preoperative chemoradiation experienced a delay in surgery because of chemoradiation toxicity, but 6 (24%) of 25 eligible patients did not receive intended postoperative chemoradiation because of delayed recovery following pancreaticoduodenectomy. Patients treated with rapid-fractionation preoperative chemoradiation had a significantly (P < .01) shorter duration of treatment (median, 62.5 days) compared with patients who received postoperative chemoradiation (median, 98.5 days) or standard-fractionation preoperative chemoradiation (median, 91.0 days)(figure 1). No patient who received preoperative chemoradiation and pancreaticoduodenectomy experienced a local recurrence; peritoneal (regional) recurrence occurred in 10% of these patients. Local or regional recurrence occurred in 21% of patients who received pancreaticoduodenectomy and postoperative chemoradiation.

Despite the ability of surgeons to perform pancreaticoduodenectomy safely, it remains too extensive and complex a procedure to enable the consistent postoperative delivery of standard-fractionation adjuvant chemoradiation. In the absence of compelling data demonstrating superior survival results with either a preoperative or postoperative treatment approach, all available data suggests that a greater proportion of patients receive potentially beneficial adjuvant therapy when chemoradiation is administered in a neoadjuvant setting. Further, preoperative chemoradiation treatment strategies will spare a significant number of patients the morbidity and mortality associated with laparotomy, as up to one-fourth of patients will evidence metastatic disease at the time of preoperative restaging following chemoradiation.