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Neoadjuvant Chemoradiation for Localized Adenocarcinoma of the Pancreas

From the Departments of Surgery (RRW, BMC, TNP, DST), Medicine (HIH, MAM, JB, MSB, PSJ, KMM), Radiation Oncology (CL, MSA), Radiology (EKP), and Pathology (MRG); Duke University Medical Center, Durham, North Carolina

Correspondence: Address correspondence and reprint requests to: Douglas S. Tyler, MD, Duke University Medical Center, Box 3118, Durham, NC, 27710; Fax: 919-681-6701; E-mail: tyler002{at}duke.edu

	ABSTRACT

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Background: The use of neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer.

Methods: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy (EBRT; median, 4500 cGy) with 5-flourouracil–based chemotherapy. Tumors were defined as potentially resectable (PR, n = 53) in the absence of arterial involvement and venous occlusion and locally advanced (LA, n = 58) with arterial involvement or venous occlusion by CT.

Results: Five patients (4.5%) were not restaged due to death (n = 3) or intolerance of therapy (n = 2). Twenty-one patients (19%) manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors (53%) and 11 patients with initially LA tumors (19%) were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months.

Conclusions: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant (postoperative) CRT.

Key Words: Neoadjuvant therapy • Chemoradiotherapy • Adenocarcinoma • Pancreas

	INTRODUCTION

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Surgical resection traditionally has been considered the only way to "cure" adenocarcinoma of the pancreas. However, fewer than 10% of patients present with tumors that are amenable to resection, and long-term (5-year) survival after potentially curative resection is less than 20%.¹ Survival curves continue to drop off after 5 years and do not ever reach a plateau. Most patients have either occult metastatic disease or residual local disease following resection, and both distant and locoregional patterns of recurrence are common.

Multimodality therapy with surgery, radiation, and chemotherapy appears to improve local control and survival over surgery alone. Adjuvant 5-fluorouracil (5-FU)–based chemoradiation following resection improved median survival from 12 to 20 months in the landmark Gastrointestinal Tumor Study Group (GITSG) trial² and was associated with a similar survival benefit in a recent retrospective review of the large Johns Hopkins experience.¹ However, a consistent observation is that between 20% and 30% of patients do not receive planned adjuvant therapy following resection, for a variety of reasons.^1,3,4

Neoadjuvant (preoperative) CRT has several theoretical benefits over adjuvant therapy. First, making preoperative delivery the standard procedure ensures that chemoradiation is received by all patients and that it is received at a time when oxygen supply to the tumor is the greatest. Second, occult metastases are given the opportunity to manifest themselves, allowing these patients to avoid the morbidity of resection. Finally, preoperative therapy may downstage a minority of unresectable tumors to resectable lesions.

Experience with this approach has demonstrated that neoadjuvant therapy can be delivered safely and that resection can be performed following neoadjuvant therapy without increased morbidity or mortality. The large M. D. Anderson Cancer Center experience has suggested that preoperative chemoradiotherapy for potentially resectable tumors improves local recurrence and survival in resected patients.^3,5 Several other institutions have reported smaller studies of preoperative chemoradiotherapy for locally advanced tumors in which between 8% and 48% of tumors subsequently were resected.^6–12 At our institution, all patients with localized—potentially resectable or locally advanced—adenocarcinoma of the pancreas are considered candidates for neoadjuvant therapy. This article critically reviews our 5-year experience with 5-FU–based neoadjuvant chemoradiation in patients with potentially resectable and locally advanced pancreatic cancer.

	METHODS

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Between February 1995 and October 2000, 111 patients referred to our institution with pathologically confirmed adenocarcinoma of the pancreas received neoadjuvant 5-FU–based chemoradiotherapy (CRT). The characteristics of these patients are summarized in Table 1. All patients underwent thin-section, contrast-enhanced dynamic CT, and patients with evidence of distant metastatic disease were excluded. Many patients received CT scans at referring institutions; CT scans deemed adequate for the purpose of excluding metastatic disease were not repeated (30% of patients). Localized tumors were categorized as potentially resectable (PR) if (1) there was no evidence of direct invasion of the superior mesenteric artery (SMA) or celiac axis (CA) and (2) the superior mesenteric vein (SMV) and portal vein (PV) were patent. Tumors were categorized as locally advanced (LA) in the presence of soft tissue abutting or encircling the SMA or CA or occlusion of the SMV or PV. The current series includes 25 previously reported patients with locally advanced tumors.¹³

Various regimens of CRT were used. Thirty-eight patients (34%) received CRT at institutions closer to home. A planned total dose of 4500 cGy of external beam radiation therapy (EBRT) was delivered in 180-cGy fractions, 5 days per week, with or without a boost dose of 540 cGy to the tumor bed. All patients in this series received concurrent 5-FU–based chemotherapy for radiosensitization. The median total dose of EBRT received was 4500 cGy (range, 900–5040 cGy). The majority (n = 71) received infusional 5-FU alone; many patients also received bolus mitomycin-C on day 3 (n = 17), infusional cisplatin (n = 4), or the combination of 5FU, mitomycin-C, and cisplatin (n = 13). Six patients received an oral formulation of 5-FU as part of a phase I clinical trial.

Following CRT, patients were given a 3- to 4-week break for recovery of blood counts and nutrition before restaging CT was done. Patients were reclassified as having potentially resectable, locally advanced, or metastatic disease on the basis of restaging CT. The decision whether to explore patients without evidence of metastatic disease surgically was made by the attending surgeon and was based on restaging CT information, fitness for surgery, and need for surgical palliation. All surgeries—except for two resections at outside institutions—were performed by one of two attending surgeons (TP and DT). At the time of resection, the biliary and pancreatic margins were submitted for frozen section analysis and re-resected if positive. The retroperitoneal margin was marked with suture by the surgeon and evaluated by permanent section analysis.

Patient records were maintained in a prospective database (Microsoft Access) and supplemented by information obtained from retrospective review of hospital and physician records. Data were evaluated for statistical difference by two-tailed Fisher’s exact test for comparison of ratios and the Student’s t-test for comparison of continuous variables. Survival was calculated from the date of pathologic diagnosis and analyzed by the method of Kaplan and Meier (Statistica for Windows, Statsoft, Tulsa, OK).

	RESULTS

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Chemoradiotherapy
Three deaths occurred prior to restaging. A 76-year-old patient with a PR tumor and a history of coronary artery disease died of an acute myocardial infarction during CRT. The post-CRT death at an outside institution of a 62-year-old patient with a LA tumor was attributed to peritonitis secondary to bowel perforation. The most recent death occurred in early 1998, when a 67-year-old patient with a PR tumor died during CRT of cholangitis due to biliary stent malfunction; this death occurred at an outside institution.

Nine patients (8%), including the two patients who died during CRT, received < 4000 cGy of EBRT. Of 73 patients who received CRT at our institution and for whom consistent data are available, 49% required either interruption of CRT or reduction of the dose of at least one chemotherapeutic agent due to treatment toxicity. Significant toxicity occurred in 17 of 23 patients (74%) treated through 1996, as compared to 19 of 50 patients (38%) treated after 1996, when the use of cisplatin was discontinued (P < .01). Overall, 38 patients (52%) required unplanned hospitalization prior to restaging. Hospitalization was related to gastrointestinal toxicity (nausea, vomiting, diarrhea, mucositis) in 60% and hematopoietic toxicity (neutropenia, thrombocytopenia) in 12% of patients. Other indications for hospitalization included biliary tract obstruction (n = 6), jejunostomy tube malfunction (n = 2), deep vein thrombosis (n = 2), central line sepsis (n = 1), and pancreatic fluid collection (n = 1). No significant difference in hospitalization rates was seen between patients with jejunostomy tubes (23 of 44 patients [52%]) and patients without jejunostomy tubes (14 of 29 patients [48%]) or between patients with PR tumors (16 of 30 patients [53%]) and patients with LA tumors (22 of 43 patients [51%]). Despite moderate toxicity, 95% of patients were radiographically restaged in preparation for surgical therapy, and the median time interval from diagnosis to surgical exploration was 105 days (Fig. 1).

View larger version (18K): [in this window] [in a new window]   FIG. 1. Median time intervals from pathologic diagnosis to the initiation of neoadjuvant therapy, from the initiation to the end of therapy, and from the end of therapy to surgical exploration are shown.

View larger version (17K): [in this window] [in a new window]   FIG. 2. Fifty-three patients with potentially resectable tumors on initial CT received neoadjuvant chemoradiotherapy (CRT). Following CRT, 50 patients underwent restaging CT, and tumors were reclassified as potentially resectable, locally advanced, or metastatic. Thirty-seven patients with localized tumors were explored, and 28 patients underwent resection.

Standard Whipple pancreaticoduodenectomy was performed in 25 patients, pancreaticoduodenectomy with SMV reconstruction in 2 patients, and distal pancreatectomy in 1 patient. Surgical margins were negative in 20 of 28 patients (71%); 8 patients, all of whom underwent standard pancreaticoduodenectomy, had positive retroperitoneal margins. Lymph nodes were negative in 19 of 27 patients (70%); the lymph node status of one patient resected at an outside institution was not available. Two patients—including the patient resected at an outside institution—died within 30 days of surgery due to sepsis and multisystem organ failure. Significant postoperative complications occurred in 11 additional patients (39%) and included reoperation for gastrojejunostomy bleeding (n = 1), delayed gastric emptying (n = 4), amylase-poor fluid collection requiring percutaneous drainage (n = 2), chylous leak (n = 2), and enterocutaneous fistula requiring short-term TPN (n = 1). Superficial wound infections were identified in 8 patients (29%). The median postoperative length of stay was 12 days (range, 7–28 days).

Locally Advanced Tumors
Two of 58 patients with LA tumors were not restaged, due to death in one patient and intolerance of therapy in one elderly patient (Fig. 3). Eleven of 56 restaged patients (20%) demonstrated distant disease progression. Thirty-nine patients (70%) appeared to have persistent LA disease on restaging CT. LA tumors were radiographically "downstaged" to PR tumors in 6 patients (11%). All 6 patients with radiographic responses previously had been considered to have LA tumors on the basis of arterial abutment but not encasement on CT, and arterial involvement had been confirmed in one patient previously explored at our institution.

View larger version (16K): [in this window] [in a new window]   FIG. 3. Fifty-eight patients with locally advanced tumors on initial CT received neoadjuvant chemoradiotherapy (CRT). Following CRT, 56 patients underwent restaging CT. Twenty-eight patients with localized tumors were explored, and 11 patients underwent resection.

Standard Whipple pancreaticoduodenectomy was performed in 9 patients, distal pancreatectomy with SMV and PV reconstruction in one patient, and a pancreatic neck resection in one patient with dense adhesions and minimal residual tumor. Surgical margins were negative in 8 of 11 patients (73%). The retroperitoneal margin was positive in the one patient who underwent SMV and PV reconstruction and in the one patient with narrowing of the SMA on restaging CT, and the pancreatic body margin was positive in one patient who was not considered curable by total pancreatectomy. Lymph nodes were negative in 6 of 10 patients (60%) and were not assessed in the patient who underwent local excision. There were no postoperative deaths, but significant complications in 6 patients (55%) included reoperation for gastrojejunostomy obstruction (n = 2), reoperation for fistula between the transverse colon and gastrojejunostomy anastomosis (n = 1), pancreatic leak (n = 1), delayed gastric emptying (n = 1), chylous leak (n = 1), and enterocutaneous fistula requiring short-term total parenteral nutrition (TPN; n = 1). Superficial wound infections were identified in 4 patients (36%). The median postoperative length of stay was 12 days (range, 5–71 days).

Pathologic Results and Survival Following Resection
Histologic examination of all 39 resection specimens revealed significant fibrosis in all tumors, including two patients with pathologic complete responses. Resection margins were negative in 28 of 39 specimens (72%), and lymph nodes were negative in 26 of 37 specimens (70%) in which lymph node status was available. Of 39 patients who underwent resection, 19 patients (51%) had negative margins and lymph nodes.

The median survival for the entire group of resected patients has not been reached at a median follow-up of 16 months. Actuarial 1-, 2-, and 5-year survival rates are 80%, 32%, and 28%, respectively. Seventeen patients are currently disease-free at a median follow-up of 17 months. Four patients who were curatively resected died with no evidence of recurrent disease. One patient developed narcotic dependence and ultimately died from complications of inanition at 5 months after operation. A second death—in a patient with a complete pathologic response—occurred following bowel perforation sustained during feeding jejunostomy tube exchange at 7 months after operation. A third patient died 6 months after resection following removal of an infected hip prosthesis, and a fourth patient died of an undefined malabsorption syndrome 1 year after resection. Sixteen patients are deceased (n = 14) or alive with disease recurrence (n = 2); the first documented site of recurrence was locoregional in 4 patients and distant in 12 patients.

Patients resected following neoadjuvant CRT were compared to patients treated over the same time period by the same two attending surgeons with the traditional approach of resection followed by adjuvant CRT (this approach was taken because the adenocarcinoma had not been diagnosed preoperatively). Because of the small number of patients resected with distal lesions, only patients with tumors of the head, neck, or uncinate process were compared. Eleven patients with PR tumors were identified who underwent standard pancreaticoduodenectomy (n = 10) or pancreaticoduodenectomy with PV reconstruction (n = 1) for adenocarcinoma of the pancreas without preoperative CRT. The characteristics of three groups of patients are shown in Table 2: patients with PR tumors resected before CRT (resection > postop CRT) and patients with PR and LA tumors treated with CRT before resection (PR > CRT > resection and LA > CRT > resection); arrows indicate progression. Because of the prerequisite for preoperative tissue diagnosis for entry into neoadjuvant protocols, patients treated with CRT before resection might be expected to have larger primary tumors than patients resected without a preoperative diagnosis. However, pathologic tumor size in preoperatively irradiated specimens was not larger than that in nonirradiated specimens, suggesting possible tumor downsizing as a result of CRT. Despite comparable tumor size, patients treated preoperatively were more likely to have negative surgical margins (P = .04). Overall survival curves for these three groups are shown in Figure 4. Although small numbers of patients preclude meaningful statistical comparisons, these curves are virtually identical until 24 months.

View larger version (18K): [in this window] [in a new window]   FIG. 4. Overall survival in patients with proximal tumors who underwent resection followed by adjuvant CRT (Postop) was compared to patients with potentially resectable tumors (PR > CRT) and locally advanced tumors (LA > CRT) who underwent neoadjuvant CRT prior to resection.

	DISCUSSION

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The EORTC study illustrates the primary disadvantage of postoperative therapy: even in the setting of a randomized trial, 20% of patients did not receive the benefits of multimodality therapy due to death, complications, or delayed recovery. The percentage of patients who do not receive planned adjuvant therapy following resection likely is even higher at low-volume centers.¹⁹ The chief advantage of preoperative delivery of CRT is that all patients thereby receive what may be the more beneficial therapy for the majority of patients who harbor occult metastatic disease. For these patients, resection provides minimal survival benefit.²⁰ Preoperative CRT allows patients with occult metastatic disease to manifest themselves and avoid the morbidity of resection. Thus, preoperative CRT helps to select patients who stand to benefit the most from aggressive surgical therapy.

In our series, 20% of patients demonstrated distant disease progression—which was likely present at the time of diagnosis—on restaging CT following preoperative CRT. This may be lower than the rate of 26% in the M. D. Anderson Cancer Center experience³ due to our greater use of staging laparoscopy to exclude small-volume metastatic disease before CRT.²¹ Because adequate palliation usually can be accomplished through endoscopic and laparoscopic approaches, most of these patients can avoid laparotomy altogether.

Neoadjuvant Therapy for Potentially Resectable Tumors
For patients with potentially resectable (PR) tumors by CT criteria, proponents of primary surgical therapy argue that patients with local progression or complications during preoperative CRT may miss an opportunity for curative resection. Only 3 of 40 patients (8%) without evidence of distant metastatic disease on restaging CT were not explored; only 3 explored patients were unresectable due to locoregional disease alone. Therefore, although 18% of patients demonstrated local disease progression on restaging CT, at most 6 of 53 patients (11%) with initially PR tumors were unresectable due to local progression alone, a rate similar to that expected for surgical exploration without preoperative CRT. Furthermore, although preoperative CRT was associated with moderate toxicity, the "loss" of otherwise curable patients to toxicity fortunately was uncommon and has diminished with experience. In addition to the use of less toxic agents, the ability to support patients medically through CRT continues to improve.

Of the 37 patients with initially PR disease "selected" for surgical exploration, 28 patients (76%) were resected, with high rates of negative surgical margins and negative lymph nodes. Resection was accomplished with acceptable morbidity and mortality. Although median survival has not been reached, the 5-year actuarial survival of resected patients with PR tumors of the proximal pancreas (32%) is comparable to that in the more mature M. D. Anderson Cancer Center experience (23%).⁵

Neoadjuvant Therapy for Locally Advanced Tumors
For patients with locally advanced (LA) tumors by CT criteria, the potential benefits of neoadjuvant CRT clearly outweigh the risks. With current-generation CT scanning, radiographic evidence of unresectability is more than 90% predictive of unresectability at exploration.^22–24 Therefore, initial laparotomy rarely is therapeutic and usually is unnecessary for palliation, if endoscopic biliary drainage is adequate.²⁵ Furthermore, CRT is considered to be standard-of-care palliation of locally unresectable disease. Chemoradiotherapy has been associated with improvement in pain and obstructive symptoms as well as a small survival benefit over chemotherapy alone.^26,27

Our experience has been that radiographic responses to CRT are modest and often underestimate pathologic responses. The replacement of tumor with fibrosis—which typically is observed on histologic examination of resected surgical specimens—may result in little or no change in radiographic appearance. In our experience, approximately 10% of tumors considered to be "locally advanced" on restaging CT are subsequently resected with negative margins.²¹ Although the vast majority of patients with arterial encasement on restaging CT are truly unresectable, the appearance of arterial abutment on restaging CT may represent sterile fibrosis at exploration.²¹ Therefore, postchemoradiotherapy CT may overestimate unresectability to a greater extent than does prechemoradiotherapy CT. Following neoadjuvant or palliative CRT in our series, 11 of 58 initially LA tumors (19%) were resected, suggesting that tumor downstaging does occur in a minority of patients. Two of 9 patients (22%) who had previously been unresectable at exploratory laparotomy were resected following CRT. Resection was accomplished in these 11 patients with rates of venous resection, postoperative morbidity, and positive surgical margins comparable to patients with initially PR tumors.

	CONCLUSIONS

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Multimodality therapy appears to improve survival in patients with localized pancreatic cancer. However, whether therapy should be given preoperatively or postoperatively remains controversial, and a randomized trial has not been attempted and would be difficult to perform. Meanwhile, in our experience, at least 20% of patients manifest distant metastatic disease during preoperative CRT and avoid the morbidity of resection. Almost 20% of LA tumors are resected following CRT, and median survival in all resected patients has not been reached at a median follow-up of 16 months. Thus, 5-FU-based neoadjuvant CRT downstages a minority of patients with LA tumors and helps to optimize selection for resection in patients with PR tumors.

More recent neoadjuvant approaches have included the rapid-fractionation of EBRT (30 Gy over 2 weeks) to increase the biologic efficacy and shorten the course of preoperative therapy. Initial results from MDACC suggest that toxicity is decreased,²⁸ and no difference in survival following resection has been observed between patients receiving standard-fractionation (45 or 50.4 Gy) and rapid-fractionation (30 Gy) EBRT.⁵ In addition, other radiosensitizing agents, such as gemcitabine and paclitaxel, have shown promise in phase I trials.^29,30 More effective and less toxic regimens are necessary for neoadjuvant therapy to realize the ultimate goal of maximizing the number of patients who receive curative resections.

	Footnotes

 
Presented at the 54th Annual Meeting of the Society of Surgical Oncology, Washington, DC, March 15-18, 2001.

Received for publication March 17, 2001. Accepted for publication August 3, 2001.

	REFERENCES

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