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ORIGINAL ARTICLES |
From the Departments of Surgical Oncology (TMB, DBH, MEJ, APD, JNV, JEL, PWTP, DBE), Biostatistics (KRH), Pathology (KRC), Gastrointestinal Oncology (RAW, JLA), and Radiation Oncology (NAJ, CHC), The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Correspondence: Address correspondence and reprint requests to: Douglas B. Evans, MD, Department of Surgical Oncology, Box 444, UT M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; Fax: 713-745-4426; E-mail: devans{at}mdanderson.org
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Data on 132 consecutive patients who received preoperative chemoradiation followed by pancreaticoduodenectomy for adenocarcinoma of the pancreatic head between June 1990 and June 1999 were retrieved from a prospective pancreatic tumor database. Patients received either 45.0 or 50.4 Gy radiation at 1.8 Gy per fraction in 28 fractions or 30.0 Gy at 3.0 Gy per fraction in 10 fractions with concomitant infusional chemotherapy (5-fluorouracil, paclitaxel, or gemcitabine). If restaging studies demonstrated no evidence of disease progression, patients underwent pancreaticoduodenectomy. All patients were evaluated with serial postoperative computed tomography scans to document first sites of tumor recurrence.
Results: The overall median survival from the time of tissue diagnosis was 21 months (range 19–26, 95%CI). At last follow-up, 41 patients (31%) were alive with no clinical or radiographic evidence of disease. The survival duration was superior for women (P = .04) and for patients with no evidence of lymph node metastasis (P = .03). There was no difference in survival duration associated with patient age, dose of preoperative radiation therapy, the delivery of intraoperative radiotherapy, tumor grade, tumor size, retroperitoneal margin status, or the histologic grade of chemoradiation treatment effect.
Conclusion: This analysis supports prior studies which suggest that the survival duration of patients with potentially resectable pancreatic cancer is maximized by the combination of chemoradiation and pancreaticoduodenectomy. Furthermore, there was no difference in survival duration between patients who received the less toxic rapid-fractionation chemoradiotherapy schedule (30 Gy, 2 weeks) and those who received standard-fractionation chemoradiotherapy (50.4 Gy, 5.5 weeks). Short-course rapid-fractionation preoperative chemoradiotherapy combined with pancreaticoduodenectomy, when performed on accurately staged patients, maximizes survival duration and is associated with a low incidence of local tumor recurrence.
Key Words: Pancreaticoduodenectomy • Pancreatic cancer • Chemoradiation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Delivery of postoperative chemoradiotherapy is frequently delayed because of the morbidity and prolonged recovery associated with pancreaticoduodenectomy. As many as 25% to 30% of patients who undergo surgery first do not receive planned postoperative therapy.3,4,11 In addition, studies of postoperative chemoradiotherapy are prone to selection bias; the rapidly recovering patients with a superior performance status, and therefore a longer life expectancy, are the ones eligible to participate in trials of postoperative adjuvant therapy. This selection bias must be appreciated when comparing survival data from adjuvant trials with retrospective data, which generally include all patients who underwent surgery with or without some form of adjuvant therapy. In addition, this inability to reliably deliver postoperative therapy is the driving force behind the growing enthusiasm for a neoadjuvant approach to the multimodality management of localized pancreatic cancer.
Because of the risk that planned postoperative adjuvant therapy will be delayed or not delivered, we initiated studies of chemoradiotherapy given in the preoperative setting.7,11–13 Importantly, preoperative chemoradiotherapy was not given in an attempt to down-stage patients with locally advanced disease but to minimize local tumor recurrence and maximize survival duration in patients with potentially resectable disease.13 The preoperative administration of chemoradiotherapy was not associated with toxicities that delayed surgical treatment and did not increase surgical morbidity or mortality.11,13 However, standard-fractionation chemoradiotherapy (50.4 Gy, 1.8 Gy per fraction [28 fractions]; 5-FU, 300 mg/m2 daily, 5 days per week) was associated with gastrointestinal toxicity severe enough to require hospitalization in 32% of patients.12 This finding led to modification of the standard-fractionation chemoradiotherapy schema by reducing the total duration of therapy from 5.5 to 2 weeks and increasing the dose per fraction from 1.8 to 3.0 Gy (total dose of 30 Gy). Patients also received a concurrent infusion of 5-FU chemotherapy, surgical resection of the primary tumor, and an additional 10 Gy of radiation administered as intraoperative electron-beam radiation therapy (IORT). A recent report of the initial results of this rapid-fractionation treatment program suggested that treatment-related toxicity was decreased, surgery was performed safely, and local control and overall survival rates were comparable to those with standard-fractionation chemoradiotherapy.13 The 30 Gy of external-beam radiation therapy (EBRT) delivered by rapid fractionation is biologically equivalent to 36 Gy given by standard fractionation, and delivery of 30 Gy at 3 Gy per fraction plus 10 Gy of IORT is equivalent to approximately 56 Gy given by standard fractionation.14
The combination of 30 Gy of radiation and chemotherapy followed by pancreaticoduodenectomy without IORT has not been studied with respect to local tumor control and survival. Because 30 Gy given over 2 weeks is well tolerated before pancreaticoduodenectomy and because most institutions do not have IORT capability, we wanted to review our experience with neoadjuvant chemoradiotherapy in the context of our overall experience with multimodality therapy (with and without IORT) for pancreatic cancer.
The goal of this study was to analyze the effects of preoperative chemoradiotherapy schedules, IORT, patient factors, and histopathologic variables on survival duration and patterns of treatment failure in patients who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreatic head.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This analysis included patients who were previously reported and treated as part of clinical trials7,12,13 and patients who received off-protocol preoperative chemoradiotherapy. Patients were treated off-protocol if a cytologic diagnosis of malignancy was not obtained by intraoperative, percutaneous, or endoscopic biopsy; such patients had often undergone recent laparotomy during which the primary tumor was believed to be locally advanced. A second laparotomy soon after the initial attempt at resection is usually ill-advised, and neoadjuvant chemoradiotherapy is an attractive alternative in these patients if clinical and radiographic findings support the diagnosis of a pancreatic or periampullary malignancy. The other subgroup of patients treated off-protocol were those patients who had a marginal performance status. In such cases, induction chemoradiotherapy was used as a test of performance status–if chemoradiotherapy was poorly tolerated, pancreaticoduodenectomy was likely to be associated with significant morbidity and possibly death. Therefore, only those patients judged to have a performance status acceptable for major abdominal surgery (Karnofsky score of 70% or greater) after chemoradiotherapy were considered for pancreaticoduodenectomy.
To be eligible for protocol-based treatment, patients were required to have an absolute granulocyte count > 3,000/ml, a platelet count of at least 100,000/ml, and a serum creatinine level below 1.6 mg/dl. Patients with hyperbilirubinemia underwent biliary decompression with endoscopic or percutaneous endobiliary stents.
Pretreatment evaluation was standardized and consisted of physical examination, thin-section contrast-enhanced computed tomography (CT) of the abdomen, and chest radiography. All patients were required to meet the following objective criteria for tumor resectability:1 no evidence of extrapancreatic disease,2 no evidence of tumor extension to the celiac axis or superior mesenteric artery (SMA) as indicated by the presence of a fat plane between the tumor and these blood vessels on CT, and3 a patent superior mesenteric-portal vein (SMPV) confluence.15 Laparoscopy and visceral angiography were used at the discretion of the operating surgeon.
Four weeks after the completion of chemoradiotherapy, patients underwent a complete restaging evaluation, which included physical examination, laboratory studies, chest radiography, and abdominal CT. In the absence of disease progression or the interval development of serious medical comorbidity, patients were brought to surgery for planned pancreaticoduodenectomy.
Chemoradiotherapy
Patients included in this analysis received preoperative chemoradiotherapy according to one of the following treatment schemas. (1) Protocol-based standard-fractionation EBRT and concurrent 5-FU–EBRT was delivered at 1.8 Gy per fraction, Monday through Friday, to a total dose of 50.4 Gy; and 5-FU was administered concurrently at a dose of 300 mg/m2/day, 5 days per week, by continuous infusion through a central venous catheter.7,12 (2) Protocol-based rapid-fractionation EBRT and concurrent 5-FU–EBRT was delivered at 3.0 Gy per fraction, Monday through Friday, to a total dose of 30.0 Gy; and 5-FU was administered concurrently at a dose of 300 mg/m2/day, 5 days per week, by continuous infusion.13 (3) Protocol-based rapid-fractionation EBRT (30.0 Gy) and paclitaxel–paclitaxel was administered at a dose of 60 mg/m2/week for 3 weeks beginning the Friday prior to the start of EBRT.16 (4) Protocol-based rapid-fractionation EBRT (30.0 Gy) and gemcitabine–gemcitabine was administered at a dose of 400 mg/m2/week for 7 weeks beginning the Friday prior to the start of EBRT (this study is ongoing).17 (5) Patients without a cytologic or histologic diagnosis of adenocarcinoma and those who could not stay in Houston for chemoradiotherapy received off-protocol 5-FU-based chemoradiotherapy. This consisted of either rapid-fractionation EBRT (total dose 30 Gy) or standard-fractionation EBRT (total dose of either 45.0 or 50.4 Gy) and concurrent infusional 5-FU at a dose of 300 mg/m2/day, 5 days per week.
Surgery, IORT, and Pathologic Evaluation of the Resected Specimen
Pancreaticoduodenectomy was performed only in patients with no evidence of extrapancreatic disease at laparotomy. In general, random lymph node sampling for frozen-section analysis at the time of pancreaticoduodenectomy was not performed. Our technique for pancreaticoduodenectomy has been previously described in detail.18 Patients with tumor adherence to the SMPV confluence underwent either tangential or segmental resection of the involved vessel with primary repair, saphenous vein patch, or interposition grafting using the left internal jugular vein.19 In patients who had IORT, IORT was administered in a dedicated surgical suite after resection and vascular reconstruction and prior to gastrointestinal reconstruction.20 Electron-beam energies from 6 to 12 MeV were used to deliver 10 Gy to the treatment field, which included the retroperitoneum and tumor bed extending from the transected bile duct superiorly to the right kidney laterally and to the pancreatic remnant medially. The pancreas and bile duct were excluded from the treatment field.
A standardized technique was used to assess the resected pancreaticoduodenectomy specimen.21 Initial gross evaluation and identification of resection margins were performed by the surgeon and the pathologist together. Biliary and pancreatic margins were submitted for frozen-section analysis and re-resected if positive. The retroperitoneal margin was defined as the soft tissue margin immediately adjacent to the proximal 3 to 4 cm of the SMA. The operating surgeon and pathologist identified this margin, and a 2 to 3 mm full-face (en-face) section was submitted for permanent-section analysis. Tumor size was calculated after surgical resection by measuring the maximum transverse diameter of the tumor. This measurement was difficult to make in some patients after preoperative chemoradiotherapy because gross tumor was often hard to distinguish from uninvolved adjacent pancreatic parenchyma. The grade of treatment effect was assessed on permanent sections using a previously published grading system (Table 1).12
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Statistical Analysis
Survival and follow up were calculated from the time of initial cytologic or histologic diagnosis. Survival analyses were performed using the method of Kaplan and Meier.22 Univariate and multivariate analyses were performed using the Cox proportional hazards model. Analyses were performed using the statistical software package S-Plus version 3.4 (Math Soft, Inc., Seattle, WA).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There were two perioperative deaths (2%), surgery-related morbidity was not a subject of this analysis other than to calculate median intraoperative blood loss (1281 ml) and median hospital stay (13 days; day of surgery was day 1, day of discharge was counted as the last day of hospitalization).
The overall median survival from the time of tissue diagnosis was 21 months, (range 19–26, 95% CI) (Fig. 1). The 5-year survival was 23%, (range 15% to 35%, 95% CI). By univariate (data not shown) and multivariate analysis (Table 2), the survival duration was superior for women (P = .04; Figure 2) and for patients with no evidence of lymph node metastasis (P = .03; Figure 3). As shown in Table 2, there was no difference in survival duration associated with patient age, tobacco use, dose of preoperative EBRT (Fig. 4), the chemotherapy agent used, the delivery of IORT, tumor grade, tumor size, retroperitoneal margin status, or the histologic grade of chemoradiotherapy treatment effect (Fig. 5).
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Of the 8 patients who died of causes other than pancreatic cancer, 2 died in the perioperative period, 2 died of second cancers, and 4 died of treatment-related causes at various time intervals following recovery from surgery. One of the 2 perioperative deaths occurred in a 70-year-old man who developed pulmonary failure unresponsive to medical therapy and died 11 days after an uncomplicated pancreaticoduodenectomy. This patient had undergone cardiac revascularization prior to definitive treatment of his pancreatic cancer. The second perioperative death involved a 70-year-old man who had a myocardial infarction on postoperative day 3 (previously reported).7,12
Two patients died of second malignancies. A 70-year-old man developed a primary non–small-cell lung carcinoma (pathologically different from his pancreatic cancer) that caused his death 13 months after pancreaticoduodenectomy. A 59-year-old woman developed bronchoalveolar carcinoma of the lung that caused her death 4 years after pancreaticoduodenectomy.
Of the four treatment-related deaths, one was in a 70-year-old man who received off-protocol 5-FU-based chemoradiotherapy (50.4 Gy) and pancreaticoduodenectomy. His recovery from surgery was uneventful, and he was discharged from the hospital on postoperative day 14. He was seen in the outpatient center 1 week later prior to returning home and was in good condition. He was found unresponsive at home 37 days after surgery with evidence of hematemesis. Resuscitative efforts at his local hospital were unsuccessful; a request for an autopsy was denied. The second patient died of a perforated marginal ulcer 8 weeks after an uncomplicated pancreaticoduodenectomy. This was a 73-year-old man who received off-protocol preoperative 5-FU-based chemoradiotherapy (the patient had significant cardiovascular comorbidity, and there was concern over peripancreatic adenopathy on initial imaging studies). Because he recovered from mild to moderate chemoradiotherapy-related toxicity to achieve a favorable performance status, he was considered to be an appropriate candidate for pancreaticoduodenectomy. His perioperative course was uncomplicated, and he was discharged after a 15-day hospitalization. The patient was readmitted 7 weeks after surgery with acute abdominal pain and was found to have a perforated marginal ulcer, which was repaired surgically; he died in the postoperative period of multisystem organ failure. A request for an autopsy was denied. The third patient was a 72-year-old woman who underwent preoperative 5-FU-based chemoradiotherapy (50.4 Gy) and pancreaticoduodenectomy with resection of the SMPV confluence (and ligation of the splenic vein) in 1991. This represented one of our early cases of venous resection and reconstruction and the only case in which Gore-Tex was used as an interposition graft. She did well for 7 months, at which time ascites developed secondary to occlusion of the portal vein interposition graft causing extrahepatic portal hypertension. Multiple paracenteses demonstrated no cytologic evidence of malignancy. The extrahepatic portal hypertension resulted in worsening gastrointestinal function, hypoalbuminemia, and a decline in performance status. She died of aspiration pneumonia 9 months after pancreaticoduodenectomy, largely because of her debilitated condition. Permission for autopsy was denied. The fourth patient died of gastrointestinal hemorrhage due to an arterial-enteric fistula 14 months after pancreaticoduodenectomy. This 81-year-old man had a marginal performance status at the time of initial presentation and therefore was treated with endoscopic biliary decompression and off-protocol 5-FU-based chemoradiotherapy (30 Gy). He tolerated this therapy well and therefore was reconsidered for pancreaticoduodenectomy, which was performed without complication. He did well until 14 months after surgery, when he developed upper gastrointestinal hemorrhage; evaluation ultimately led to arteriography, which demonstrated an arterial-enteric fistula from the stump of the gastroduodenal artery to the afferent jejunal limb in the setting of type IX hepatic arterial anatomy (common hepatic artery arising from the SMA). This was treated with hepatic artery embolization, which successfully stopped the bleeding; however, the patient ultimately died of multisystem organ failure secondary to hemorrhage-induced hypotension. Autopsy results demonstrated no evidence of recurrent pancreatic carcinoma.
The first site of failure was determined radiographically in 75 of the 79 patients who had recurrences; in 4 patients, the site of recurrence was not accurately documented because of the lack of radiographic imaging upon decline in performance status. Fifty-eight (73%) of the 79 patients who had recurrences developed distant metastases as their first manifestation of recurrence (lung, 16; liver, 41; adrenal, 1); 8 patients (10%) developed local (tumor bed) recurrence (4 had isolated local recurrence, 4 had peritoneal recurrence in addition to local recurrence); and 9 patients (11%) developed peritoneal carcinomatosis (without local or distant recurrence) as the first pattern of failure. Of the 8 patients who had radiographic evidence of local recurrence, 3 received 30 Gy of EBRT without IORT (8% of the 39 patients in that treatment group), 3 received 30 Gy with IORT (6% of 49 patients), and 2 received > 30 Gy of EBRT (45 or 50.4 Gy) without IORT (11% of 19 patients). None of the 25 patients who received 45 or 50.4 Gy of EBRT plus IORT had local recurrence as the first site of recurrence.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Multivariate analysis (Table 2) suggests that female sex and the absence of metastatic disease in regional lymph nodes were the only factors associated with improved survival duration. A larger sample size is necessary to narrow the rather large confidence intervals—thus our emphasis on developing a chemoradiotherapy schema with acceptable toxicity that would be appropriate for multi-institutional study. We are not aware of any prior data to suggest a survival difference based on patient sex. Lymph node status, in contrast, is a well-known prognostic factor in patients with localized resectable pancreatic cancer.23–25 The percentage of patients found to have metastasis in regional lymph nodes (48% in our study) is lower than that reported in other studies. It is likely that preoperative chemoradiotherapy did have a "down-staging" effect, resulting in a lower than expected proportion of node-positive patients. The histological extent of treatment effect (Table 1) did not correlate with survival duration by multivariate analysis. However, as seen in Fig. 5, this is because the survival curves (grades I and IIA vs. grades IIB and III) did not diverge until after 2 years of follow-up. The use of histological response to neoadjuvant therapy as a surrogate marker of treatment efficacy remains an active area of investigation.
No patient in this study had a grossly positive margin of resection; 16 patients were found to have microscopic evidence of adenocarcinoma within the retroperitoneal margin. The retroperitoneal margin is the soft tissue margin directly adjacent to the SMA and could also be appropriately termed the mesenteric margin. It is clearly the most frequent site of margin positivity (gross and microscopic) in patients who undergo pancreaticoduodenectomy.26,27 The reasons for our low rate of margin positivity are likely multifactorial: the use of accurate preoperative imaging, a standardized surgical technique, and preoperative chemoradiotherapy. The individual impact of these three variables is impossible to assess. It is critically important to emphasize that patients with CT evidence of low-density tumor extension to the SMA are not considered to have resectable tumors at our institution. Furthermore, the retroperitoneal dissection along the right lateral border of the SMA and all technical aspects of pancreaticoduodenectomy are standardized; importantly, all mesenteric soft tissue to the right of the SMA is removed en-bloc with the main specimen in all patients. The survival duration of the 16 positive-margin patients in our study should not be used to suggest that chemoradiotherapy can compensate for a grossly positive margin of resection.
As demonstrated in previous studies from our institution, local tumor control is excellent with multimodality therapy.7,13 In the present study, all patients were evaluated with serial postoperative CT scans, and local recurrence was diagnosed radiographically as a component of the first site of recurrence in only 8 (6%) of 132 patients. This low rate of local recurrence is likely due to the combined use of objective radiographic criteria for patient selection, a standardized operative technique, and chemoradiotherapy. Importantly, we used clearly defined CT criteria for the selection of patients to undergo surgery and provided accurate histological assessment of the retroperitoneal margin. These two pieces of information are critical to any discussion on local recurrence following pancreaticoduodenectomy and should be accurately analyzed in all future multimodality treatment protocols. Prior studies of pancreaticoduodenectomy and postoperative chemoradiotherapy including the Gastrointestinal Tumor Study Group trial did not include standardized criteria for resection or accurate pathologic assessment of margin status.1,2 These factors, combined with imprecise assessment of recurrent disease, make it impossible to assess the impact of chemoradiotherapy on local control after pancreaticoduodenectomy in previously published studies of postoperative adjuvant chemoradiotherapy. Variables such as EBRT and systemic chemotherapy cannot be studied as part of a multimodality treatment program unless preoperative staging, surgery, and pathologic assessment of the resected specimen are standardized and clearly defined. The results herein serve as an example of the importance of such standardization to the conduct of clinical research.
An important finding in this study—with implications for the future use of combined modality therapy in patients with localized pancreatic cancer—is that rapid-fractionation, 2-week EBRT (30 Gy) is associated with a survival duration similar to that with standard-fractionation, 5.5-week EBRT (45 to 50.4 Gy). Furthermore, the recently reported interim results of the ESPAC-1 study, in which adjuvant radiotherapy did not improve survival duration over pancreaticoduodenectomy alone,5 suggest that EBRT may not be an essential treatment component. While we are not ready to remove EBRT from the study of protocol-based treatment for localized pancreatic cancer, the availability of more potent radiation-sensitizing agents and techniques to ensure complete surgical resection make the study of shorter-course, less toxic EBRT attractive in contemporary clinical trial design.
Our analysis suggests that rapid-fractionation preoperative chemoradiotherapy combined with pancreaticoduodenectomy, when performed on accurately staged patients with localized pancreatic cancer, maximizes survival duration and is associated with a low incidence of local tumor recurrence. Future treatment schemas should therefore emphasize the use of systemic therapy in an effort to treat micrometastatic disease in the liver and lungs, the predominant sites of tumor recurrence. Our current neoadjuvant therapy program combines 2 weeks of EBRT with 7 weeks of systemic gemcitabine followed by restaging evaluation in preparation for pancreaticoduodenectomy.
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Footnotes |
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Received for publication July 26, 2000. Accepted for publication November 20, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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