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© 2002 American Society for Clinical Oncology Preoperative Paclitaxel and Concurrent Rapid-Fractionation Radiation for Resectable Pancreatic Adenocarcinoma: Toxicities, Histologic Response Rates, and Event-Free OutcomeByFrom the Pancreatic Tumor Study Group, University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Peter W.T. Pisters, MD, Department of Surgical Oncology, Box 444, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; email: ppisters{at}mdanderson.org
PURPOSE: To evaluate the toxicity of a preoperative regimen of paclitaxel and concurrent external-beam radiation therapy, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with localized, potentially resectable pancreatic adenocarcinoma were treated with 30 Gy external-beam radiation therapy and concomitant weekly 3-hour infusions of paclitaxel (60 mg/m2). Radiographic restaging was performed 4 to 6 weeks after chemoradiation, and patients with localized disease underwent pancreatectomy with EB-IORT. RESULTS: Thirty-five patients completed chemoradiation; 16 (46%) experienced grade 3 toxicity. Four patients (11%) required hospitalization for dehydration due to grade 3 nausea and vomiting. Twenty (80%) of 25 patients who underwent surgery underwent pancreatectomy; EB-IORT was used in 13 patients. There were no histologic complete responses to preoperative therapy; 21% of specimens demonstrated more than 50% nonviable cells (grade 2b treatment effect). With a median follow-up period of 46 months, the 3-year overall survival rate with chemoradiation and pancreatectomy was 28%. CONCLUSION: Preoperative paclitaxel-based concurrent chemoradiation is feasible. The toxicity of this regimen seems greater than that with fluorouracil. The histologic responses and survival are similar, suggesting no advantages to paclitaxel-based preoperative treatment.
THE TREATMENT OF patients who have localized pancreatic adenocarcinoma by surgery alone is associated with a median survival of 12 to 14 months and a high incidence of local-regional tumor recurrence.1 Prospective and retrospective data on the results of pancreatectomy with preoperative or postoperative chemotherapy or chemoradiation are relatively limited and conflict with regard to whether combined-modality treatment provides a survival benefit.2 Nonetheless, given the adverse prognosis for virtually all patients with pancreatic adenocarcinoma and the fact that some reports suggest a possible survival benefit with combined-modality treatment,3-5 there remains considerable interest in combined-modality treatment approaches for this disease. Over the past decade, a number of institutions6-8 and the Eastern Cooperative Oncology Group9 have investigated preoperative chemoradiation and surgery for patients with localized pancreatic adenocarcinoma. The most intensively studied radiosensitizer in these studies has been fluorouracil (5-FU), which has been used alone7,8 or with mitomycin.6,9 Our previous experience with preoperative 5-FU–based chemoradiation demonstrated that this approach is safe and feasible.7,8 We combined 5-FU with a short course/high dose per fraction radiation treatment schedule (rapid fractionation) with minimal treatment-related toxicities.8 Rapid-fractionation chemoradiation was delivered almost exclusively on an outpatient basis, and patients who received chemoradiation followed by pancreaticoduodenectomy and electron-beam intraoperative radiation therapy (EB-IORT) had a median survival duration of 25 months. These encouraging results have stimulated our continued interest in treatment sequencing strategies that deliver chemotherapy, chemoradiation, or both before surgery and established preoperative 5-FU–based chemoradiation as our institution’s standard approach for nonprotocol treatment of patients with localized, biopsy-proven pancreatic adenocarcinoma. Paclitaxel promotes microtubule assembly and prevents microtubule depolymerization, leading to an accumulation of cells in the most radiosensitive phase of the cell cycle—the G2/M phase.10,11 In addition, paclitaxel has been demonstrated to radiosensitize human pancreatic cancer cells in vitro.12 In light of this, paclitaxel-based chemoradiation has been investigated in phase I trials in non–small-cell lung,13 head and neck,14 gastric,15,16 endometrial,17 and breast18 cancers. On the basis of this interest, we initiated a pilot study of paclitaxel and concurrent external-beam radiation therapy (EBRT) before surgery and EB-IORT for patients with localized, potentially resectable pancreatic adenocarcinoma. The objectives of this study were to evaluate toxicity, histologic response, and event-free outcome.
Patients The study protocol was approved by the University of Texas M.D. Anderson Cancer Center’s institutional review board for clinical investigation, and written informed consent was obtained from all patients before treatment. This study was supported by philanthropic and grant sources; there was no industry funding for this protocol. All patients had a pretreatment cytologic or histologic diagnosis of adenocarcinoma of the pancreatic head or uncinate process. Patients with tumors other than adenocarcinoma or with tumors in the body or tail of the pancreas were excluded. The protocol required that a low-density mass in the pancreatic head be visible on computed tomographic (CT) scan; this requirement was intended to exclude patients with periampullary carcinoma of nonpancreatic origin. All patients underwent a standard pretreatment evaluation that included thin-section, contrast-enhanced, multiphase spiral CT of the abdomen, chest radiography, and physical examination. The protocol required patients to have potentially resectable disease as assessed by physical examination and the following objective radiographic criteria: (1) no evidence of extrapancreatic disease; (2) no evidence of tumor extension to the superior mesenteric artery (SMA) or celiac axis, as indicated by the presence of a soft tissue plane between the tumor and these blood vessels on contrast-enhanced CT; and (3) a patent superior mesenteric-portal vein confluence. Staging laparoscopy was performed selectively at the discretion of the operating surgeon. Laparoscopy involved the establishment of a periumbilical port for camera placement and a single upper abdominal port to allow exposure of the liver.
Patients were also required to have a Karnofsky performance status of Evaluation during chemoradiation included daily assessment of toxicity and weekly history, physical examination, and assessments of body weight, performance status, complete blood cell count, and liver function. Four to 6 weeks after the completion of chemoradiation (before surgery), patients underwent a complete restaging evaluation, which included a physical examination, laboratory studies, and repeat chest radiography and abdominal CT.
Chemoradiation
Paclitaxel (60 mg/m2) was administered weekly by 3-hour intravenous infusion in 3 successive weeks, beginning 4 days before the initiation of EBRT (days 1, 8, and 15). Premedication included dexamethasone (20 mg orally 12 and 6 hours before paclitaxel), diphenhydramine (25 mg intravenously 1 hour before paclitaxel), and ranitidine (50 mg intravenously 1 hour before paclitaxel). The second and third doses of paclitaxel were adjusted if necessary on the basis of the AGC obtained on days 7 and 14, respectively. For an AGC of 500 to 1,000/mL, a 5% paclitaxel dose reduction was mandated; for an AGC below 500/mL, paclitaxel was withheld. Toxicities were graded according to the World Health Organization toxicity criteria.
Surgery and Assessment of Response Perioperative mortality was defined as death within the first 30 days after surgery or before hospital discharge. Major surgical complications were defined as any occurrence of anastomotic leak, postoperative intra-abdominal or gastrointestinal hemorrhage or fistula, intra-abdominal abscess, pneumonia, catheter-related sepsis, thromboembolic events, reoperation, or death during the hospitalization for pancreaticoduodenectomy. Standardized histologic evaluation of the pancreaticoduodenectomy specimen was performed as previously described.23 All specimens were evaluated by a single pathologist (K.R.C.). Tumor size was calculated after surgical resection by measuring the maximal transverse diameter of the tumor. However, this was occasionally impossible after preoperative chemoradiation because gross tumor often could not be demarcated from uninvolved adjacent pancreatic parenchyma. The retroperitoneal margin was defined as the soft tissue margin directly adjacent to the proximal 3 to 4 cm of the SMA. This margin was identified by the surgeon immediately on specimen removal and evaluated jointly by the surgeon and pathologist by microscopic examination of a 2- to 3-mm full-face (en-face) section of the margin. Histologic response to preoperative chemoradiation was characterized and graded with a previously published grading scheme.7 A histologic complete response was defined as the presence of no residual viable tumor on histologic evaluation of the entire surgical specimen. The radiographic response to chemoradiation was evaluated by a single radiologist (C.C.) by comparing pretreatment and restaging CT scans. Radiographic responses were classified with the Response Evaluation Criteria in Solid Tumors criteria.24
Follow-up and Statistical Analysis
Treatment The flow of patients through the treatment protocol is illustrated in Fig 2. Treatment was initiated in 37 patients with adenocarcinoma of the pancreatic head believed to be resectable on the basis of pretreatment staging evaluation. Two patients experienced hypersensitivity reactions to the first dose of paclitaxel and were taken off the study. The remaining 35 patients completed paclitaxel-based chemoradiation and are included in the toxicity analysis reported herein. Three patients required paclitaxel dose reductions owing to treatment-related granulocytopenia; two patients required the withholding of single doses of paclitaxel because of an AGC below 500/mL.
Ten (29%) of the 35 patients who completed chemoradiation did not undergo surgery owing to disease progression or unrelated comorbidities. Seven of these 10 patients were found to have metastatic disease at the time of postchemoradiation (preoperative) restaging: liver metastases were found in five patients, and lung metastases and peritoneal disease were found in one patient each. Of the six patients with intra-abdominal (liver or peritoneum) metastases, two had undergone visualization of the liver during pretreatment laparotomy (one patient) or laparoscopy (one patient). Another patient was found to have locally advanced disease at restaging, with tumor involvement of the SMA. On retrospective review of this patient’s CT scans, it was apparent that this arterial involvement was present at the time of initial staging. Two patients did not undergo surgery because of medical complications that were believed to be unrelated to chemoradiation: one patient experienced a cerebrovascular accident in the week before planned surgery, and one patient developed clinically significant ischemic heart disease that necessitated myocardial revascularization. Twenty-five (71%) of 35 patients underwent laparotomy for planned pancreaticoduodenectomy. Five patients were found to have unresectable disease at surgery because of unsuspected liver metastases (four patients) or peritoneal implants (one patient) not seen on preoperative imaging. Two of these five patients had undergone prereferral laparotomy for attempted tumor resection, at which time there was no evidence of extrapancreatic disease. No patient was found at surgery to have unresectable disease by virtue of local tumor extension to involve peripancreatic vascular structures or viscera (ie, CT-occult locally advanced disease). Twenty patients (57% of those who completed chemoradiation; 80% of patients who were restaged as M0 and underwent laparotomy) underwent successful pancreatectomy (pancreaticoduodenectomy in 18 patients and total pancreatectomy in two patients). Superior mesenteric or portal vein resection and reconstruction were necessary in seven patients (35%); one of these patients also required segmental hepatic artery resection and reconstruction. One patient who could not return to M.D. Anderson Cancer Center for surgery underwent pancreaticoduodenectomy at another institution and is therefore excluded from the histologic analysis. This patient did not receive EB-IORT. Of the remaining 19 patients, 13 received EB-IORT (10 Gy). The other six patients (all of whom underwent pancreaticoduodenectomy with vascular resection and reconstruction) did not receive EB-IORT for practical reasons; the added operative time required for EB-IORT was believed to be unjustified for these patients, who had already undergone lengthy, complicated operations.
Toxicities of Chemoradiation and Surgery
All 25 patients who underwent surgery did so within 7 weeks of the completion of chemoradiation. No patient experienced a delay in surgery because of chemoradiation-related toxicity. There were no perioperative deaths, and no patient required reoperation. Five major complications occurred in four patients: sterile fluid collections in two patients, intra-abdominal abscess in one patient, pneumonia in one patient, and gastrointestinal bleeding in one patient.
Radiographic and Histologic Responses to Preoperative Chemoradiation Histologic findings in the 19 patients who underwent pancreaticoduodenectomy at M. D. Anderson Cancer Center are listed in Table 2.7,8,26 One patient was found to have neuroendocrine carcinoma on final pathology review; the remaining patients had pancreatic adenocarcinoma. Tumor size could not be measured in five patients because of difficulty in delineating the tumor/pancreatic parenchyma interface after chemoradiation. The median tumor size in the remaining 13 specimens was 3.5 cm (range, 2.0 to 5.0 cm). No patient experienced a histologic complete response to preoperative chemoradiation.
Surgical margins were grossly negative in all patients who underwent pancreaticoduodenectomy or total pancreatectomy. A microscopically positive retroperitoneal margin was found in six patients (32%). Two patients had positive pancreatic parenchymal margins after initial transection of the gland at the pancreatic neck; these patients underwent total pancreatectomy in order to clear microscopic residual disease. The common hepatic duct margins were histologically negative in all patients. Positive regional lymph nodes were identified in 10 (53%) of 19 patients. Table 2 compares the histologic responses and findings observed with paclitaxel-based chemoradiation to those observed in similarly staged patients treated with 5-FU (300 mg/m2/d, Monday to Friday) and EBRT (30 Gy in 10 fractions) in a previous study.8
Survival and Disease Recurrence
Of the 19 patients who underwent pancreatectomy for adenocarcinoma, 17 died, 16 of recurrent pancreatic cancer and one of complications after hip replacement surgery 54 months after diagnosis, without evidence of recurrent pancreatic cancer. Two of 19 patients remain alive without evidence of recurrent pancreatic cancer 44 and 63 months after diagnosis, respectively. The one patient found to have neuroendocrine carcinoma is alive with metastatic disease 46 months after diagnosis. The first site of treatment failure was documented in all 16 patients who developed recurrence after pancreatectomy for adenocarcinoma. The first site of treatment failure was the liver in 15 patients and lung in one patient; no patient experienced local or regional recurrence as the first site of treatment failure. The median recurrence-free survival in the 19 patients with pancreatic adenocarcinoma who underwent chemoradiation and pancreatectomy was 9 months, and the 3-year recurrence-free survival rate was 15% (95% CI, 0% to 31%).
This pilot study confirms the feasibility and generally acceptable overall toxicity profile of paclitaxel given by short-duration infusion (60 mg/m2 over the course of 3 hours weekly) concurrently with rapid-fractionation EBRT. With this combined-modality approach, 16 (46%) of 35 of patients experienced grade 3 toxicities; no patient experienced a grade 4 toxicity or chemoradiation-related delay in the planned timing of surgery. The median survival of patients who underwent preoperative paclitaxel-based chemoradiation and surgical resection was 19 months. This compares favorably with the median survival of 12 to 14 months reported for patients with pancreatic adenocarcinoma treated by surgery alone but is lower than the 25-month median survival we have previously observed with 5-FU–based chemoradiation and surgery.8 Clearly, retrospective comparisons of outcome are subject to bias and inadequate patient numbers. Nevertheless, the median survival durations seen in our trials of preoperative chemoradiation, whether with 5-FU or paclitaxel, seem consistently longer than those seen in reports of pancreaticoduodenectomy alone.3,27 Whether this is attributable to a bona fide treatment effect, selection bias, or both remains open to speculation. Frequently cited advantages of preoperative treatment for patients with presumed localized pancreatic cancer include early treatment of micrometastatic disease and optimized patient selection for surgery—patients who have disease progression or develop medical problems during preoperative treatment are spared the morbidity, potential mortality, and costs of pancreaticoduodenectomy. In this study, all resected patients received trimodality therapy, and 10 of 35 patients who completed chemoradiation were not subjected to nontherapeutic laparotomy. Patient selection for surgery is optimized by the short delay (6 to 8 weeks) for delivery of preoperative therapy because clinically occult metastatic disease or significant comorbidity can manifest before surgery. Optimization of patient selection for pancreaticoduodenectomy undoubtedly contributes to the relatively longer median survival duration and low operative mortality rates reported for patients receiving preoperative chemoradiation followed by surgery.7,8,28 Furthermore, as this report illustrates, more than one-third of patients (15 of 35 in this report) presenting with ostensibly localized pancreatic adenocarcinoma are spared the morbidity and costs of pancreaticoduodenectomy as a result of preoperative chemoradiation, in contrast to regimens that use surgery followed by adjuvant therapy. There has been continued interest in paclitaxel-based chemotherapy and chemoradiation for proximal gastrointestinal tumors, including esophageal cancer,29 gastric cancer,16 and pancreatic adenocarcinoma.15 Safran et al15 reported results of a phase I trial of weekly paclitaxel (beginning at 30 mg/m2 by 3-hour intravenous infusion) with 50 Gy of EBRT in patients with gastric and pancreatic adenocarcinoma. At this radiation dose, the dose-limiting toxicities of paclitaxel occurred at 60 mg/m2 per week and included abdominal pain, nausea, and anorexia. Among the 13 patients with assessable pancreatic cancer, four experienced partial responses (overall response rate, 31%). The recommended paclitaxel dose in combination with standard-fractionation EBRT for phase II study was 50 mg/m2 per week. A subsequent study of this dose and schedule in patients with locally advanced pancreatic cancer yielded a response rate of 26% and a median survival of 8 months.30 Gastrointestinal toxicity was the most common cause for dose modifications. The overall toxicity profile of the 50-mg/m2 of paclitaxel per week and 50-Gy radiation regimen seems comparable to that for the 60-mg/m2 of paclitaxel and 30-Gy radiation regimen used in our study. These similar results demonstrate the complex interrelationship between dose of radiation sensitizer, radiation dose and fractionation scheme, and toxicity. It is likely that other factors including radiation field size and radiosensitizer delivery method (bolus v continuous infusion) will also affect the observed toxicity of chemoradiation. We administered paclitaxel via weekly 3-hour intravenous infusion. This approach was based on a trial that established the safety of a weekly dose of 60 mg/m2 of paclitaxel combined with 60 Gy of EBRT administered over the course of 6 weeks in patients with non–small-cell lung cancer.13 More recently, other investigators have reported pilot31 or phase I14,32 trials of continuous-infusion paclitaxel (24 hours a day for 531,32 or 714 days per week) combined with EBRT for patients with mesothelioma,32 non–small-cell lung cancer,32 or locally advanced squamous cell carcinoma of the head or neck.14,31 These studies have demonstrated that continuous-infusion paclitaxel with concurrent EBRT is feasible and tolerable. On the basis of the phase I trials, the doses of continuous-infusion paclitaxel recommended for phase II trials were 21 and 10.5 mg/m2 per day for the 5- and 7-day infusions, respectively. The 24-hour continuous-infusion approach has been studied because it is thought that the dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration for antineoplastic activity and radiosensitization.12,33 Further investigation is needed to determine the optimal dose, schedule, and duration of paclitaxel infusion for concurrent administration with EBRT. Our previous experience with preoperative chemoradiation for pancreatic adenocarcinoma was restricted to 5-FU–based treatment.7,8 This was delivered with both standard-fractionation (50.4 Gy, 1.8 Gy per fraction, 28 fractions) and rapid-fractionation (30 Gy, 3 Gy per fraction, 10 fractions) radiation schedules. The rapid-fractionation regimen was based on the principle that the total radiation dose required to achieve a given biologic effect decreases as the dose per fraction increases.34,35 We have previously demonstrated that the shorter-course rapid-fractionation regimen is associated with a lower hospital admission rate, less overall toxicity, and similar local-regional tumor control and survival duration compared with standard-fractionation chemoradiation.28 The interim results of the European Study Group of Pancreatic Cancer also question the routine use of standard-fractionation chemoradiation as adjuvant therapy for localized pancreatic cancer.36 On the basis of these results, the 5-FU plus a 30-Gy radiation regimen became our institution’s standard preoperative treatment for patients with localized, radiographically resectable pancreatic adenocarcinoma. Comparison of the current results with our previous experience with 5-FU–based rapid fractionation chemoradiation is informative.8 The overall patterns of histologic response and event-free outcome after combined-modality treatment with 5-FU–based and paclitaxel-based chemoradiation seem comparable. However, the overall toxicity of paclitaxel-based treatment was greater than that of 5-FU–based therapy, and more patients treated with paclitaxel and EBRT had unplanned hospital admissions. The response and toxicity rates of paclitaxel-based chemoradiation are, in our experience, comparable to those reported by Safran et al,15,30 even though we used a different radiation schedule. Furthermore, the relative toxicities of paclitaxel-based and 5-FU–based chemoradiation we have seen are similar to those reported by Adelstein et al29 in a nonrandomized comparison of sequential phase II protocols of 5-FU–based and paclitaxel-based (175 mg/m2 over the course of 24 hours) chemoradiation for patients with locally advanced esophageal cancer. On the basis of these reports, we cannot identify any specific advantage to short-duration-infusion paclitaxel-based chemoradiation over 5-FU–based chemoradiation. In conclusion, weekly paclitaxel given by 3-hour infusion in combination with rapid-fractionation EBRT and surgery plus EB-IORT is feasible and tolerable for patients with resectable pancreatic adenocarcinoma. However, the overall toxicity seems relatively greater and histologic responses similar to those observed in our previous experience with continuous-infusion 5-FU and radiation. Thus, at this time, we cannot identify any advantages to paclitaxel-based chemoradiation for pancreatic adenocarcinoma. Further studies are required to determine whether a different dose and schedule of paclitaxel or coadministration of additional radiation sensitizers with EBRT would enhance treatment response and reduce toxicity. Our current phase II studies in resectable pancreatic cancer utilize gemcitabine and cisplatin induction chemotherapy followed by preoperative gemcitabine-based concurrent chemoradiation.37
Supported in part by the Lockton Fund for Pancreatic Cancer Research, the Various Donor Fund for Pancreatic Cancer Research, and grant no. R01 CA75517-04 from the National Institute of Health, Bethesda, MD (D.B.E.). We thank Alice Madary, Adrienne Duncan, Melissa Burkett, and Vivian Z. Garcia for their assistance in the preparation of the manuscript.
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Wolff RA, Evans DB, Gravel DM, et al: Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. Clin Cancer Res 7: 2246-2253, 2001 Submitted November 13, 2001; accepted March 4, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70%, an absolute granulocyte count (AGC) more than 3,000/mL, a platelet count of at least 100,000/mL, a serum creatinine level less than 1.0.6 mg/dL, and a serum bilirubin level less than 2 mg/dL. When necessary, biliary decompression was accomplished endoscopically by placement of a 10.0F or 11.5F polyethylene stent. Patients with evidence of fever, active infection, or previous malignancies other than nonmelanoma skin cancer, stage I laryngeal cancer, or stage IA cervical cancer within the past 5 years were also excluded. 
One patient was retrospectively determined to have locally advanced disease at presentation.
