The argument for pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer

Best Practice & Research Clinical Gastroenterology Vol. 20, No. 2, pp. 365–382, 2006 doi:10.1016/j.bpg.2005.11.005 available online at http://www.sciencedirect.com

10 The argument for pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer Christopher H. Crane*

MD

Associate Professor Department of Radiation Oncology, Unit 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

Gauri Varadhachary

MD

Assistant Professor

Robert A. Wolff MD Associate Professor Department of Gastrointestinal Oncology and Digestive Diseases, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Peter W.T. Pisters MD Professor

Douglas B. Evans

MD

Professor Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Although not universally accepted, chemoradiation is considered a standard adjuvant treatment for patients with resected pancreatic cancer. Theoretical advantages of reduced toxicity and increased efficacy with the use of pre-operative chemoradiation compared to post-operative adjuvant chemoradiation have recently been validated with the publication of a phase III trial in the adjuvant treatment of rectal cancer. Additional advantages of pre-operative chemoradiation that apply specifically to pancreatic cancer include increased access to therapy in patients treated before surgery, addressing the systemic disease recurrence risk without delay, and optimal patient

* Corresponding author. Tel.: C1 713 563 2340; Fax: C1 713 563 2366. E-mail address: [email protected] (C.H. Crane).

1521-6918/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.

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selection for pancreaticoduodenectomy through exclusion of patients with rapidly progressive metastatic disease. Critical components of a pre-operative treatment strategy for pancreatic cancer include adherence to a strict definition of resectability, accurate radiographic staging capable of identifying patients with potentially resectable disease, and a safe and efficient means of obtaining a tissue diagnosis and relieving biliary obstruction. Herein, we discuss the rationale for the use of pre-operative chemoradiation in pancreatic cancer, the results of treatment, and future strategies to address the pattern of disease recurrence. Key words: resectable; pancreatic cancer; radiotherapy; chemotherapy; pre-operative; neoadjuvant; borderline resectable; molecular targeted therapy.

DIAGNOSIS AND STAGING OF PANCREATIC CANCER Unfortunately, pancreatic cancer is currently clinically evaluated, staged and managed differently from center to center in the United States and in Europe. Optimally, the initial goals in the evaluation and treatment of patients with suspected pancreatic cancer are to determine resectability, obtain a histologic diagnosis, safely establish biliary decompression, and develop a stage-specific treatment strategy. The most important initial step is to accurately classify patients into resectable (stages I and II), unresectable (unresectable, stage III), and metastatic (stage IV) groups based on radiographic imaging. They can then be treated with appropriate standard therapy or enrolled on clinical trials that evaluate treatment designed to improve outcome. The most significant issue in the management of patients with pancreatic cancer is the accurate pre-operative identification of patients with stage I or II tumours that can be completely resected. In clinical practice today, imprecise pre-operative assessment of the feasibility of complete gross tumour resection commonly leads to futile surgery as tumour involving the superior mesenteric vessels, portal vein, or celiac axis is discovered intraoperatively. This often leads to incomplete gross removal of tumour, and eventual disease-related death. The variation in the quality of pre-operative assessment and surgery (frequency of complete gross resection) from center to center creates considerable heterogeneity among patients accrued to clinical trials, and makes the interpretation of the value of either adjuvant systemic therapy or chemoradiation exceedingly difficult. Clinical trials cannot accurately evaluate the value of adjuvant therapy if significant numbers of patients with incurable gross residual disease are included. Various diagnostic studies that are commonly used for pancreatic cancer include preoperative imaging with multidetector computed tomography (CT), endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance imaging (MRI), serum CA 19-9, and laparoscopy. Abdominal computed tomography (CT), optimized for imaging the pancreas, is the most common diagnostic imaging technique used to reliably confirm and determine the stage of suspected pancreatic cancer (discussed elsewhere in this edition). In many centers, EUS guided fineneedle biopsy of the pancreas is the procedure of choice for establishing the diagnosis of pancreatic cancer and biliary decompression can be established with the endoscopic placement of an endobiliary stent. Though, if biliary decompression is necessary, it is helpful to perform a CT scan prior to this procedure, since post-procedure pancreatitis if it occurs can prevent the accurate staging of the primary tumour. Changes in the most recent American Joint Committee on Cancer staging system for exocrine pancreatic cancer1 reflect a clinical definition of resectability based on computed tomographic assessment. The T-stage designation classifies T1–T3 tumours as potentially resectable and T4 tumours as locally advanced (unresectable). Tumours with any involvement of the superior mesenteric artery (SMA) or celiac artery are

Pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer 367

classified as T4; however, tumours that involve the superior mesenteric, splenic, or portal veins are classified as T3 because these veins can be resected and reconstructed, provided that they are patent.2 Therefore, three criteria are necessary for resectability: (1) localized disease, (2) lack of involvement of the celiac axis or superior mesenteric artery, and (3) patency of the superior mesenteric/portal venous confluence.

CHEMORADIATION AS A COMPONENT OF MULTIDISCIPLINARY MANAGEMENT General principles Chemoradiation has been shown to reduce the probability of local tumour recurrence in patients with gastrointestinal malignancies who have undergone potentially curative surgery.3–6 Locoregional control rates of 90% or greater are achieved in virtually every tumour site where combined modality approaches are the standard (head and neck cancer, breast cancer, sarcoma, rectal cancer). Improved local tumour control with the use of postoperative chemoradiation has also been shown to improve overall survival in many gastrointestinal tumour sites, including pancreatic cancer.3–5 Chemoradiation accomplishes this by eradicating microscopic residual disease in the tumour bed after complete tumour resection or through the reduction in regional lymph node recurrence. Indeed, the patients that stand to benefit the most are those with microscopically close or positive margins. Chemoradiation may be over-treatment for tumours with wide negative margins and conversely, may be futile in those with gross residual disease. In the case of pancreatic cancer, the retroperitoneal margin is nearly always close and often positive. Therefore, it is reasonable to conclude that locoregional therapy in pancreatic cancer can be optimized with complete gross tumour resection and treatment of microscopic disease at the retroperitoneal margin with chemoradiation. With appropriate patient selection, multidisciplinary teamwork, and combined modality therapy, local disease control rates of 90% or greater are achievable in pancreatic cancer.7 Such attention to locoregional disease is a critical starting point for future improvement in outcome in patients with potentially resectable pancreatic cancer. Post-operative adjuvant chemoradiation for resected pancreatic cancer Large, rationally conceived and well-conducted clinical trials are the foundation of evidence-based medicine. Based on limited data indicating a modest overall survival benefit,5,8–10 chemoradiation is the standard adjuvant treatment in patients with resected pancreatic cancer in the United States. The data from randomized trials in pancreatic cancer5,9–11 are exceedingly difficult to interpret due to many factors such as inadequate dose and schedule of radiotherapy and chemotherapy, lack of protocol compliance, inadequate statistical power, and particularly lack of surgical quality control. The most revealing indicator of the latter is the high local tumour recurrence rates in the reported randomized trials evaluating post-operative chemoradiation.5,10,11 Pre-enrolment computed tomography to exclude obvious gross residual disease was not required on these studies. Local tumour recurrence (or more likely) persistence was identified as a component of the first site of failure in 39% of patients enrolled on the GITSG trial,5 53% of patients enrolled on the EORTC trial,10 and 62% of patients enrolled on the ESPAC-1 trial.11 Given the universally recognized propensity for early and frequent distant disease

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recurrence in pancreatic cancer patients, first-site local recurrence rates this high can only mean that significant numbers of patients with incomplete gross resections—incurable tumours—were enrolled in these trials. It is therefore inappropriate to assume that these high rates of local failure and poor overall survival simply represent ineffective (or harmful as has been concluded11) post-operative adjuvant chemoradiation without taking into consideration the quality of the surgery, the pathologic assessment, the radiographic imaging, and the radiotherapy planning and delivery. Including large numbers of incurable patients on clinical trials (unless they are balanced in both arms) makes the evaluation of adjuvant therapy, which is only capable of benefiting potentially curable patients, a futile endeavour. Indeed, the negative impact of persistent/recurrent local tumour will become even more apparent as systemic therapies improve and distant disease-related mortality is reduced. In order to properly address the value of adjuvant therapy in potentially resectable pancreatic cancer in the future, surgical quality control must be introduced into clinical trial design, imaging prior to protocol entry must be required, and stratification for either the surgeon or hospital should be included. General oncologic advantages of pre-operative chemoradiation The theoretical advantages of pre-operative chemoradiation compared to postoperative chemoradiation for pancreatic cancer include increased efficacy and reduced toxicity related to (i) more effective chemotherapy delivery with an intact blood supply, (ii) the avoidance of hypoxia-related chemoradiation resistance and (iii) the avoidance of late radiation-related toxicity. Tumour hypoxia is a well-known mechanism of resistance to radiotherapy and chemotherapy. Oxygen prolongs the half-life of the free radicals created by X-rays that cause DNA damage to tumour cells. Interruption of the tumour’s blood supply by initial surgery may disrupt perfusion of the tumour bed, thereby creating hypoxic resistant residual tumour cells and limiting chemotherapy delivery to the tumour bed. In contrast, the cells at the periphery of an in situ tumour (including those that are nearest to the retroperitoneal margin) are the most oxygenated and the most sensitive to cytotoxic therapy. In addition, in the case of pancreaticoduodenectomy, the gastrointestinal reconstruction has to be irradiated in the post-operative setting, limiting the radiation dose and introducing the possibility of mucosal or anastomotic injury of the reconstructed bowel. In contrast, the irradiated duodenum is removed after pre-operative chemoradiation and unirradiated jejunum is used in the reconstruction, virtually eliminating the possibility of late radiation injury to these structures. The toxicity and efficacy advantages of pre-operative chemoradiation had been controversial until the question was successfully tested in a randomized phase III trial comparing pre-operative chemoradiation to post-operative chemoradiation in rectal cancer.12 In that study, 823 patients with clinically staged resectable, but locally advanced rectal cancer were randomized to pre-operative chemoradiation versus postoperative chemoradiation. Given the fact that two similar trials in the United States had previously been closed pre-maturely due to poor accrual, this trial represents quite an achievement. It showed that even though approximately 25% more patients in the preoperative arm had tumours in the anatomically constrained low pelvis, which typically have a higher incidence of close and positive margins, 5-year local recurrence rates favoured the pre-operative arm (6% versus 13%, pZ0.006). Importantly, no significant differences were seen in the rate of perioperative complications between the two groups, and both acute and chronic WHO-grade 3 or 4 toxicities were significantly

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lower in the pre-operative arm. The overall inferior tolerability of post-operative chemoradiation therapy resulted in only 54% of patients in the post-operative arm receiving the prescribed dose of radiotherapy and only 50% received the prescribed dose of chemotherapy, compared to 92 and 89%, respectively, in the pre-operative arm. The most striking toxicity difference between the arms was a lower incidence of anastomotic stricture in the pre-operative arm (4% versus 12%, p!0.003). This was likely the result of the removal of the irradiated rectum and reconstruction with unirradiated colon. Late complications of chemoradiation are not common in pancreatic cancer patients with the use of similar doses of radiotherapy, but clinically significant rates of radiation-related gastrointestinal injury could be obscured by the higher rate of disease-specific death. Thus, if disease-specific survival improves in the future with the development of more effective adjuvant therapies, pre-operative approaches would have an even greater toxicity advantage. This German Rectal Cancer Study is proof of principal that pre-operative therapy offers efficacy and toxicity advantages that are clinically significant compared to post-operative therapy for gastrointestinal malignancies.12 Unique advantages of pre-operative therapy for radiographically resectable pancreatic cancer In addition to the a priori safety and efficacy advantages, there are many unique advantages to the use of pre-operative treatment of patients with localized pancreatic cancer owing to its uniquely aggressive biology. Most compelling is the ability to treat virtually all patients that present with localized, resectable pancreatic cancer with therapy that immediately addresses the limitations of curability—micrometastatic disease that is already metastatic to regional lymph nodes, liver, lung or peritoneum. The immediate use of systemic therapy for a disease that is systemic at diagnosis in virtually the majority of patients is particularly appealing. A second important advantage is improved patient selection for pancreatic surgery—an operation associated with significant patient morbidity even when performed in experienced hands. Finally, pancreatic surgery appears to be safer following pre-operative chemoradiation due to a reduced risk of pancreatic anastomotic leak because of the pancreatic fibrosis induced by pre-operative therapy, and the R0 resection rate may be improved. Timely access to therapy Radiotherapy works in a predictable or ‘deterministic’ fashion, killing a fixed fraction of cells with each treatment, and is particularly effective for microscopic residual disease. However, residual microscopic clonogens can repopulate in the tumour bed if radiotherapy is not initiated in a timely fashion (optimally within 6–8 weeks of surgery), thus limiting the efficacy of radiotherapy. Delayed gastric emptying and pancreaticojejunal anastomotic leaks may be the cause of delayed post-operative recovery after pancreaticoduodenectomy. Delays in implementation of therapy lead to the potential for repopulation of residual microscopic clonogens at the retroperitoneal margin and root of mesentery. The efficacy of chemoradiation is directly related to the ability of the maximum safe radiotherapy dose (50.4 Gy) to control microscopic tumour cells. If these clonogens are allowed to proliferate prior to the delivery of therapy or if gross disease remains after surgery, chemoradiation is less effective or ineffective. If one assumes that adjuvant therapy is beneficial in pancreatic cancer patients, then timely access to therapy should be maximized. However, chemotherapy or chemoradiation

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treatment may be difficult or impossible to delivery in a timely fashion following pancreaticoduodenectomy due to prolonged recovery, underlying medical comorbidities which complicate the care of patients in their later years of life, or the rapid development of tumour recurrence. In contrast, nearly all patients with radiographically resectable pancreatic cancer are candidates for pre-operative chemoradiation. Improved patient selection for pancreatic surgery Another advantage of the use of pre-operative therapy is that it introduces a period of time for the surgeon to observe patients with borderline performance status, allowing for a more accurate assessment of surgical risk. This time interval also allows for better patient selection for pancreaticoduodenectomy because patients with rapidly progressive systemic disease can be identified either at the time of restaging evaluation or during surgical exploration at the time of planned pancreaticoduodenectomy. Nontherapeutic resections can thus be avoided in high-risk surgical candidates or in patients with rapidly progressive distant metastatic disease. In prospective trials, approximately 25% of patients who begin a program of pre-operative treatment do not undergo successful resection of their primary tumour as a consequence of disease progression or evolution of clinically significant medical co-morbidity.13 These patients are spared the morbidity and prolonged recovery sometimes associated with pancreaticoduodenectomy—an operation which would not have helped them if performed at diagnosis. In a series of trials performed at The University of Texas M.D. Anderson (M.D. Anderson), patients who demonstrated disease progression after pre-operative chemoradiation and therefore did not undergo pancreaticoduodenectomy had a median survival of only 7 months.14–16 Reduced post-operative complications Intuitively, most clinicians assume that surgery is more difficult or that complication rates are higher after chemoradiation. Ironically, however, the use of chemoradiation prior to pancreaticoduodenectomy has been reported to lead to a lower rate of pancreaticoduodenal leaks. Pancreaticojejunal anastomotic leak is the most common complication following pancreaticoduodenectomy. In a multivariate analysis of 120 resected patients enrolled on a randomized trial at M.D. Anderson, pre-operative chemoradiation was associated with a reduced risk of anastomotic leak.17 This reduction in leak rate may be related to radiation-related glandular fibrosis, decreased exocrine output, and a lower risk of clinical and subclinical pancreatitis. Therefore, pancreatic surgery appears to be better tolerated by patients after chemoradiation. Potential for improving R0 resection rate It is clear from several studies that patients with R1 resections (positive retroperitoneal margin on pathology) have worse survival rates than patients with R0 resections (negative retroperitoneal margin), independent of other prognostic factors including nodal status. The high frequency of positive-margin resections in clinical studies supports the concern that the retroperitoneal margin of excision, even when negative, may include a few millimetres of normal tissue, making surgery alone inadequate local therapy for most patients. Pre-operative chemoradiation can ‘sterilize’ the tumour periphery allowing for improved R0 resection rate especially in patients with borderline resectable tumours. Pre-operative chemoradiation to the retroperitoneal margin prior

Pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer 371

to surgery appears to improve both the margin negative resection rate, and the prognosis of patients with microscopic positive resections. Fourteen percent of patients treated with neoadjuvant chemoradiation at M.D. Anderson have had a microscopic positive margins (R1), none have had gross positive margins (R2), and patients with R1 resection have had a similar outcome to those patients with negative margin (R0). Local recurrences have occurred in only 10% of patients. In contrast, patients treated with initial surgery with R1 or R2 resections without the use of neoadjuvant chemoradiation have consistently been reported to have inferior local tumour control and survival.19 Thus, high quality CT imaging, appropriate patient selection, pre-operative chemoradiation, followed by pancreaticoduodenectomy optimizes the treatment of the retroperitoneal margin and minimizes local tumour recurrence. Clinical studies evaluating pre-operative chemoradiation in resectable pancreatic cancer Pre-operative chemoradiation has been used as a strategy to improve tumour control rates in patients who have resectable disease at the time of clinical evaluation. The rationale for the use of pre-operative therapy, as opposed to post-operative adjuvant therapy, has been discussed in detail elsewhere.22 Starting in 1988, investigators at the University of Texas M.D. Anderson have conducted a series of clinical trials evaluating pre-operative chemoradiation.14,23,24 These trials have had identical eligibility criteria using a CT-based definition of resectable disease, a requirement of biopsy proven adenocarcinoma of the pancreatic head, a uniform pancreaticoduodenectomy technique, and a standardized system for pathologic evaluation of surgical specimens including resection margins (as described elsewhere20). The initial pre-operative regimen at M.D. Anderson reported in 1992 was 50.4 Gy over 5.5 weeks (standard fractionation to the tumour and regional lymph nodes) with concurrent protracted infusional 5-fluorouracil (300 mg/m2/day, Monday–Friday). In addition, intraoperative radiotherapy was used in selected cases. Because of the significant acute gastrointestinal toxic effects (nausea, vomiting, and dehydration) hospital admission was required in approximately one-third of patients. Therefore, that radiation dose was modified in favour of a short course of ‘rapid-fractionation’ radiotherapy (30 Gy in 10fx over 2 weeks to the tumour and regional lymph nodes) using the same chemotherapy with a supplemental 10 Gy dose of intraoperative radiotherapy delivered at the time of surgical resection in all patients. The effective dose delivered to the tumour bed with the latter approach is comparable with that delivered with standard fractionation, based on linear quadratic modeling.27 Efficacy measures in these studies have included eventual resection, the degree of pathologic cell kill based on a standardized evaluation,22 and median survival. Although the pancreatic tumours remained technically resectable after chemoradiation, approximately 40% were not resected due to the recognition of metastatic disease at the time of radiographic restaging 4–5 weeks later.21 A pathologic partial response to therapy (O50% of the tumour cells non-viable) was seen in approximately 40% of the specimens. Local tumour control and median survival were similar with the standardfractionation (50.4 Gy in 5.5 weeks) and rapid-fractionation chemoradiation regimens and comparable to results of reported with post-operative chemoradiation (median survivals 18 and 25 months, respectively). Prior to the advent of gemcitabine, paclitaxel was investigated as a pre-operative radiosensitizer in a group of patients with resectable

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pancreatic cancer. Paclitaxel did not provide an advantage over 5-FU-based chemoradiation in terms of toxicity, resection rate, local treatment effect, or overall survival.16 Most recently, gemcitabine was incorporated with the same rapidfractionation radiotherapy schedule and technique.23 The dose of 400 mg/m2 given weekly for 7 weeks was chosen based on a phase I trial in patients with locally advanced disease.24 The use of intraoperative radiotherapy was omitted in that study due to the possibility of toxic effects of the combination of IORT and gemcitabine. A total of 86 patients were enrolled in this clinical trial23 (full manuscript pending). Toxicities were similar to those observed in the initial phase I trial. Despite a longer elapsed time from enrolment to surgery (pancreaticoduodenectomy) compared to previous trials with 5FU and EBRT (11–12 weeks rather than 7–9 weeks), 74% of patients underwent successful pancreaticoduodenectomy (compared to 57–60% with 5-FU-based chemoradiation). A pathologic partial response was seen in over half of the surgical specimens and there were two pathologic complete responses—something not observed in the 5-FU studies. Currently, patients with potentially resectable pancreatic cancer seen at our institution are receiving systemic therapy using a combination of gemcitabine and cisplatin, followed by gemcitabine-based chemoradiation prior to planned pancreaticoduodenectomy on protocol. Unfortunately, many reports of pre-operative therapy for pancreatic cancer have included heterogeneous patient populations, enrolling patients with locally advanced or marginally resectable pancreatic cancer. Conversely, many chemoradiation studies intended for locally advanced patients have included radiographically resectable patients and concluded that chemoradiation has ‘downstaged’ tumours (see discussion below), leading to the conversion of locally advanced tumours to resectable tumours. Few investigators report clear anatomic definitions of locally advanced disease and many studies incorporate intraoperative assessment of local tumour extent, data which is subjective and not reproducible. In general, patients with locally advanced pancreatic cancer should not be included in studies of pre-operative therapy for clearly resectable disease and patients with resectable tumours should not be included in studies intended for locally advanced disease. Doing so confounds reports of resection rates, the ‘downstaging’ potential of chemoradiation, and complicates interstudy comparisons. Therein lies the importance of using accurate, reproducible anatomic definitions for resectability based on high-quality CT imaging. Barriers to pancreatic pre-operative therapy Difficulties associated with the delivery of pre-operative therapy include the need for a pre-treatment pancreatic biopsy and the frequent need for intermediate-term palliation of jaundice using endoscopically placed biliary stents.28,29 Pre-operative chemoradiation (prior to planned pancreaticoduodenectomy) should, in general, only be administered upon cytologic confirmation of malignancy. Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is currently the procedure of choice to obtain a cytologic diagnosis of adenocarcinoma. Recent reports of EUS-guided FNA of the pancreas have demonstrated the accuracy and safety of the procedure.30,31 When FNA specimens are interpreted by an experienced cytopathologist, false-positive results should are very rare, and false-negative results are becoming less common as physician experience increases. The majority of patients with adenocarcinoma of the pancreatic head have biliary obstruction at the time of diagnosis due to obstruction of the intrapancreatic portion of

Pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer 373

the common bile duct. The delivery of chemoradiation prior to pancreaticoduodenectomy delays surgery and therefore requires that patients with biliary obstruction receive some form of non-operative biliary decompression. This is usually performed with an endoscopically placed polyethylene stent. Some investigators have suggested that prosthetic biliary drains may increase the risks of chemoradiation-related morbidity and subsequent operative morbidity and mortality.31–33 In a recently published study by the Eastern Cooperative Oncology Group (ECOG), stent-related recurrent biliary obstruction with cholangitis was believed to be the cause of 38% of hospital admissions for treatment-related complications prior to pancreaticoduodenectomy.32 This experience prompted a review of the risk of stent-related morbidity at our institution.28 Among a cohort of 154 patients treated with a 3–5 weeks course of pre-operative chemotherapy and concurrent EBRT (30 or 50.4 Gy), non-operative biliary decompression was performed in 101 patients (66%): endobiliary stent placement in 77 and percutaneous transhepatic catheter placement in 24. Stentrelated complications (occlusion or migration) occurred in only 15 patients. Inpatient hospitalization for antibiotics and stent exchange was necessary in seven of 15 patients (median hospital stay, 3 days). No patient experienced uncontrolled biliary sepsis, hepatic abscess, or stent-related death. The overall risk for biliary stent occlusion (with or without cholangitis) among patients receiving chemoradiation was approximately 15%.28 This experience was not reproduced when the pre-operative interval was increased from 6–8 weeks to 3–4 months. As the pre-operative interval increased, so did the incidence of plastic stent occlusion. For this reason, we began placing covered metal stents in patients whose pre-operative interval was anticipated to be greater than 6–8 weeks.34

NOVEL APPROACHES TO CHEMORADIATION Gemcitabine-based chemoradiation trials for locally advanced disease The introduction of gemcitabine was a modest step forward in the treatment of pancreatic cancer. Its value as a systemic agent in pancreatic cancer and the recognition of its radiosensitizing properties stimulated the study of combinations of gemcitabine with EBRT for patients with localized pancreatic cancer.24,35–37 Several strategies have been investigated including seven-weekly injections of gemcitabine with short course EBRT (30 Gy), twice-weekly gemcitabine with 50.4 Gy of EBRT, weekly gemcitabine with 50.4 Gy of EBRT, and full dose weekly gemcitabine with escalating doses of radiation. Most of these studies suggested gastrointestinal toxicity as a dose-limiting factor, but hematologic toxicity has also been observed. At the present time, there is no standard approach for combining gemcitabine and radiation, but several variables appear to be important in predicting the MTD. These include variations in the size of the radiation portal, the total radiation dose, possibly the dose of radiation per fraction, and whether gemcitabine is administered once or twice weekly.38 Three multiinstitutional studies have been completed evaluating gemcitabine-based chemoradiation. In a small study performed in Taiwan, 34 patients with locally advanced pancreatic cancer were randomized to receive 5-FU based chemoradiation (500 mg/m2 daily for 3 days, every 14 days with radiation to a total dose of 50.4–61.2 Gy) or gemcitabine and radiation (600 mg/m2 weekly with equivalent doses of radiation).39 The objective response rate to gemcitabine and radiation was 50% and only 13% for 5-

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FU chemoradiation. In addition, median survival was substantially better using gemcitabine compared with 5-FU (14.5 months versus 6.7 months, pZ0.027). The efficacy results must be interpreted with caution because of the limited accrual (34 patients) and the poor results in the control group. Although the authors concluded that there was no increase in toxicity in the gemcitabine arm, therapy was actually poorly tolerated in both arms. Only 75% of patients were able to complete the full dose of radiotherapy and roughly one-third of the patients in both arms were hospitalized for 2–6 weeks due to the acute toxicity of treatment. A phase II study conducted in patients with locally advanced pancreatic cancer by the Cancer and Leukaemia Group B evaluated gemcitabine given at 40 mg/m2 twice weekly. In that study, there were 35 and 50% grade 3 or 4 gastrointestinal and hematologic toxicities, respectively, and the median survival was only 8.5 months.40 Not surprisingly, the Cancer and Leukaemia Group B abandoned this approach in locally advanced pancreatic cancer. Both of these studies used regional nodal fields that likely contributed to the significant gastrointestinal toxicity. In contrast, the approach that was developed at the University of Michigan delivers the manufacturer’s recommended dose of gemcitabine (1 g/m2) and a slightly lower radiotherapy dose (36 Gy in 15 fractions over 3 weeks), with conformal radiation fields encompassing the gross tumour volume alone. At that institution, the irradiation of a smaller volume of normal tissue was reported to be well tolerated.41 Investigators have since embarked on a multiinstitutional phase II study evaluating the same regimen. Preliminary results indicate that approximately 25% of patients experience grade 3 or 4 gastrointestinal toxicity.42 Several points about gemcitabine-based chemoradiation are worth emphasizing. Similar to its value as a systemic agent,43 gemcitabine is probably only modestly better than 5-fluorouracil when it is used with radiotherapy, but it is not tolerated as well.44 The gastrointestinal toxicity reported in the three multiinstitutional studies using gemcitabine demonstrate that the therapeutic ratio is narrow with the combination of gemcitabine and radiation. Typically either the radiation dose or the gemcitabine dose must be attenuated if the combination is to be given safely. Finally, compared with radiotherapy fields that target the gross tumour only, elective regional nodal irradiation results in increased gastrointestinal toxicity. Certainly, if gemcitabine is used in combination with irradiation on oesophageal, gastric, or duodenal mucosa, the volume of mucosa being treated should be minimized or there will be a significant risk of severe acute toxicity. While it is reasonable for investigators and clinicians with experience using any of these regimens to use them, a dose and schedule that is well tolerated in their experience should be used, particularly if the goal is to build on these studies through the incorporation of novel chemotherapeutic agents such as those that target tumour specific molecular pathways. Capecitabine-based chemoradiation The substitution of capecitabine for infusional or bolus 5-FU is less controversial than the use of concurrent gemcitabine, and has similar efficacy to intravenously administered 5-FU.45 It is an orally administered agent that has a clinical benefit response similar to that of gemcitabine in patients with locally advanced or metastatic pancreatic cancer46 and unlike gemcitabine can be given at systemic doses with radiation with a favourable toxicity profile.47,48 As demonstrated in a recently completed phase I trial conducted at our institution evaluating bevacizumab-based chemoradiation (discussed below), adjustment of the capecitabine dose when grade 2

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toxicity occurred was sufficient to limit grade 3 or greater toxicity to less than 5%48 [Manuscript in press, 11/2005]. In contrast to gemcitabine and EBRT, the favourable acute toxicity profile of capecitabine makes it an attractive chemoradiation platform upon which to integrate biologic agents. Molecular targeted therapy Oncology has entered an era of molecular therapy. In GI tumours, most notably colon cancer, agents such as bevacizumab and cetuximab have begun to change the standard of care for patients with advanced disease, and very recently erlotinib has shown some benefit in pancreatic cancer. Most investigations of these and other drugs have focused on their benefits as components of systemic therapy in patients with advanced disease, although investigation of their benefits in the adjuvant setting are now underway in colon cancer. However, these molecular therapies may play important roles as radiosensitizers. In pancreatic cancer, the anti-VEGF agent bevacizumab has been combined with gemcitabine as a treatment for patients with advanced disease, and the drug’s radiosensitizing properties are now being appreciated clinically. The possible mechanisms of radiosensitization are not clear, but could include enhanced lethality of the endothelial cell,49 the tumour cell,50 or the improvement in vascular physiology leading to a reduction in tumour hypoxia.51 The first report of bevacizumab as a radiosensitizer was reported by Willett et al.52 In the six patients treated on this study, bevacizumab was administered prior to the initiation of radiation in a group of patients with rectal cancer. Rapid changes in tumour perfusion, interstitial intratumoural pressure, and circulating endothelial cells, were all observed. In a recently completed phase I dose escalation study conducted at our institution, capecitabine and Table 1. Selected trials for patients with locally advanced pancreatic cancer. Study

Design

Arms

Endpoints

ECOG 1200

Randomized phase IIa

Primary: resectability

ECOG/RTOG 4201

Randomized phase III

RTOG PA 0411

Phase II

Gem 500 mg/m2CcisplatinC5-FU, followed by PVI 5-FUCXRT 50.4 GyC5.5 weeks Gem 500 mg/m2 weekly !5CXRT 50. 4 Gy over 5.5 weeks Gem 1 g/m2 weekly!3 (max. seven cycles) XRT 50.4 Gy over 5.5 weeksCGem 600 mg/m2 followed by Gem 1 g/m2 weekly!3 (max. five cycles) XRT 50.4 Gy over 5.5 weeksCcape 825 mg/m2 (PO BID Mon–Fri)CBev 5 mg/ kg every 2 weeks followed by Gem 1 g/m2 weekly!3 (max. three cycles)CBev 5 mg/ kg every 2 weeks

Primary: median OS Secondary: RR, RFS, toxicity, QOL Primary: 1-year OS Secondary: RR, toxicity, QOL

PVI, protracted venous infusion; 5-FU, 5-fluorouracil; Gem, gemcitabine; Cape, capecitabine; Bev, bevacizumab; XRT, radiotherapy; OS, overall survival; RR, response rate; RFS, relapse-free survival; QOL, quality of life; BID, twice daily; PO, orally; RTOG, Radiation Therapy Oncology Group; ECOG, Eastern Cooperative Oncology Group. a Intended for ‘marginally resectable’ patients without vessel encasement.

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bevacizumab were administered in combination with radiation (50.4 Gy) to 47 patients with locally advanced pancreatic cancer. The study demonstrated that bevacizumab is generally safe when combined with chemoradiation in patients with locally advanced pancreatic cancer. The acute toxicity was minimal and easily managed with dose adjustments of capecitabine, without interruption or attenuation of either the bevacizumab or radiation dose. Even though there was a 43% incidence of grade 2 gastrointestinal toxicity and a 21% incidence of grade 2 hand-foot syndrome, adjusting the dose of oral capecitabine in 43% of patients for grade 2 toxicity was sufficient to avoid grade 3 toxicity in the majority of patients. In addition, limiting radiotherapy fields to the gross tumour volume alone was probably a factor that contributed to minimizing the incidence of grade 3 acute toxicity. Bevacizumab did not appear to enhance acute toxicity; however, tumours with invasion of the duodenum appeared to be at higher risk for bleeding or perforation. Overall, the tumours in nine (20%) of 46 evaluable patients had an objective partial response to initial therapy. This included six of 12 tumours treated at a dose of 5 mg/kg of bevacizumab.48 The Radiation Therapy Oncology Group Table 2. Selected multiinstitutional trials for patients with resectable adenocarcinoma of the pancreas. Study

Design

Arms

ACOSOG Z5031

Phase II

XRT (50.4 Gy/5.5 weeks)CPVI 5-FUCIFNC CDDP weekly

EORTC 40013

Phase II/III (adjuvant/ post-op)

Surgery Gem Surgery Gem, then GemCXRT

ESPAC-3

Phase III

5-FUCLV (no XRT) Gem (no XRT)

ECOG/GI Intergroupa

Randomized phase II (adjuvant/post-op)

Surgery GemCC-225 CapeCC-225CXRT (50.4 Gy/5.5 weeks) GemCC-225 Surgery GemCBev CapeCBevCXRT (50.4 Gy/5.5 weeks) GemCBev

ACOSOG Z5041a

Phase II (preoperative/ pre-op)

GemCBev Surgery CapeCXRT (45 Gy/5 weeks)CBev

SWOG S0527a

Phase II (preoperative/ pre-op)

GemCOx C-225CXRT (50.4 Gy/5.5 weeks) Surgery GemCOx

ECOG, Eastern Cooperative Oncology Group; GI, gastrointestinal; PVI, protracted venous infusion; 5-FU, 5-fluorouracil; CDDP, cisplatin; Gem, gemcitabine; Cape, capecitabine; C-225, cetuximab; Bev, bevacizumab; XRT, radiotherapy; RTOG, Radiation Therapy Oncology Group; ACOSOG, American College of Surgical Oncology Group; IFN, Interferon; SWOG, Southwest Oncology Group; Ox, oxaliplatin; EORTC, European Organization for Research and Treatment of Cancer; ESPAC, European Study Group for Pancreatic Cancer. a In development.

Pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer 377

(RTOG) is conducting a phase II trial to evaluate capecitabine-based chemoradiation with bevacizumab (RTOG PA04-11, Table 1) which will be followed by systemic therapy with concurrent gemcitabine and bevacizumab. Patients with tumour invasion of the duodenum are specifically excluded due to the risk of duodenal hemorrhage. The American College of Surgical Oncology Group has proposed a phase II pre-operative study (Z5041) in patients who have radiographically resectable tumours. This study will incorporate concurrent bevacizumab and gemcitabine before pancreaticoduodenectomy and capecitabine, radiotherapy, and bevacizumab after pancreaticoduodenectomy (Table 2). The recommended dose of bevacizumab for further study is 5 mg/kg every 2 weeks with radiotherapy (50.4 Gy in 28 fractions) and concurrent capecitabine (825 mg/m2 twice daily Monday through Friday). Similarly, epidermal growth factor (EGFR) inhibitors hold promise as radiosensitizers, although none of the currently available inhibitors (gefitinib, erlotinib, or cetuximab) have been evaluated in multiinstitutional trials in combination with radiotherapy. Phase I studies are ongoing at Brown University and Memorial Sloan Kettering evaluating gemcitabine-based chemotherapy in combination with erlotinib. Cetuximab has been shown to improve local tumour control and overall survival in combination with EBRT alone in locally advanced head and neck cancer.53 A phase II study at our institution is evaluating gemcitabine, oxaliplatin and cetuximab, followed by capecitabine, radiation therapy (50.4 Gy) and cetuximab, followed by gemcitabine and cetuximab until progression. Trials that combine cetuximab or erlotinib with bevacizumab and EBRT for the treatment of pancreatic cancer are anticipated in the near future.

DOWNSTAGING LOCALLY ADVANCED, UNRESECTABLE DISEASE Patients with locally advanced disease often have complete encasement of the SMA or celiac axis. In this setting, even the most active chemoradiation therapy regimens that cause marked tumour cell killing would not be expected to result in a margin-negative resection. In contrast, there are patients who have marginally resectable disease, in whom the pancreatic tumour abuts or cuffs a portion of the SMA or other vascular structure. There is a widespread perception that unresectable pancreatic tumours can be converted to resectable ones with the use of chemoradiation. The interpretation of whether this actually occurs is limited by inconsistent and subjective definitions of resectability and by inadequate pre-operative radiologic assessments of resectability. Probably the most variable factor in determining resectability and thus interpreting whether a tumour has been converted to resectable from unresectable is the meaning of vascular involvement. Although most surgeons would agree that tumour encasement of either the celiac artery or the SMA constitutes unresectable disease, opinions vary with regard to more limited arterial involvement. It is probably in this group of patients that, theoretically, active cytotoxic therapy could lead to ‘downstaging’. Another factor affecting the determination of resectability and of whether resectability can be increased is the meaning of tumour involvement of the superior mesenteric/portal venous confluence. Tumour extension to a venous structure without occlusion is not an absolute contraindication to resection. As described elsewhere in this edition, these veins can be successfully resected and reconstructed at the time of pancreaticoduodenectomy. However, many surgeons would consider this type of tumour extension, seen either during surgery or on pre-operative imaging, as evidence of unresectability. Thus, the attribution of increased resectability to chemoradiation in

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some studies could simply be due to a difference in surgical opinion and practice. Thus, the existence of broader definitions of locally advanced pancreatic cancer gives the impression that resectability is increased more commonly than it actually is. Another potential confounding variable in the interpretation of resectability is the lack of reproducible imaging before and after chemoradiation. Imaging that is not designed to address the issue of vascular involvement may not have resolution that is adequate for making an assessment. Thus, computed tomographic scans taken of the same patient at different times may result in different interpretations, even without therapy being administered. An objective clinical definition of resectability is critical in the assessment of patients with localized pancreatic cancer. In order to evaluate whether a particular therapy has converted an unresectable tumour to a resectable one, reproducible imaging with adequate resolution during phase contrast administration before and after chemoradiation must be used.54 Although many studies have reported increased resectability following chemoradiation has occurred, very fulfilment of the criteria is the exception rather than the rule. Even with loose criteria and inconsistent imaging technique, ‘downstaging’ after 5-fluorouracil-based chemoradiation is uncommon. Review of the available literature suggests that a small number (8–16%) of clinically unresectable cases treated with 5-fluorouracil-based chemoradiation have eventually undergone marginnegative resection.55–61 The use of newer radiosensitizing agents and combinations with radiotherapy could result in increased local tumour response and possibly increased resectability in patients with locally advanced disease, but this has not been clearly demonstrated yet. Ideally, all studies using novel chemoradiation regimens should adhere to a strict CT-based definition of locally advanced pancreatic cancer that includes arterial involvement (low-density tumour inseparable from the SMA or celiac axis on contrast-enhanced CT) or occlusion of the superior mesenteric/portal venous confluence when the issue of converting an unresectable tumour to a resectable one is addressed. As the quality of pancreatic imaging has improved, there is growing recognition of a distinct subset of marginally or borderline resectable tumours. Although a consensus definition does not exist, our institutional criteria for a borderline resectable pancreatic cancer include: tumour abutment of less than1808 of the SMA, short segment abutment of the common hepatic artery (typically at the origin of the gastroduodenal artery), and segmental venous occlusion.62 The National Comprehensive Cancer Network (NCCN) has defined this subgroup as locally advanced, resectable tumours. These patients are at a high risk for margin positive resection with initial surgery. In our opinion, these patients should be considered for pre-operative therapy to improve their chances of negative margin resection. In our institution, most of these patients are offered pre-operative therapy and patients whose tumours show radiographic stability or regression and an improvement in serum tumour markers then are candidates for pancreaticoduodenectomy. Mehta et al has reported on the Stanford University experience using pre-operative infusional 5-FU and radiation in patients with marginally resectable disease.63 Fifteen patients received chemoradiation and of these, nine (60%) ultimately underwent surgical resection with negative margins. Two patients were reported to have complete pathological responses. Pre-operative therapy for borderline resectable tumours is also part of the focus of an ECOG randomized phase II trial in which patients will receive either gemcitabine-based chemoradiation, or a regimen of 5-FU, gemcitabine, and cisplatin, followed by 5-FU-based chemoradiation (Table 1).

Pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer 379

RADIOTHERAPY TECHNIQUE AND DOSE The standard dose of radiotherapy in the post-operative setting is typically 50.4 Gy in 28 fractions. Field reductions are often made after 45 Gy. Standard-fractionation EBRT to 50.4 Gy has also been used in the pre-operative setting. As discussed above, 30 Gy in 10 fractions has provided equivalent local tumour control especially when combined with gemcitabine as a radiosensitizer. It is likely that the majority of the benefit from chemoradiation results from the treatment of the retroperitoneal margin. While there may not be universal agreement about the size and shape of standard radiation fields, the SMA origin and the celiac axis must be covered with adequate margins. A three- or four-field technique using anterior, posterior, and opposed lateral fields allows critical tissues, such as the liver, kidneys, stomach, spinal cord, and small bowel, to be spared. For tumours located in the pancreatic head, the anterior and posterior fields typically cover the T11-L3 vertebral bodies, although the visceral anatomy is quite variable in relation to the bony anatomy. The porta hepatis should be identified on CT and included in all fields. Inferiorly, the goal is to cover the tumour and duodenal bed with a 2-cm margin. The right border of the anterior and posterior fields and the anterior extent of the lateral fields are defined by the pre-operative location of the duodenum. The left border of the anterior and posterior fields is placed 2 cm to the left of the vertebral body edge, as long as there is adequate coverage of the pre-operative tumour volume. This usually means that the upper right border of the anterior and posterior fields is located 4–5 cm to the right of the vertebral body edge, and the anterior aspect of the lateral field is 5–6 cm from the anterior vertebral body edge. Blocking is placed over the inferior pole of the right kidney in the anterior and posterior fields, bisecting the vertebral bodies in the lateral fields. Corner blocks are typically placed in the anterior aspect of the lateral fields as well. Care should be taken not to block the preoperative tumour volume or the porta hepatis in the lateral fields. For lesions of the pancreatic body and tail, similar principles are applied to field location and the splenic hilum is covered while the porta hepatis and duodenal bed are not; the right field border is typically located 2 cm from the right vertebral body edge. Similar treatment fields are recommended for patients with an intact pancreas if the goal is pre-operative therapy with planned surgical resection. However, if the concurrent chemotherapeutic agent is gemcitabine, we recommend conformal radiation fields confined to the gross tumour, grossly enlarged adenopathy, superior mesenteric artery and celiac axis.

CONCLUSION Theoretical advantages of pre-operative therapy compared to post-operative therapy are now supported by phase III data in the adjuvant treatment of rectal cancer. In pancreatic cancer patients, additional advantages include addressing the systemic failure risk earlier, increased access to therapy and potential avoidance of futile surgery in patients with rapidly progressive metastatic disease. In the case of pancreatic cancer, accurate, reproducible imaging that reliably predicts resectability is essential to select patients that are appropriate for a pre-operative approach. Also, accurate tissue diagnosis and the non-invasive re-establishment of biliary outflow are also critical. The success of pre-operative chemoradiation programs depends on multidisciplinary

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coordination, appropriate patient selection and safe and coordinated delivery of therapy.

Practice points † patient selection is the key to successful pancreaticoduodenectomy. † clinical staging using multidetector computed tomography accurately identifies patients with resectable tumours. † efficacy and toxicity advantages of pre-operative chemoradiation have been demonstrated over post-operative chemoradiation in rectal cancer patients. † using a pre-operative treatment strategy allows better patient selection for pancreaticoduodenectomy and increased access to therapy for patients. † enrolment of patients on clinical trials is critical for the overall improvement of existing treatment strategies in pancreatic cancer. REFERENCES 1. Exocrine pancreas. In Greene FL, Page DL & Fleming ID et al (eds.) AJCC Cancer Staging Manual, 6th edn. New York: Springer, 2002, pp. 157–164. 2. Tseng JFRC, Lee JE, Pisters PW et al. Pancreaticoduodenectomy with vascular resection: margin status and survival duration. J Gastrointest Surg 2004; 8: 935–949 [discussion 949–50]. 3. Macdonald JS, Smalley SR, Benedetti J et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725– 730 [comment]. 4. Krook JE, Moertel CG, Gunderson LL et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324: 709–715 [see comments]. 5. Anonymous. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Gastrointestinal Tumor Study Group. Cancer 1987; 59: 2006– 2010. 6. Kapiteijn E, Marijnen CA, Nagtegaal ID et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345: 638–646. 7. Breslin TM, Hess KR, Harbison DB et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg 2001; 8: 123–132. 8. Sohn TA, Yeo CJ, Cameron JL et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000; 4: 567–579. 9. Lim JE, Chien MW & Earle CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg 2003; 237: 74–85. 10. Klinkenbijl JH, Jeekel J, Sahmoud T et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999; 230: 776–782 [discussion 782–4]. 11. Neoptolemos JP, Stocken DD, Friess H et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200–1210. 12. Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731–1740 [see comment]. 13. Raut CP, Evans DB, Crane CH et al. Neoadjuvant therapy for resectable pancreatic cancer. Surg Oncol Clin N Am 2004; 4: 639–661. 14. Pisters PWT, Wolff RA, Janjan NA et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin Oncol 2002; 20: 2537–2544. 15. Breslin TM, Hess KR, Harbison DB et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol 2001; 8: 123–132.

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