Phase 1 Trial of Preoperative, Short-Course Carbon-Ion Radiotherapy for Patients With Resectable Pancreatic Cancer

Transcription

1 Phase 1 Trial of Preoperative, Short-Course Carbon-Ion Radiotherapy for Patients With Resectable Pancreatic Cancer Makoto Shinoto, MD 1,2 ; Shigeru Yamada, MD, PhD 1 ; Shigeo Yasuda, MD, PhD 1 ; Hiroshi Imada, MD, PhD 1 ; Yoshiyuki Shioyama, MD, PhD 3 ; Hiroshi Honda, MD, PhD 2 ; Tadashi Kamada, MD, PhD 1 ; Hirohiko Tsujii, MD, PhD 1 ; Hiromitsu Saisho, MD, PhD 4 ; and Working Group for Pancreas Cancer BACKGROUND: The authors evaluated the tolerance and efficacy of carbon-ion radiotherapy (CIRT) as a short-course, preoperative treatment and determined the recommended dose needed to reduce the risk of postoperative local recurrence without excess injury to normal tissue. METHODS: Patients radiographically defined with potentially resectable pancreatic cancer were eligible. A preoperative, short-course, dose-escalation study was performed with fixed 8 fractions in 2 weeks. The dose of irradiation was increased by 5% increments from 30 grays equivalents (GyE) to 36.8 GyE. Surgery was to be performed 2 to 4 weeks after the completion of CIRT. RESULTS: The study enrolled 26 patients. At the time of restaging after CIRT, disease progression with distant metastasis or refusal ruled out 5 patients from surgery. Twenty-one of 26 patients (81%) patients underwent surgery. The pattern of initial disease progression was distant metastasis in 17 patients (65%) and regional recurrence in 2 patients (8%). No patients experienced local recurrence. The 5-year survival rates for all 26 patients and for those who underwent surgery were 42% and 52%, respectively. CONCLUSIONS: Preoperative, short-course CIRT followed by surgery is feasible and tolerable without unacceptable morbidity. Cancer 2013;119: VC 2012 American Cancer Society. KEYWORDS: preoperative, short course, carbon-ion radiotherapy, pancreatic cancer, phase 1. INTRODUCTION The number of deaths from pancreatic cancer in Japan exceeds 26,000 per year, and the incidence is increasing year by year. 1 Pancreatic cancer is the fifth leading cause of cancer death, and it is considered 1 of the most lethal cancers in Japan. Complete surgical resection has traditionally been considered the only curative treatment, but high rates of local and systemic failure persist in patients who undergo curative resections, and the 5-year survival rate is <20%. 2,3 In an effort to improve outcomes, multidisciplinary approaches have been used. Previous randomized trials have suggested the prominent role of chemotherapy as adjuvant treatment. 2,4,5 Thus, in Japan, the use of gemcitabine as adjuvant treatment in patients with resectable pancreatic cancer is recommended in terms of efficacy and safety. 6 Nonetheless, the role of neoadjuvant treatment is still controversial. Recent prospective and retrospective studies suggest that the combination of preoperative chemoradiation and surgery improves survival duration; however, randomized controlled trials have not been performed In terms of strategy for local tumor control, radiotherapy may have an important role, because local recurrence rates remain high after surgery alone (range, 40%-80%). 2,11-13 Carbon-ion radiotherapy (CIRT) offers the potential advantage of improved dose localization and enhanced biologic effect. 14 Preoperative CIRT is expected to be effective in eliminating the retroperitoneal microinvasion of malignant cells, which cannot be removed by surgery. When a combination of CIRT and surgery is used to maximize local tumor control, patients with resectable pancreatic cancer may benefit in terms of improved overall survival. The objective of the current study was to investigate the safety of preoperative, short-course CIRT for patients with resectable pancreatic cancer. MATERIALS AND METHODS Patient Eligibility Patients were eligible if they had radiographically assessable, radically resectable pancreatic cancer without involvement of the hepatic artery, celiac trunk, or superior mesenteric artery and if they were without evidence of metastatic disease. Eligible patients were aged <80 years and had an Eastern Cooperative Oncology Group performance status of <2 and Corresponding author: Makoto Shinoto, MD, Hospital of Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba, Japan; Fax: (011) ; shinoto@nirs.go.jp 1 Hospital of Research Center for Charged Particle Therapy, National Institute of Radiological Sciences. Chiba, Japan; 2 Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 3 Department of Heavy Particle Therapy and Radiation Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 4 Department of Internal Medicine and Clinical Oncology, Kaken Hospital, Chemotherapy Research Institute, Chiba, Japan DOI: /cncr.27723, Received: March 20, 2012; Revised: May 23, 2012; Accepted: May 31, 2012, Published online June 28, 2012 in Wiley Online Library (wileyonlinelibrary.com) Cancer January 1,

2 Figure 1. These computed tomography images illustrate dose distribution for treatment planning. Colored isodose lines indicate 95%, 90%, 70%, 50%, 30%, 20%, and 10% dose areas (from inside to outside). adequate organ function to tolerate surgery. Patients were excluded if they had received prior therapy for pancreatic cancer or previous radiotherapy to the upper abdomen and if they had a concomitant malignancy, active inflammatory bowel disease, active gastric/duodenal ulcer, mental disorder, or other severe concurrent disease. The treatment protocol for the current study was reviewed and approved by the National Institute of Radiological Sciences Ethics Committee of Human Clinical Research, and all patients signed an informed consent form before the initiation of therapy. Carbon-Ion Radiotherapy All patients were positioned in customized cradles (Moldcare; Alcare, Tokyo, Japan) and immobilized with a low-temperature thermoplastic shell (Shellfitter; Kuraray, Osaka, Japan). A set of 2.5-mm-thick or 5-mm-thick computed tomography (CT) images was taken for treatment planning with the immobilization devices under respiratory gating. Three-dimensional treatment planning of CIRT was performed using the HIPLAN software program (National Institute of Radiological Sciences, Chiba, Japan). 15,16 Field arrangements generally were designed using a 3-field plan. The clinical target volume was defined as the gross tumor volume with a 5-mm margin and the locoregional elective lymph node and neuroplexus region. The locoregional elective lymph node region included the celiac, superior mesenteric, peripancreatic, portal, and para-aortic region for pancreatic head cancers and the splenic region for pancreatic body and tail cancers. The planning target volume included the clinical target volume with a 5-mm margin for possible positioning Table 1. Dose-Escalation Schedule and the Number of Treated Patients Dose Level CIRT, GyE No. of Patients No. who Underwent Resection Abbreviations: CIRT, carbon-ion radiotherapy; GyE, gray equivalents. errors, respecting anatomic boundaries such as stomach, duodenum, small intestine, and transverse colon. In patients who had tumors located close to critical organs, the margins were reduced accordingly. The tumor extent was evaluated by CT, magnetic resonance imaging (MRI), and positron emission tomography (PET). A typical dose distribution is illustrated in Figure 1. Patients received CIRT out daily 4 days per week (Tuesday through Friday). In a dose-escalated study, we started irradiation at a dose of 30 Gray equivalents (GyE) in 8 fractions, fixed the irradiation fractions, and increased the radiation dose by increments of 5%. Doses of carbon ion were expressed in photon equivalent doses, which were defined as the physical doses multiplied by the relative biologic effectiveness of the carbon ions. 16 The doseescalation schedule is provided in Table 1. Surgery All patients underwent restaging CT scans to evaluate resectability before surgery. Resectable disease was defined 46 Cancer January 1, 2013

3 Preoperative CIRT for Pancreatic Cancer/Shinoto et al Figure 2. The treatment schema is illustrated for preoperative carbon-ion radiotherapy (CIRT) and surgery. Patients received CIRT in 8 fixed fractions (8fr.) over 2 weeks and underwent surgery 2 to 4 weeks after the completion of CIRT. as the absence of distant metastasis and no infiltration of main arteries, such as the common hepatic, celiac, and superior mesenteric arteries. Invasion of the portal vein, superior mesenteric vein, or splenic vein was not a contraindication to resection, and these vessels were resected if necessary. Patients were to undergo surgical resection 2 to 4 weeks after the completion of CIRT (Fig. 2). Patient Evaluation for Toxicity and Response Acute reactions of normal tissues after CIRT were classified according to National Cancer Institute Common Toxicity Criteria (version 2.0) within 90 days of the start of CIRT. Late reactions were classified according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring system or Late Effects in Normal Tissues (LENT) Subjective, Objective, Management, and Analytic scales scoring system. A dose-limiting toxicity (DLT) was defined as any grade 3 or greater acute toxicity. Toxicities that were not caused by CIRT were not classified as DLTs, for example, cholangitis from a blocked biliary stent and symptoms related to tumor progression, such as pain or bowel obstruction. Patients were evaluable for DLT regardless of whether they underwent surgery after preoperative CIRT. Patient cohorts consisted of a minimum of 3 patients at each dose level. If no DLT was observed in the initial 3 patients, then the dose was escalated in successive cohorts. If DLT was observed in 1 or 2 of the initial 3 patients at a given level, then 3 additional patients were evaluated at the same level. If only 1 or 2 of these patients experienced DLT, then the next level of dose schedule would begin enrollment. If 3 or more patients experienced DLT at a given level, then the previous level would be considered the maximally tolerated dose (MTD). Tumor response was determined by comparing pre- CIRT and post-cirt CT scans and was assessed using Response Evaluation Criteria in Solid Tumors. A complete response (CR) was defined as disappearance of the primary tumor, and a partial response (PR) was defined as a decrease 30% in the greatest dimension of the primary tumor. The response rate was defined as the percentage of patients achieving either a CR or a PR. Progressive disease was defined as an increase 20% in the greatest dimension of the primary tumor. Stable disease was identified as a tumor response not definable as CR, PR, or progressive disease. Furthermore, histologic response to preoperative CIRT was judged by an assessment of cytologic change in conjunction with quantification of the amount of viable residual carcinoma cells. A grade 0 treatment response was defined as the destruction of no tumor cells, a grade 1 response was defined as the destruction of less than twothirds of tumor cells, a grade 2 response was defined as the destruction of greater than two-thirds of tumor cells, and a grade 3 response indicated the presence of no viable tumor cells. Follow-Up Patients were followed by CT, MRI, or PET scans every 3 to 6 months. Local recurrence was defined in terms of lesions occurring in the planning target volume based on CT, MRI, or PET scans. The absence of local recurrence was described as local control. Recurrent disease was diagnosed by imaging studies, and biopsy confirmation was not obtained. Statistical Analysis The primary endpoint of this study was to evaluate acute reactions in normal tissues that determine the MTD and response rate of preoperative CIRT. The secondary endpoint was to assess the rates of late toxicity, local control, and overall survival. Local control and overall survival were calculated from the first day of CIRT using the Kaplan-Meier method. RESULTS Patient Characteristics Twenty-nine patients were recruited into this study between April 2003 and December Three patients were ineligible because of liver metastases that became obvious before CIRT. Thus, 26 patients were enrolled in the study. The characteristics of the eligible patients are listed in Table 2. The median age was 66 years (range, years). The Eastern Cooperative Oncology Group performance status was 0 in 20 patients and 1 in 6 patients. The median serum CA 19-9 level was U/mL (range, ,200 U/mL). Three to 6 patients were treated at each dose level until the MTD was reached. Cancer January 1,

4 Toxicity Acute and late toxicities are listed in Table 3. All patients completed the scheduled treatment course without treatment breaks, and no DLT was observed. One patient developed acute grade 3 toxicity, which was a liver abscess caused by intraportal chemotherapy for liver metastases after surgery; however, it was not classified as a DLT, because we judged that it was not caused by CIRT. One patient developed late grade 4 toxicity, consisting of deterioration of liver function because of portal vein stenosis 3 months after pancreaticoduodenectomy with combined resection of the long segment of the superior mesentericsplenic-portal vein confluence. No other serious adverse effects were observed. Table 2. Patient Characteristics at Baseline Characteristic All patients 26 Sex Men 15 Women 11 Median age (range), y 66 (40-79) ECOG PS Tumor location Head 16 Body-tail 10 Clinical stage: UICC 6th IIA 15 IIB 11 Surgery PD 15 DP 5 TP 1 Bypass 2 No surgery 3 No. of Patients Abbreviations: DP, distal pancreatectomy; ECOG PS, Eastern Cooperative Oncology Group performance status; PD, pancreatoduodenectomy; TP, total pancreatectomy; UICC 6th, International Union Against Cancer TNM Classification of Malignant Tumors, 6th edition. Response Regarding local response, 1 patient achieved a PR, the remaining 25 patients had stable disease, and no patients had progressive disease at the completion of CIRT. All 26 patients completed all planned CIRT. The radiographic findings of local effects for the 26 patients at restaging before surgery were stable disease in 25 patients and a PR in 1 patient. Twenty-one patients (81%) underwent resection, and no patient experienced a delay in planned surgery. The resections included 15 pancreaticoduodenectomies, 5 distal subtotal pancreatectomies, and 1 total pancreatectomy. Five patients did not undergo surgery, 4 because of metastatic progression and 1 because of refusal. No patient was had unresectable disease based on local tumor extension. The median time from the last day of CIRT to surgical resection was 20 days (range, days). Pancreatic ductal adenocarcinoma was confirmed in all resected patients. Nineteen of 21 patients (90%) underwent complete resection with no microscopic residual tumor (R0), and the other 2 patients had microscopically positive pancreatic transection margins (R1). One of the 2 patients who had a positive pancreatic cut-end margin, and according to an intraoperative rapid diagnosis, was believed to require total pancreatectomy to achieve radical resection, but this was not done because of her advanced age. Although she experienced regional recurrence after adjuvant chemotherapy, she received definitive CIRT, and the disease was controlled. The other patient with positive pancreatic transection margins did not receive adjuvant therapy because of refusal. Nevertheless, he had no evidence of recurrence. The histologic characteristics of the 21 resection specimens are listed in Table 4. All tumor specimens revealed evidence of grade 1 or 2 treatment effects, indicating that there were no marked differences among the respective dose levels. The median follow-up for survivors was 33.8 months. At last follow-up, 10 of 26 patients were alive, and 9 were disease free. Disease progression was noted in 19 patients, including 5 patients who did not undergo Table 3. Acute and Late Toxicities Acute Toxicities Late Toxicities NCI-CTC RTOG/EORTC Toxicity No No Skin Gastrointestinal Liver Portal vein Leakage Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; NCI-CTC, National Cancer Center Common Toxicity Criteria; RTOG, Radiation Therapy Oncology Group. 48 Cancer January 1, 2013

5 Preoperative CIRT for Pancreatic Cancer/Shinoto et al Table 4. Histologic Characteristics of the 21 Resection Specimens Dose Level No. of Patients Figure 4. Survival curves are illustrated for all 26 patients and for the patients who underwent surgical resection (n ¼ 21) versus those who did not undergo surgical resection (n ¼ 5). Figure 3. The local control rate is illustrated. resection. The pattern of initial disease progression was distant metastases in 17 patients (65%) and regional recurrence (defined as extra-ptv recurrence) in 2 patients (8%). None of the patients (100%) experienced local recurrence (Fig. 3). Two patients who experienced regional recurrence underwent salvage surgery or received definitive CIRT, and their disease was completely controlled. The median relapse-free survival was 6.2 months. The relapse-free survival rates at 1 year, 3 years, and 5 years were 40%, 23%, and 23%, respectively. The median overall survival was 18.6 months. The overall survival rates at 1 year, 3 years, and 5 years were 69%, 42%, and 42%, respectively, in all 26 patients. For the 21 patients who underwent surgery, the median overall survival has not yet been reached; the overall survival rates at 1 year, 3 years, and 5 years were 81%, 52%, and 52%, respectively (Fig. 4). This study did not reach the MTD, but dose level 5 was considered the recommended dose because of its prominent local control effect. DISCUSSION The objective of the current prospective study was mainly to evaluate the safety of preoperative, short-course CIRT in patients with resectable pancreatic cancer. In this doseescalation study, all patients completed the planned 2-week CIRT without developing severe toxicity. No patient experienced a decline in performance status or a delay in surgery. Spitz et al suggested that preoperative chemoradiation was more beneficial than postoperative chemoradiation. 17 Their experience indicated that pancreatic resection was too extensive and complex a procedure to enable the consistent postoperative delivery of standard-fractionation, adjuvant chemoradiation. Those authors reported that 24% of patients in their study did not receive postoperative adjuvant therapy because of delayed recovery from surgery. Other previous studies reported that preoperative chemoradiation did not increase the incidence of perioperative complications 18,19 ; however, grade 3 or greater toxicity was observed in approximately 20% to 40% of patients who received preoperative chemoradiation. 7,17,20 One meta-analysis of preoperative therapy for patients with resectable pancreatic cancer demonstrated that the rate of grade 3/4 toxicity was an estimated 26.3%. 21 In our current study, there was no grade 3/4 toxicity during preoperative CIRT. This is because carbon ions can be concentrated to a localized lesion, and damage to normal tissue is reduced. Our protocol comprised a short course received in only 8 fractions over 2 weeks, and the time to surgery also was short. There was little change, such as fibrosis after radiation, and the influence of the surgical maneuver was minimal. Conversely, pathologic evaluation did not reveal any CRs, and the pathologic response was not very prominent relative to the local control rate, because the time from the start of CIRT to surgery was too short for its adequate evaluation. In fact, 1 patient who had a positive dissected peripancreatic tissue margin had no evidence of local recurrence without any treatment. Cancer January 1,

6 A 2-month or 3-month protocol usually is adopted as preoperative therapy. Standard-fractionation, preoperative radiotherapy with concurrent chemotherapy is received for 5 to 6 weeks; then, patients undergo surgical resection 4 to 6 weeks after they complete chemoradiation. Preoperative chemoradiation may reduce the risk of local recurrence after surgery and contribute to prolonging median survival. Furthermore, this assessment may identify patients who present with rapid progressive or disseminated disease at restaging and, thus, have a very poor prognosis; for these patients, surgery is unlikely to provide any benefit. Conversely, there is the potential risk of tumor progression during neoadjuvant therapy; that is, patients who initially have resectable tumors may present with local or distant tumor progression at restaging, which may not have occurred in the setting of an initial tumor resection. Conversely, in preoperative, short-course CIRT, the risk of local or distant tumor progression during pretreatment is low because of the powerful local control achieved with CIRT. The high resection rate (81%) after preoperative treatment in our study was discriminative compared with reports from previous studies (range, 63%-73%). 21,22 Furthermore, since 2006, the resection rate has been 94% (15 of 16 patients). This may be associated with the development of multidetector CT or MRI technology, which improves the accuracy of predicting resectability or the detection of micrometastases to the liver. 23 Preoperative, short-course CIRT decreased the risk of postoperative local recurrence, although 65% of patients experienced distant metastases, and their prognosis was dismal; we considered that distant metastases already existed at the beginning of preoperative treatment in the form of microscopic metastases. In our study, concurrent or adjuvant chemotherapy was not permitted without obvious disease failure, although such treatments may be of further help in improving the prognosis of patients who had distant metastasis that became clinically evident after surgery. The combination of chemotherapy with CIRT may prolong the disease-free interval and survival, but a radical cure cannot be expected for patients who have microscopic metastatic disease, because current chemotherapy does not have enough power to eliminate pancreatic cancer cells completely. For patients who have microscopic metastases, it is important to avoid unnecessary surgery. For that reason, a more accurate diagnostic modality for pretreatment evaluation has to be established. If the probability of distant metastasis cannot be ruled out in patients who have resectable pancreatic cancer, then the treatment strategy may be switched from surgery to systemic chemotherapy or chemoradiation. In conclusion, the current results indicate that preoperative, short-course CIRT followed by early surgery is feasible and tolerable in patients who have potentially resectable pancreatic cancer. Although our sample size was too small to allow us to draw definitive conclusions, we believe it is reasonable to expect that a reduction in the risk of local recurrence will lead to an increase in the cure rate. The efficacy of this regimen will require investigation in a phase 2 study. FUNDING SOURCES This study was supported by the Research Project with Heavy Ions at the National Institute of Radiological Sciences-Heavy Ion Medical Accelerator in Chiba (NIRS-HIMC). CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. REFERENCES 1. Matsuda T, Marugame T, Kamo KI, et al. Cancer incidence and incidence rates in Japan in 2005: based on data from 12 population-based cancer registries in the Monitoring of Cancer Incidence in Japan (MCIJ) Project. Jpn J Clin Oncol. 2011;41: Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297: Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg. 1993;165:68-72; discussion Ueno H, Kosuge T, Matsuyama Y, et al. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer. 2009;101: 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: Yamaguchi K, Tanaka M. EBM-based clinical guidelines for pancreatic cancer 2009 from the Japan Pancreas Society: a synopsis. Jpn J Clin Oncol. 2011;41: Hong TS, Ryan DP, Blaszkowsky LS, et al. Phase I study of preoperative short-course chemoradiation with proton beam therapy and capecitabine for resectable pancreatic ductal adenocarcinoma of the head. Int J Radiat Oncol Biol Phys. 2011;79: Sasson AR, Wetherington RW, Hoffman JP, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: analysis of histopathology and outcome. Int J Gastrointest Cancer. 2003;34: Moutardier V, Magnin V, Turrini O, et al. Assessment of pathologic response after preoperative chemoradiotherapy and surgery in pancreatic adenocarcinoma. Int J Radiat Ooncol Biol Phys. 2004;60: White RR, Xie HB, Gottfried MR, et al. Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer. Ann Surg Oncol. 2005;12: Nitecki SS, Sarr MG, Colby TV, et al. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg. 1995;221: Willett CG, Lewandrowski K, Warshaw AL, et al. Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy. Ann Surg. 1993;217: Westerdahl J, Andren-Sandberg A, Ihse I. Recurrence of exocrine pancreatic cancer local or hepatic? Hepatogastroenterology. 1993;40: Cancer January 1, 2013

7 Preoperative CIRT for Pancreatic Cancer/Shinoto et al 14. Brown KM, Siripurapu V, Davidson M, et al. Chemoradiation followed by chemotherapy before resection for borderline pancreatic adenocarcinoma. Am J Surg. 2008;195: Kanai T, Furusawa Y, Fukutsu K, et al. Irradiation of mixed beam and design of spread-out Bragg peak for heavy-ion radiotherapy. Radiat Res. 1997;147: Kanai T, Endo M, Minohara S, et al. Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy. Int J Radiat Oncol Biol Phys. 1999;44: Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. JClinOncol. 1997;15: Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127: Hoffman JP, Weese JL, Solin LJ, et al. A pilot study of preoperative chemoradiation for patients with localized adenocarcinoma of the pancreas. Am J Surg. 1995;169:71-77; discussion Hoffman JP, Lipsitz S, Pisansky T, et al. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 1998;16: Gillen S, Schuster T, Meyer Zum Buschenfelde C, et al. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages [serial online]. PLoS Med. 2010;7:e Le Scodan R, Mornex F, Girard N, et al. Preoperative chemoradiation in potentially resectable pancreatic adenocarcinoma: feasibility, treatment effect evaluation and prognostic factors, analysis of the SFRO-FFCD 9704 trial and literature review. Ann Oncol. 2009;20: Kim YE, Park MS, Hong HS, et al. Effects of neoadjuvant combined chemotherapy and radiation therapy on the CT evaluation of resectability and staging in patients with pancreatic head cancer. Radiology. 2009;250: Cancer January 1,