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Journal of Clinical Oncology, Vol 25, No 3 (January 20), 2007: pp. 326-331 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.5663 Impact of Chemoradiotherapy After Disease Control With Chemotherapy in Locally Advanced Pancreatic Adenocarcinoma in GERCOR Phase II and III Studies
From the Departments of Radiation Oncology and Medical Oncology, Tenon Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP); Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris; Department of Gastroenterology, Beaujon Hospital, AP-HP, Clichy; Clinique Saint Jean, Lyon; Department of Radiation Oncology, Grenoble University Hospital, Grenoble, France; and the Department of Medical Oncology, Ospedali Riuniti, Bergamo, Italy Address reprint requests to Florence Huguet, MD, Service d'Oncologie Radiothérapie, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France; e-mail: florence.huguet{at}tnn.aphp.fr
PURPOSE: The management of locally advanced (LA) pancreatic cancer patients remains controversial. To select patients who could benefit from chemoradiotherapy (CRT), the therapeutic strategy used by the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) consisted of initial chemotherapy (CT) for at least 3 months. The decision to administer CRT or continue CT in nonprogressive patients was the investigator's choice. PATIENTS AND METHODS: Retrospective analysis of outcome in 181 patients with LA pancreatic cancer (76 women and 105 men; mean age, 61 years; range, 37 to 85 years) enrolled onto prospective phase II and III GERCOR studies was performed to compare the survival of patients who received CRT with that of patients who continued CT alone. RESULTS: Median progression-free survival (PFS) and overall survival (OS) times for the 181 patients were 6.3 and 11.4 months, respectively. Fifty-three patients (29.3%) had metastatic disease after 3 months of CT and were not eligible for CRT. Among the 128 remaining patients (70.3%) who had no disease progression and who were, therefore, eligible for CRT, 72 (56%) received CRT (group A), whereas 56 (44%) continued with CT (group B). The two groups were balanced for initial characteristics (performance status, sex, age, and type of CT), as well as for induction CT results. In groups A and B, the median PFS times were 10.8 and 7.4 months, respectively (P = .005), and the median OS times were 15.0 and 11.7 months, respectively (P = .0009). CONCLUSION: These results suggest that, after control of disease by initial CT, CRT could significantly improve survival in patients with LA pancreatic cancer compared with CT alone. A prospective phase III study is ongoing to evaluate this strategy.
Pancreatic adenocarcinoma is the fifth most common cause of cancer death in the Western world.1 The estimated number of new cases of pancreatic cancer in France is approximately 5,000 per year.2 The prognosis of this cancer is very poor, with less than 5% of patients still alive after 5 years.3 Surgical resection is the only possibility for cure, and only 5% to 20% of these tumors are considered resectable at diagnosis.4 Indeed, metastases are present at diagnosis in 50% of patients. In patients with metastatic disease, median survival time ranges from 3 to 6 months.3 For the other 30% of patients, the tumor is surgically unresectable but confined to the pancreatic region without distant metastases, with median survival time ranging from 5 to 11 months.5 Optimal therapy for patients with locally advanced (LA) pancreatic carcinoma remains controversial. Currently, there are two therapeutic options. In the early 1980s, fluorouracil (FU) -based concomitant chemoradiotherapy (CRT) was shown to be better than radiotherapy alone.5 The results of two randomized trials comparing CRT versus chemotherapy (CT) were contradictory. The first trial, an Eastern Cooperative Oncology Group study,6 concluded that survival was similar with CT and CRT. The second trial, a Gastrointestinal Tumor Study Group phase III study,7 found that CRT was more effective. Gemcitabine has improved the outcome of patients with advanced disease (26% LA, 74% metastatic) by improving survival with a clinical benefit.8 Furthermore, a fraction of patients with LA disease developed metastases within a few weeks and died very quickly despite the type of treatment.9 CRT is a time-consuming and constraining therapy with adverse effects. To select patients who might benefit from CRT, the therapeutic strategy used by the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) consisted of initial CT for at least 3 months. The decision to administer CRT or continue CT in patients whose disease had not progressed was left up to the investigator. In this study, we retrospectively analyzed the data from 181 patients with LA pancreatic adenocarcinoma who were included prospectively in the multicenter GERCOR phase II and III studies based on the same criteria. The aim of this study was to assess whether initial CT effectively identified patients with rapidly progressing disease who were unlikely to benefit from radiotherapy and to evaluate the potential benefit of administering CRT after initial CT in patients whose disease had not progressed and who had an Eastern Cooperative Oncology Group performance status (PS) of less than 2.
Patients The multicenter GERCOR phase II studies of leucovorin, FU, and gemcitabine (FOLFUGEM) 1,10 FOLFUGEM 2,11 and gemcitabine and oxaliplatin (GEMOX)12 and the GERCOR-Italian Group for the Study of Digestive Tract Cancer phase III study of gemcitabine alone versus GEMOX (Gem-GEMOX)13 included 497 patients with advanced pancreatic adenocarcinoma between July 1997 and February 2003 to evaluate the efficiency of various CT regimens (Table 1). These studies included both patients with LA and patients with metastatic pancreatic adenocarcinoma. In patients with LA disease, administration of CRT was recommended if the disease had not progressed after 3 months of CT and if PS was less than 2. The investigators could follow this recommendation or choose to continue CT. Data from all the patients with LA cancer enrolled onto these studies were analyzed, as well as the data from 14 additional patients who received compassionate care with the same therapeutic strategy after completing the GEMOX phase II trial and before beginning the Gem-GEMOX phase III trial.
Eligibility Criteria Eligibility criteria were the same in all studies.10-13 Eligible patients had histologically confirmed pancreatic adenocarcinoma. None of the patients had any evidence of distant metastases confirmed by abdominal computed tomography scan and chest x-ray at enrollment; however, tumors were unresectable because of encasement or occlusion of the superior mesenteric vein or portal vein and/or direct involvement of the celiac axis, superior mesenteric artery, inferior vena cava, or aorta assessed by surgical exploration or computed tomography scan. Patients with evidence of peritoneal carcinomatosis were excluded from the study. Patients with Vater's ampulloma or adenocarcinoma of the biliary tract were not eligible. Patients were not to have received prior CT or radiotherapy, had a Karnofsky PS  60%, and were between 18 and 75 years old with a life expectancy of more than 3 months. Pain and biliary obstruction had to be controlled before inclusion onto the study. Adequate hematologic (neutrophil count > 1,500/µL and platelet count > 100,000/µL), renal (serum creatinine < 1.5x the upper limit of normal [ULN]), and hepatic (alkaline phosphatase < 5x ULN and bilirubin < 1.5x ULN) function were required. The four prospective studies were approved by the institutional review board (Comité Consultatif de Protection des Personnes pour la Recherche Biomédicale). Written informed consent was obtained from each patient before inclusion onto any study.
Treatment Plan Concomitant CRT. CRT was only administered when the patient's general condition (PS < 3) made it possible and if there was no disease progression after at least 3 months of CT. CRT was recommended and not obligatory. CRT was started at least 28 days after the last cycle of CT. The investigators recommended that patients be treated according to a schedule adapted from the study by Whittington et al.14 A planning computed tomography scan was required to define target volumes. The following volumes were based on the International Commission on Radiation Units and Measurements 50 Report15: the gross tumor volume (GTV) was determined during the planning computed tomography scan slice by slice using the computed tomography simulation software or the three-dimensional treatment planning software; the clinical target volume (CTV) was defined as the GTV, the pancreatic area, the regional lymph nodes, and adjacent organs; and the planning target volume 1 (PTV1) included the CTV plus a safety margin of 1 cm in all transverse directions and 2 cm craniocaudally to allow for breathing. In general, the PTV could be determined by taking into account the following structures: the upper field limit was at the top edge of the thoracic vertebral body 11, the lower limit was at the base of the lumbar vertebral body 3, the dorsal field limit was in the middle of the vertebral bodies T11 to L3, and the ventral limit was 2 cm beyond the anterior limit of the CTV. After 45 Gy, the reduced PTV (PTV2) was limited to the GTV and the retroperitoneal para-aortic lymph nodes between the celiac trunk and the upper mesenteric artery plus a safety margin of 15 mm in all transverses directions. Typical fields are presented in Figure 1. Organs at risk (OARs) were the kidneys, the spinal cord, and the liver. All OARs had to be contoured to generate dose-volume histograms and maximum-tolerated doses. Treatment was performed with a linear accelerator of at least 10 MV energy with an isocentric technique. PTV1 was treated with four isocentric fields, two anteroposterior and two lateral, treated all days. PTV2 was treated with two opposite fields, anterior and posterior or oblique, to minimize the dose to OARs, especially kidneys. Customized blocks or multileaf settings were used to minimize the radiation dose to the normal tissues and OARs. Dose-volume histograms of PTV, kidneys, liver, and spinal cord were mandatory to select the optimal dose distribution plan. The prescribed total dose at the reference point (isocenter) of the PTV was 55 Gy in fractions of 1.8 Gy five times weekly. During the last 2 weeks of treatment, the patients received a boost of 10 Gy in 8 fractions (four 1.25-Gy fractions/wk) restricted to the initial tumor volume and the celiac area (PTV2) administered as a second daily fraction. During the 5 weeks of irradiation, patients received a continuous daily infusion of FU 250 mg/m2/d by outpatient pump 7 days a week.
Baseline Treatment Evaluations Baseline biologic analyses (CBC, serum creatinine, bilirubin, AST, ALT, alkaline phosphatase, and CA 19-9 levels) and tumor measurement (computed tomography scan) were performed within the week and the month preceding treatment initiation, respectively. Within the 3 days preceding each cycle, a physical examination and CBC were performed. PS, weight, pain assessment using a visual analog scale, and analgesic consumption were recorded to evaluate the clinical benefit.
Assessment of Efficacy
Statistics
Patient Characteristics One hundred sixty seven of the 497 patients enrolled onto the four GERCOR studies10-13 had LA pancreatic cancer (Table 1). Fourteen additional patients were treated with a compassionate GEMOX regimen. The demographic and clinical characteristics of the 181 patients analyzed in this study are listed in Table 2.
After 3 months of initial CT, 128 patients (71%) had no local or metastatic progression and remained in acceptable general condition (PS < 2), and they were eligible to receive CRT. The 53 remaining patients (29.3%) were not (45 patients had progressive disease, and eight were lost to follow-up). Among the 128 patients who were eligible for CRT, 72 patients (56%) received CRT (group A), and 56 patients (44%) did not receive CRT and continued CT (group B; Fig 2).
Toxicity Toxicity of CT. Toxicities of each CT regimen have been previously reported.10-13 Toxicity of CRT. Data collection concerning the toxicity of CRT was not planned in the FOLFUGEM 1, FOLFUGEM 2, GEMOX, or Gem-GEMOX trials.
Efficacy The 128 remaining patients (70.3%) had no disease progression and a PS less than 2, and thus, they were eligible to receive CRT. For these patients, the PFS and OS times were 8.7 and 13.1 months, respectively, with 57% of patients still alive after 1 year. Seventy-two of these patients (56%) received CRT (group A), whereas 56 (44%) continued CT alone (group B). The two groups were well balanced for initial characteristics (sex, age, PS, and type of CT) and results (response rate, clinical benefit response, percentage of weight loss, and evolution of the PS; Table 3). In groups A and B, the median PFS times were 10.8 and 7.4 months, respectively (P = .005; Fig 3A); and the median OS times were 15.0 and 11.7 months, respectively (P = .0009; Fig 3B); 1-year survival rates were 65.3% and 47.5%, respectively.
Treatment of patients with LA pancreatic cancer is still under debate. The results of CT alone for this form of cancer are often difficult to evaluate in the literature because most trials pool patients with LA and metastatic cancers. Many investigators administer CRT on the first intention and then CT until the disease progresses.6,9,17,18 Table 4 lists the main results of phase II and III trials of FU-based CRT and gemcitabine-based CT that have individualized patients with LA tumors. Few studies have compared CT and CRT.5-7 Two of the studies demonstrated that CRT was more effective than CT.5,7 Recently, Chauffert et al26 have reported the results of a phase III trial that compared CRT (60 Gy of irradiation with a combination of FU and cisplatin) followed by gemcitabine with gemcitabine alone to assess whether CRT improves survival. An intermediate analysis showed that survival was lower in patients with initial CRT compared with those who received gemcitabine as the initial treatment (8.4 v 14.3 months, respectively; P = .014), and the study was stopped after 119 patients had been included. The reasons for these results are being investigated. An important concern about administering CRT as first-line treatment in patients with LA pancreatic cancer is that approximately 30% of them have occult metastatic disease at diagnosis and, thus, they will clearly not benefit from this locoregional treatment.
In the present study, we tested another treatment option for these patients by using CT first followed by CRT in patients with controlled tumors (ie, stable disease or with an objective response). Our results show that this strategy is potentially effective for selecting a subgroup of patients without early metastatic course who can potentially benefit from CRT. Administration of CT as first-line treatment provides approximately 3 months to help identify patients with undetectable metastases. Hence, the tumor progressed in 29% of patients in our study during the first 3 months of CT, so they did not receive CRT. The median OS time was only 4.5 months in these patients. In contrast, patients without tumor progression during the 3 months of CT had a median OS time of 13.1 months. As a result, the patients who received CRT had significantly better survival than those who continued CT alone, with median OS times of 15 and 11.7 months, respectively (P = .0009). Although all patients were enrolled onto prospective studies with the same eligibility criteria, our study is retrospective, which precludes drawing definitive conclusions about this strategy. Baseline characteristics and the results of initial CT between the CRT and the continuous CT groups were not statistically different. However, there was a trend for favorable prognostic factors in the CRT group. In addition, the choice of receiving CRT or continuing CT was based on the investigator's decision; thus, undefined factors could have influenced their decision. In a phase II trial, Mishra et al27 tested a similar strategy using first-line CT and treated 20 patients with LA pancreatic cancer using CT with combined irinotecan and gemcitabine followed by radiotherapy (50.4 Gy) and concurrent twice-weekly gemcitabine. As in this study, 35% of patients exhibited disease progression after two cycles of CT. Time to progression and OS time were 5.1 and 8.8 months, respectively. In the subgroup of patients without progressive disease, the median OS time was 9.6 months. In a large, recently presented retrospective series, Rana et al28 compared CRT with (73 patients) or without (245 patients) CT induction. Results were in favor of first-line CT followed by CRT compared with CRT alone (OS, 11.9 v 8.5 months, respectively; P = .0004). In our study, the duration of treatment in the CRT group was deliberately limited in time, and it was completed the last day of irradiation. We did not propose maintenance CT until disease progression. In a phase II study by Epelbaum et al,29 the treatment proposed consisted of an induction phase of CT with gemcitabine (7 weeks) in 20 patients, followed by CRT (50.4 Gy and concurrent gemcitabine 400 mg/m2 weekly) in patients who had both clinical benefit response and reduced or stable tumor size. Overall, 10 patients (50%) were eligible to receive CRT. In contrast to our study, the administration of gemcitabine was continued after the completion of CRT. In a phase II study by Schneider et al,30 the authors administered subsequent CT with gemcitabine after the CRT was completed. They reported a grade 4 hematologic toxicity rate of 25%. Many studies of CRT use a therapeutic sequence with prior CRT and then CT until disease progression,6,9,29,30 but increased toxicity of CT after CRT limits this strategy. In conclusion, our results strongly suggest that, in patients with LA pancreatic cancer, CT should be administered as first-line treatment. CRT could be administered thereafter in nonprogressive patients who remain in acceptable condition (ie, PS < 2) because it seems that CRT potentially increases survival compared with CT continuation. However, because of possible bias in this retrospective analysis, a prospective study is mandated to validate this therapeutic strategy. Such a randomized phase III trial is ongoing with the GERCOR and Arbeitsgemeinschaft Internisttische Onkologie (AIO) groups.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant:Thierry André, Roche; Aimery de Gramont, Roche, Sanofi-Aventis Stock: N/A Honoraria: Thierry André, Sanofi-Aventis, Pfizer Inc, Merck Lipha; Pascal Hammel, Sanofi-Aventis; Frédéric Selle, Bristol-Myers Squibb Co; Aimery de Gramont, Roche, Sanofi-Aventis, Yakult; Christophe Louvet, Sanofi-Aventis, Pfizer Inc Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Florence Huguet, Thierry André, Pascal Artru, Jacques Balosso, Aimery de Gramont, Christophe Louvet Provision of study materials or patients: Florence Huguet, Thierry André, Pascal Hammel, Pascal Artru, Frédéric Selle, Elisabeth Deniaud-Alexandre, Philippe Ruszniewski, Emmanuel Touboul, Roberto Labianca, Aimery de Gramont, Christophe Louvet Collection and assembly of data: Florence Huguet, Thierry André, Christophe Louvet Data analysis and interpretation: Florence Huguet, Thierry André, Emmanuel Touboul, Aimery de Gramont, Christophe Louvet Manuscript writing: Florence Huguet, Thierry André, Pascal Hammel, Aimery de Gramont, Christophe Louvet Final approval of manuscript: Florence Huguet, Thierry André, Pascal Hammel, Pascal Artru, Jacques Balosso, Frédéric Selle, Elisabeth Deniaud-Alexandre, Philippe Ruszniewski, Emmanuel Touboul, Roberto Labianca, Aimery de Gramont, Christophe Louvet
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Van Cutsem E, van de Velde H, Karasek P, et al: Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430-1438, 2004 22. Rocha Lima CM, Green MR, Rotche R, et al: Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:3776-3783, 2004 23. Reni M, Passoni P, Panucci MG, et al: Definitive results of a phase II trial of cisplatin, epirubicin, continuous-infusion fluorouracil, and gemcitabine in stage IV pancreatic adenocarcinoma. J Clin Oncol 19:2679-2686, 2001 24. Stathopoulos GP, Rigatos SK, Dimopoulos MA, et al: Treatment of pancreatic cancer with a combination of irinotecan (CPT-11) and gemcitabine: A multicenter phase II study by the Greek Cooperative Group for Pancreatic Cancer. Ann Oncol 14:388-394, 2003 25. El-Rayes BF, Zalupski MM, Shields AF, et al: Phase II study of gemcitabine, cisplatin, and infusional fluorouracil in advanced pancreatic cancer. J Clin Oncol 21:2920-2925, 2003 26. Chauffert B, Mornex F, Bonnetain F, et al: Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: A FFCD-SFRO study. J Clin Oncol 24:180s 2006 (suppl; abstr 4008) 27. Mishra G, Butler J, Ho C, et al: Phase II trial of induction gemcitabine/CPT-11 followed by a twice-weekly infusion of gemcitabine and concurrent external beam radiation for the treatment of locally advanced pancreatic cancer. Am J Clin Oncol 28:345-350, 2005[CrossRef][Medline] 28. Rana V, Krishnan S, Abbruzzese JL, et al: Neoadjuvant chemotherapy improves outcomes of chemoradiation therapy for locally advanced pancreatic cancer. J Clin Oncol 24:187s, 2006 (suppl, abstr 4036) 29. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher's exact tests, when suitable, were used to compare qualitative data (initial characteristics of patients and results of initial CT). Differences were assumed to be significant when P < .05. 
