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Journal of Clinical Oncology, Vol 26, No 7 (March 1), 2008: pp. 1080-1085 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.8223 Concomitant Administration of Weekly Oxaliplatin, Fluorouracil Continuous Infusion, and Radiotherapy After 2 Months of Gemcitabine and Oxaliplatin Induction in Patients With Locally Advanced Pancreatic Cancer: A Groupe Coordinateur Multidisciplinaire en Oncologie Phase II Study
From the Hôpital Tenon and Hôpital Saint Antoine, Groupe Hospitalo-Universitaire Est, Université Paris VI, Paris; Centre Hospitalier Universitaire de Grenoble, Université Joseph Fourier, Grenoble; Institut Sainte Catherine, Avignon; Centre Hospitalier Universitaire Saint André, Université Victor Segalen, Bordeaux; Clinique Saint-Jean, Lyon; and Centre de Radiothérapie, Le Mans, France Address reprint requests to Laurence Moureau-Zabotto, MD, Hopital Tenon, service de radiothérapie, 4 rue de la Chine, 75020 Paris, France; e-mail: moureaul{at}marseille.fnclcc.fr
Background According to previously reported Groupe Coordinateur Multidisciplinaire en Oncologie (GERCOR) studies in locally advanced pancreatic cancer (LAPC), concomitant chemoradiotherapy (CCRT) may be recommended for patients who do not experience disease progression after systemic induction chemotherapy (CT). To further improve patient outcome with classical fluorouracil (FU)-based CCRT, this study was designed to prospectively investigate a CCRT with FU infusion and weekly oxaliplatin after 2 months of gemcitabine and oxaliplatin (GEMOX) induction chemotherapy. Patients and Methods Nonpretreated patients with LAPC having WHO performance status (PS) of 0 to 2 received four induction cycles of GEMOX (gemcitabine 1 g/m2 on day 1 and oxaliplatin 100 mg/m2 on day 2; day 1 of a 15-day cycle). One month after cycle 4, patients who did not experience disease progression with PS 0 to 2 received 45 Gy over 5 weeks + 10 Gy (as a concomitant boost during the last 2 weeks) of radiotherapy (RT), with daily 250 mg/m2 FU as a continuous infusion and 60 mg/m2of oxaliplatin weekly. Results Of 59 patients, 50 patients (84.7%) received CCRT, whereas nine patients did not because of disease progression (seven patients), CT toxicity (one patient), or personal decision (one patient). Forty-four patients (74.5%) completed the fully planned CCRT. Median progression-free survival and overall survival durations were 7.6 and 12.2 months, respectively, for the whole population and 9.4 and 12.6 months, respectively, for patients who completed CCRT. CCRT grade 3 to 4 toxicities (National Cancer Institute Common Toxicity Criteria) were neutropenia (10.4%), thrombocytopenia (8.4%), nausea and vomiting (16.7%), and diarrhea (12.5%). Conclusion Concomitant administration of weekly oxaliplatin, continuous-infusion FU, and RT in patients with LAPC is feasible, with an acceptable acute and late safety profile. The encouraging results observed despite a nonoptimal patient selection (owing to the short induction time) indicates that further randomized evaluation to better define the specific role of oxaliplatin in CCRT is deserved.
The incidence of pancreatic carcinoma has increased over recent decades, and it is now the fourth leading cause of cancer-related death in the world.1 Despite certain advances in diagnosis, surgical procedures, radiotherapy (RT), and/or chemotherapy (CT), the prognosis of patients with pancreatic cancer remains extremely poor, with approximately 4% of patients alive at 5 years.2 Surgical resection offers the only possibility for cure, but only 10% to 20% of tumors are resectable at the time of diagnosis.3 Metastases are present at diagnosis in 50% of patients, and median survival ranges from 3 to 6 months.4 For the 30% to 40% remaining patients, the tumor is unresectable but confined to the pancreatic area without distant metastasis, and median survival ranges from 6 to 10 months.5 Optimal therapy for patients with locally advanced pancreatic cancer (LAPC) remains controversial. In the early 1980s, fluorouracil (FU)-based concomitant chemoradiotherapy (CCRT) was proven to be superior to RT alone: a study conducted by the Gastrointestinal Tumor Study Group compared radiotherapy alone (40 to 60 Gy) with CCRT with bolus FU and showed significant improvement in medial survival with CCRT from 5 to 10 months.6 Two other studies compared CT alone (FU and streptozotocin, mitomycin, and FU) to CCRT with bolus FU. The first study,7 with substantial methodologic bias, did not show a difference between FU alone and CCRT, whereas the second8 showed a significant difference in favor of CCRT. Therefore, CCRT was considered as the reference palliative treatment consisting of two or three monthly fractions of 20 Gy, combined during the first 3 days of each fraction, with a bolus of 500 mg/m2 of FU. One feasibility study of daily continuous-infusion FU combined with RT (60 Gy) was undertaken. The maximum-tolerated dose of FU was 250 mg/m2/d. Median survival was 12 months, with 19% of patients alive at 2 years.9 However, this reference treatment of CCRT in patients with LAPC has not been widely adopted. Considering the frequent metastatic evolution of LAPC, and the potential side effects of CCRT, many patients are treated with CT alone. Most trials investigating various CT regimens include patients with LAPC as well as those with metastatic disease. Given available data on patients with LAPC included in phase III studies, median survivals of patients treated with CT alone (8.7 to 11.7 months)10-12 seem to be in the same range as those of patients treated with CCRT alone (8.3 to 11.4 months).6-8,13 Such a comparison should be cautiously taken into account, because data for CCRT come mainly from older studies with small sample sizes, longer accrual periods, and lack of computed tomography imaging for staging, as compared with the CT studies. Furthermore, some patients included in the CT studies could have benefited from CCRT after CT induction and/or second-line therapies. During the last 10 years, patients with LAPC included in the successive Groupe Coordinateur Multidisciplinaire en Oncologie (GERCOR) studies were treated with initial CT to select, after 3 months, patients who did not experience disease progression who might potentially benefit from CCRT. The choice between CCRT or CT prolongation for such patients was based on investigator decision. This experience was recently summarized by Huguet et al.14 Approximately 30% of LAPC patients experienced metastatic disease progression after 3 months and so were not considered for CCRT. For the remaining 70% of patients, 56% received CCRT and 44% had further CT treatment alone. Patients treated with CCRT had a better outcome as compared with patients treated with CT alone. This strategy should be confirmed via an ongoing randomized study. Several schedules of CCRT have been tested to improve the efficiency of the classical FU bolus CCRT, such as RT combined with FU infusion, FU with cisplatin, or gemcitabine. In rectal cancer, it has been shown that combined chemoradiotherapy regimens of continuous-infusion FU, folinic acid, and oxaliplatin are efficient and well tolerated. Given that oxaliplatin has been shown to be a good radiosensitizer,15-20 CCRT with FU and oxaliplatin deserves to be investigated in patients with LAPC. Gemcitabine combined with oxaliplatin (GEMOX) has been shown to be a safe and efficient regimen in the management of patients with advanced pancreatic carcinomas.21 This regimen was the first combined treatment to be superior to gemcitabine alone in terms of clinical benefit and response rate, but not in terms of overall survival (OS).11 However, whether second-line therapies affected OS (ie, cross-over to the GEMOX regimen for patients randomly assigned to the gemcitabine arm) remained unresolved in this study. We report here the results of a phase II trial in patients with LAPC using GEMOX CT induction for 2 months followed by a systematic CCRT regimen of 55 Gy with FU infusion and weekly oxaliplatin for patients who did not experience disease progression.
Eligibility Criteria All eligible patients had histopathologically confirmed nonresectable pancreatic adenocarcinoma without evidence of visceral metastasis; patients with Vater's ampulloma, adenocarcinoma of the biliary tract, and/or neuroendocrine tumors were not eligible. Central review of pathology was not performed. Eligible patients had not received prior radiotherapy, had a WHO performance status (PS) ofuuu 0 to 2, were older than 18 years, had no uncontrolled infection, and had adequate hematologic (neutrophil count  1,500/mL; platelet count 100,000/mL), renal (serum creatinine  3 mg/dL or clearance 40 mL/min), and hepatic (bilirubin 1.5 x the upper limit of normal values and alkaline phosphatases 5 x the upper limit of normal) function. Pain and biliary obstruction had to be controlled in all patients before inclusion in the study. Unresectability was assessed by an experienced surgeon either during laparotomy or by radiologic work-up (abdomino-pelvic computed tomography scan and/or magnetic resonance imaging [MRI] ± ultrasound endoscopy) showing portal and/or mesenteric and/or celiac vascular involvement. Any extrapancreatic disease was an exclusion criterion. The protocol was approved by the institutional ethics committee (Hôpital Pitié-Salpetrière, Paris, France), and written informed consent was obtained from each patient.
Staging, Response, and Toxicity Assessment
Treatment A planning computed tomography scan was required to define target volumes. The radiation fields were based on tumor volume estimated by the pretreatment computed tomography scan. The following volumes were based on the International Commission on Radiation Units and Measurements 50 Report23: 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 was defined as the GTV, the pancreatic area, the regional lymph nodes, and adjacent organs; the planning target volume 1 (PTV1) included the clinical target volume plus a safety margin of 1 cm in all transverse directions and 2 cm craniocaudally to allow for breathing. 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 transverse directions. Typical fields were previously described.15 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 with at least 10 MV of energy with an isocentric technique. PTV1 was treated with four isocentric fields, two anteroposterior and two lateral, treated on all days. PTV2 was treated with two opposite fields, anterior and posterior or oblique, to minimize the dose to OARs, especially the 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 PTV1 was 45 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 eight fractions (four 1.25-Gy fractions/wk) restricted to the PTV2 administered as a second daily fraction. In case it was not possible to deliver two daily fractions, the 10-Gy boost was delivered during a sixth week of RT, without concomitant CT (five fractions of 2 Gy in 1 week). No central nor quality assurance of the radiation fields was planned in the study. 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 and a weekly administration of oxaliplatin on days 1, 8, 15, 22, and 29 in 1-hour intravenous perfusion (initially 50 mg/m2 and then increased to 60 mg/m2 in absence of toxicity > grade 2 after the first three patients). Unacceptable toxicity criteria were defined as follows: grade 4 toxicity or toxic death, grade 3 toxicity of more than 3 weeks' duration after the end of the CCRT, or treatment stopping on patient request because of intolerance. CT was administered first in the morning and the RT session was scheduled at least 2 hours later. Proton pump inhibitors were given for the first time at day 1 of CCRT and for 1 year. The use of sucralfate was optional. Antiemetics were routinely prescribed according to the customary usage of each physician. The use of corticosteroids was allowed, as well as the use of erythropoietin. All patients had a permanent venous access device.
In case of neutrophils count greater than 500/mm3 but less than 1,000/mm3, and/or platelets greater than 50,000/mm3 but less than 75,000/mm3, CT was delayed until recovery, but RT was pursued. In case of neutrophils count less than 500 and/or platelets less than 50,000, both CT and RT were delayed until recovery and FU/oxaliplatin doses were lowered 25% with full-dose RT. In case of grade 2 neuropathy lasting more than 15 days, oxaliplatin dose was lowered 25%; and in case of neurotoxicity
Statistical Methods Survival was calculated from day 1 of CT until death. Disease-free survival was calculated from day 1 of CT until the date of local or distant relapse. Survival curves were obtained using the Kaplan and Meier methods.24 All end points were updated on June 30, 2007.
Patients From November 2003 to July 2005, 59 eligible patients were accrued, and their characteristics are listed in Table 1.
Induction Chemotherapy Fifty-four of 59 patients completed the four planned cycles of induction chemotherapy. For five patients, treatment was stopped because of either early progression or toxicity. A total of 223 cycles were administered, with a median of four cycles per patient (range, one to four cycles), and a mean of 3.8 cycles. All patients were evaluated for toxicity. Maximal toxicity data are listed in Table 2. Almost 27% of patients presented a grade 3 to 4 toxicity, without any grade 3 neurotoxicity nor febrile neutropenia.
CCRT Fifty patients underwent CCRT (84.7%), whereas nine patients did not for the following reasons: progressive disease or removed from study before first evaluation (seven patients), CT toxicity (one patient), and personal decision (one patient). Forty-four patients (74.5%) received the full planned CCRT dose-intensity. The initial dose of oxaliplatin was 50 mg/m2, which was increased to 60 mg/m2 as planned by the protocol, because none of the first three included patients developed toxicity more than grade 2. Six patients started CCRT but did not complete the full planned treatment and were removed from the study for the following reasons: toxicity (three patients), protocol deviation (one patient; six cycles of GEMOX instead of four), and personal reasons (two patients). Toxicity data related to CCRT are available for 48 of 50 patients and are listed in Table 3. Grade 3 to 4 toxicities were observed in 35.5% of patients, mainly gastrointestinal grade 3 toxicity. Three febrile neutropenia episodes were observed. Late toxicities are defined by all toxicity events recorded from 60 days after CCRT completion to death or study withdrawal. Data were available for the 44 patients who completed CCRT and are listed in Table 4. Almost 27% of patients presented a grade 3 to 4 toxicity, mainly hematologic grade 3. One patient had a grade 3 persistent neuropathy and one other a febrile neutropenia episode. No gastrointestinal bleeding was observed.
Tumor Response The tumor responses were radiographically evaluated after induction CT and 2 months after completion of CCRT. Response rates are listed in Table 5.
Survival With a median follow-up of 30 months, median progression-free survival (PFS) and OS of the whole population were 7.6 and 12.2 months, respectively, with 52.1% of patients alive at 1 year and 20.8% of patients alive at 2 years. For the 44 patients who completed CCRT, median PFS and OS were 9.4 and 12.6 months, respectively. For the 15 patients who did not receive CCRT, or for whom CCRT was not fully completed, median PFS and OS were 4.1 and 8.6 months, respectively.
There is no consensus on whether patients with LAPC should receive CT alone, CCRT, or the combination of both treatments. We previously postulated that primary CT helps to identify patients who may potentially benefit from CCRT, therefore sparing almost 30% of patients from unnecessarily enduring this intense treatment.14 The outcome of patients not experiencing disease progression after 3 months of CT induction seems to be better if subsequent CCRT is administered as compared with continuation of CT. However, in this review, the decision to administer CCRT or to continue CT in patients not experiencing disease progression was not randomized and was based on the investigator's choice, which may have implied uncontrolled bias according to patient's specific factors and individual investigator's habits. This precludes drawing definitive conclusions about this strategy, which is currently prospectively investigated through an international randomized trial comparing CT alone versus CT induction followed by CCRT. The present work is the first GERCOR prospective study where patients with LAPC not experiencing disease progression systematically received CCRT. Only approximatively 15% of patients could not receive CCRT, which is lower than the 29% rate described by Huguet et al.14 This may be due to the low number of CT cycles administered (four cycles), as well as the earlier evaluation (2 months v 3 months) before the decision to treat with CCRT, which was done to restrict the cumulative dose of oxaliplatin to less than 800mg/m2 and consequently to limit the risk of cumulative neuropathy; only four cycles of GEMOX induction have been administered to allow the planned oxaliplatin-based CCRT. As a result, the tolerance of induction chemotherapy (26.7% of grade 3 to 4 events, without any grade 3 neuropathy) was better than that reported in the literature with the GEMOX regimen. The risk of further cumulative neuropathy will no longer be a limiting problem because the GEMOX regimen cannot be considered as a standard of care for advanced pancreatic cancer after the results of the Eastern Cooperative Oncology Group 6201 study results.25 The limited duration of induction CT finally resulted in a high proportion of patients with metastasis progression at the end of CCRT in this study (26% + 12% nonassessable patients), and then failed to optimize patient selection to demonstrate any substantial benefit of CCRT. Despite this, the median OS achieved in this study (12.2 months) is in the upper level of the survival rate range reported for patients with LAPC. The results achieved with this concomitant association of RT and FU plus oxaliplatin, which has never been previously described in LAPC, are promising. Furthermore, this combination was well tolerated. The 36.7% rate of grade 3 to 4 events compares favorably with the tolerance of a cisplatin with FU plus RT combination, where the rate of grade 3 to 4 events has been reported to be more than 60% and up to 85%.26-28 Addition of oxaliplatin to FU plus RT does not seem to impair the tolerance of FU plus RT, where the grade 3 to 4 event rate is reported to range between 20% and 51%.26,28,29 Results of FU plus oxaliplatin plus RT tolerance also compares favorably with the different schedules of gemcitabine-based CCRT.30 In conclusion, concomitant administration of weekly oxaliplatin, continuous-infusion FU, and RT after CT induction in LAPC is active and feasible, with an acceptable safety profile. Duration of induction CT should, however, be longer than 2 months to achieve an optimal selection of patients who might potentially benefit from CCRT. The strategy using CT induction followed by CCRT deserves prospective randomized validation, which is currently being investigated. Thereafter, this oxaliplatin-based CCRT regimen could be compared with classical FU-based CCRT in future randomized studies to assess the specific role of oxaliplatin in CCRT for patients with LAPC.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Thierry André, Sanofi-Aventis; Christophe Louvet, Sanofi-Aventis Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Laurence Moureau-Zabotto, Thierry André, Emmanuel Touboul, Jacques Balosso, Christophe Louvet Provision of study materials or patients: Laurence Moureau-Zabotto, Jean-Marc Phélip, Pauline Afchain, Laurent Mineur, Thierry André, Véronique Vendrely, Gerard Lledo, Olivier Dupuis, Florence Huguet, Emmanuel Touboul, Jacques Balosso, Christophe Louvet Collection and assembly of data: Laurence Moureau-Zabotto, Thierry André, Christophe Louvet Data analysis and interpretation: Laurence Moureau-Zabotto, Thierry André, Christophe Louvet Manuscript writing: Laurence Moureau-Zabotto, Thierry André, Emmanuel Touboul, Christophe Louvet Final approval of manuscript: Laurence Moureau-Zabotto, Jean-Marc Phélip, Pauline Afchain, Laurent Mineur, Thierry André, Véronique Vendrely, Gerard Lledo, Olivier Dupuis, Florence Huguet, Emmanuel Touboul, Jacques Balosso, Christophe Louvet
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
