Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial's pre-planned analysis and case report of a 5.5-year disease-free survival

Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced... Background: To explore possible improvement in the treatment of locally advanced pancreatic carcinoma (LAPC) we performed a randomized, non-comparative phase II study evaluating docetaxel - plus either daily continuous 5 FU or weekly cisplatin concurrent to radiotherapy. We report here the results of the docetaxel plus 5 FU regimen stopped according to the interim analysis. The docetaxel plus cisplatin arm was continued. Methods: Forty (40) chemotherapy-naive patients with unresectable LAPC were randomly assigned (1:1) to either 2 2 continuous fluorouracil (5-FU) 200 mg/m /day (protracted IV) and docetaxel (DCT) 20 mg/m /week or DCT 20 mg/ 2 2 m and cisplatin (CDDP) 20 mg/m , plus concurrent radiotherapy for a period of 6 weeks. The radiation dose to the primary tumor was 54 Gy in 30 fractions. The trial’s primary endpoint was the 6-month crude non-progression rate (NPR). Secondary endpoints were tolerance, objective response rate, and overall survival. Accrual was to be stopped if at 6 months more than 13 disease progressions were observed in 20 patients. Results: Eighteen (18) progressions occurred at 6 months in the 5-FU-DCT arm. Six-month NPR was 10% (95%CI: 0-23). Six and 12-month survivals were 85% (95%CI: 64-95) and 40% (95%CI: 22-61); median overall survival was 10.1 months. Median progression-free survival was 4.3 months. We report the case of one patient who was amenable to surgery and has been in complete response (CR) for 5.5 years. Toxicities grade ≥ 3 were reported in 75% of patients; no treatment-related death occurred. Severe toxicities were mainly vomiting (35%), abdominal pain (10%) and fatigue (10%). Conclusions: Combination of 5-FU, docetaxel and radiotherapy has inadequate efficacy in the treatment of LAPC despite good tolerance for the 5-FU-DCT regimen. Trial Registration: ClinicalTrials.gov: NCT00112697 Background diagnosis has remained unchanged, around (15%-20%), Pancreatic cancer (PC) is an extremely aggressive malig- over the past decades [2]. More than 50% of patients with th nancy and the 4 cause of all cancer deaths worldwide [1]. PC are unresectable because of the metastatic spread of Unfortunately, because of the typically late onset of symp- the disease at initial presentation, and the remaining 30% toms and the persistent lack of early detection, the rate of unresectable are due to local extension with vascular PC cases amenable to surgical resection at the time of involvement [3]. Overall, the acknowledged 5-year survival rate for exocrine pancreas adenocarcinoma is around 3% - * Correspondence: ducreux@igr.fr 5% [4,5]. In case of loco-regional disease development, Institut Gustave Roussy, Villejuif, France survival is relatively better. However, with a median Full list of author information is available at the end of the article © 2011 Oberic et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Oberic et al. Radiation Oncology 2011, 6:124 Page 2 of 7 http://www.ro-journal.com/content/6/1/124 survival of only 6 to 8 months the patient’s chances of sur- FNCLCC and the participating institutions. Trial registra- viving several years remain low. About 10%-15% of tion: Current Controlled Trials NCT00112697; resected patients survive more than 5 years and less than 5% more than 10 years [5,6]. Patient Population Compared to radiotherapy alone, 5-FU concurrent Patients of age > 18 years and < 75 years with pathologi- radiotherapy has become a widespread standard that can cally confirmed unresectable locoregional advanced ade- be used in locally advanced PC, either pre- or post-opera- nocarcinoma of the exocrine pancreas were eligible. tively [7]. In the pre-operative setting, chemoradiation is Other histological subtype of pancreatic tumors including used to gain locoregional control in the treatment of neuroendocrine tumor and ampulla of Vater were not border line resectable cancer [8]. Chemoradiation facili- eligible. Unresectability was defined by a surgeon and tates or makes the resection possible, especially when the evaluated after laparotomy or according to CT-scan and/ tumor is too large or if it makes contact with the vascular or endoscopic criteria, including vascular involvement. system. Post-operative chemoradiation is used to Measurable disease was required. Patients with clinical or improve survival [9]. Although there is no definite evi- radiologic diagnosis of metastases were excluded. No dence of the superiority of either its tolerance or efficacy prior chemotherapy was allowed; patients were required compared to bolus 5-FU, continuous (protracted) 5-FU to have a Karnofsky performance status (PS) higher than intravenous infusion, delivered with concurrent radio- 70, adequate baseline bone marrow function (i.e., neutro- therapy (RT), is of common use in the treatment of a philes count > 1,500/μL and platelets > 100,000/μL), nor- number of gastrointestinal cancers including pancreatic mal serum creatinine levels (< 120 μmol/l), and bilirubin and colorectal carcinoma [10,11]. Continuous infusion levels < 1.5 times the upper limit of normal (ULN) after insures a more constant concentration of radio-sensitiz- biliary drainage. Patients with prior history of another ing agent at the tumor site throughout the period of primary tumor within the last 10 years, except adequately radiotherapy. Although 5-FU-based chemoradiation has treated in situ carcinoma of the cervix uteri and basal or an acceptable response rate (20%) and a low toxicity, squamous cell skin carcinomas, and patients with grade the ideal schedule has not yet been established [12]. II peripheral neuropathy according to NCI-CTC criteria Docetaxel (DCT) is a semisynthetic taxane with a large were excluded. Written informed consent was obtained spectrum of antitumoral activity including pancreatic according to the French regulations. cancer [13]. The activity of this drug in first-line meta- static patients has been demonstrated as has its radiosen- Treatment Plan sitizing potential [14-16]. Several phase II and phase III Patients were randomly assigned to receive continuous 2 2 trials have shown that the addition of both cisplatin and 5-FU 200 mg/m /day and docetaxel (DCT) 20 mg/m / fluorouracil to docetaxel did not increase toxicity [17]. week (Figure 1) or weekly docetaxel and cisplatin. Treat- The Federation Nationale des Centres de Lutte contre ment was administered for at least six weeks unless dis- le Cancer (FNCLCC) has designed this randomized phase ease progression was documented, unacceptable toxicity, II study to explore the possibility of combining DCT with or patient refusal occurred. Premedication included ade- either cisplatin or 5-FU to improve concurrent chemo- quate antiemetic therapy, dexamethasone (IV) before and radiation therapy in the treatment of non resectable each docetaxel infusion and prophylactic granulocyte LAPC. We report here the study arm where docetaxel colony-stimulating factor (C-GSF) treatment in case of was combined to 5-FU and briefly discuss a long-term severe hematotoxicity. survival case. Dose adjustments were based on the worst toxicity observed during the previous cycle. Radiotherapy con- Methods sisted of an initial 54 Gy in 30 fractions (dose specified Patients participating in this non-comparative, multicen- at the isocenter) with minimum photon energy of 6 ter, phase II study were centrally randomized at the MeV. The initial field covered the gross tumor volume Gustave-Roussy Institute in Villejuif, France using mini- and regional nodes, including the celiac axis. mization on center, performance status and age. An interim analysis was planned after inclusion of 20 Response and Toxicity Evaluation patients in each arm. The results we report here are only Because evaluating tumor response in LAPC is difficult, for the 5-FU-docetaxel concurrent radiotherapy arm that we used progression instead of objective response as the was discontinued after the interim analysis. This research main study endpoint. Progressive disease (PD) was was carried out in compliance with the Helsinki Declara- defined as the appearance of a metastasis or protein-rich tion. The protocol was approved by the Ethical Commit- ascites or duodenal stenosis, and/or an increase > 30% of tee of Kremlin-Bicêtre, the review committees of the the lesion size calculated as the sum of the two longest Oberic et al. Radiation Oncology 2011, 6:124 Page 3 of 7 http://www.ro-journal.com/content/6/1/124 1 8 15 22 29 36 Day Radiotherapy 1.8 Gy/day Docetaxel IV 20 mg/m²/week 5FU IV 200 mg/m²/day Figure 1 Treatment schedule: 5-FU + docetaxel + radiotherapy. perpendicular diameters of the tumor. Tumors were eval- considered as active and stopped. Secondary endpoints uated with the modified RECIST scale at week 12 (i.e. 5 included adverse events, progression-free survival (PFS), weeks after the treatment’s end) and every 2 months overall survival (OS), and objective response (OR) thereafter until disease progression or patient’sdeath. according to the RECIST criteria. Adverse events were Toxicities were graded according to the NCICTC scale evaluated before each cycle of treatment. Overall and (version 2.0) for chemotherapy, and according to the progression-free survivals were estimated using the RTOG criteria for radiotherapy. Kaplan-Meier method. Overall survival was defined as the time from randomization to the date of death or to Statistical Design the date of lost follow-up and progression-free survival as The primary endpoint was the 6-month crude non-pro- the time from randomization to disease progression or gression rate (NPR). All eligible patients who initiated death, whatever its cause, or last follow-up. study treatment were included in the primary endpoint Written informed consent was obtained from the analysis. Considering a 35% control rate, the trial power patient for publication of this case report and accompa- to detect a 6-month crude NPR of 60% was 93% with a nying images. A copy of the written consent is available type I error of 4% based on a Fleming design [18]. An for review by the Editor-in-Chief of this journal.’ interim analysis was planned after the first 20 enrolled patients experienced the treatment protocol for 6 Results months. Enrollment was to be continued with 20 addi- Results are reported only for arm A which was closed tional patients if between 8 and 12 cases of non-progres- prematurely, i.e. continuous infusion of 5-FU plus doce- sion were observed at 6 months. With 7 patients or less, taxel and radiotherapy. the regimen would be considered non efficient and the corresponding arm terminated. Conversely with more Patient characteristics than 13 out of 20 patients exhibiting non progressive Between November 2003, and August 2005, 20 patients diseases, the experimental arm would therefore be were included in 6 centers. Patient characteristics are Oberic et al. Radiation Oncology 2011, 6:124 Page 4 of 7 http://www.ro-journal.com/content/6/1/124 listed in Table 1. Median age was 62 years, and all Chemotherapy patients had PS between 80 and 100. The primary Median treatment duration was 6 cycles (range: [3 - 7]). tumor location was mainly the head of the pancreas, in Two patients received more than 130 mg/m of DCT or 70% of the enrolled patients. One patient presented 8750 mg/m of 5-FU:one becausehereceivedone 1.8 lesions in both pancreas head and body. T3 and T4 Gy fraction of radiotherapy on week 7, the other one because of weight gain during treatment. Two patients tumors represented the majority of cases, 40% and 35% received less than 120 mg/m : one because of non respectively. hematologic toxicity (hyperglycemia during cycle 4, grade 4 vomiting and low blood pressure at cycle 6) and Treatment Duration and Dose-Intensity All 20 patients received chemotherapy and radiotherapy one received a decreased dose of DCT (106 mg/m )for (CTRT). 6 weeks. The median relative dose-intensity was 99% of the theoretical dose (83%-106%) for DCT, and 98% (12%-106%) for 5-FU. Overall no treatment was stopped. Table 1 Patient and tumor characteristics Patients % Radiotherapy The median number of treatment sessions was 30 [26 - Sex 31]. Fifteen patients (75%) received the planned dose of Female 9 45% radiotherapy,i.e.54Gyin30fractions.Onlyone devia- Male 11 55% tion was observed with respect to the protocol with a Age case of non-toxicity-related prolongation of treatment ≤ 60 years 9 45% where the patient received 31 fractions of 1.8 Gy, i.e. 55.8 > 60 year 11 55% Gy in total. Four patients (20%) received less than 54 Gy. Median [min - max] 62 [44 - 74] - Three patients received 28 fractions in 7 weeks, i.e. 50.4 Performance status Gy. Causes of treatment delay were mainly maintenance 80% 7 35% of radiotherapy machines and bank holidays. One patient 90% 7 35% suffered also from a pelvis fracture at week 4 and another 100% 6 30% experienced an unspecified toxicity at week 7. One Diagnostic method patient received only 26 fractions in 6 weeks, i.e. 46.8 Gy. Histologic 7 35% At week 6, he received only one instead of 5 fractions Cytologic 13 65% because of grade 4 vomiting and hypotension; 5-FU che- Tumor differentiation motherapy and radiotherapy were subsequently inter- Well 7 35% rupted. Overall, the median number of administered Moderately 1 5% cycles was 6; there were no interruptions of treatment, Poorly or not 6 30% and the dose intensity was 98% of the theoretical dose. Missing 6 30% Median dose of radiotherapy was 54 Gy; only 3 patients TNM classification* received less than the theoretical dose. T2N0 1 5% T3N0 4 20% Toxicity T3N1 4 20% All patients were evaluated for adverse events (Table 2). T4N0 3 15% Twelve patients (60%) experienced grade 3-4 toxicities T4N1 4 20% during CTRT treatment. There were no treatment-related Missing** 4 20% deaths. The most relevant severe toxicity involved the gas- Localization trointestinal tract in 17 patients (85%) including vomiting Head and body 1 5% (35%), nausea (20%), abdominal pain (10%), anorexia (5%), Head alone 14 70% diarrhea (5%), stomatitis (5%) and dyspepsia (5%). Grade 3 Body alone 4 20% fatigue was observed in two patients. Grade 4 low blood Tail alone 1 5% pressure (1 pt) and gastrointestinal bleeding (1 pt) related Size of lesions (mm)*** to tumor progression occurred in two distinct patients. Primitive 39 [10 - 79] Five patients experienced grade 2 weight loss. At week 12 Primitive + lymph nodes 42 [10 - 79] (i.e., 5 weeks after radiochemotherapy treatment comple- Total 20 100% tion), toxicities of any grades affected 16 patients (80%) *All tumors were M0. and ranged from general (10 pts), hematologic (10 pts) ** Missing: 1 T3Nx (1), T4Nx (2) and TxNx (1). and gastrointestinal (9 pts) for those with highest occur- *** Median size and range for the longest tumoral diameter, data missing for rence rates to hepatic (4 pts), cardiovascular (1 pt) and one patient. Oberic et al. Radiation Oncology 2011, 6:124 Page 5 of 7 http://www.ro-journal.com/content/6/1/124 Table 2 Description of toxicities during CTRT 100% overall Type of toxicity Grade 3 Grade 4 progression-free N (%) N (%) 80% Vomiting 5 (25%) 2 (10%) Fatigue 2 (10%) - 60% Hypokalemia 2 (10%) - Anorexia 1 (5%) - 40% Diarrhea 1 (5%) - Nausea 4 (20%) - 20% Stomatitis 1 (5%) - Abdominal pain 1 (5%) 1 (5%) Dyspepsia 1 (5%) - 0% 48 12 16 20 Hyperglycemia 1 (5%) - months Deterioration of general condition 1 (5%) - Figure 2 Overall and progression-free survival. Hypotension - 1 (5%) Gastrointestinal bleeding - 1 (5%) detectable disease for a period of 66 months following tumor resection. The patient, aged 55 years, was included in the treatment protocol less than a month dermal (1 pt) for the less frequent ones. Most of them after he was diagnosed as having pancreatic cancer. were grades 1 or 2. However, the following toxicities Ultrasound examination revealed a tumoral lesion of sorted by increasing severity are to be noted: grade 2 alo- TNM grade US T3N0Mx located in the pancreas body pecia and cutaneous reaction of the hands and feet (1 pt); with no peripheral adenopathy detected. Two biopsies grade 3 hepatic toxicity (bilirubin 1 pt, GGT 1 pt) and weretaken showing thepresenceofan exocrinepan- grade 4 pulmonary emboli and cardiac complication (1 pt). creatic adenocarcinoma, and no criterion indicating the possibility of tumor surgical resection was observed. Response and Survival The patient received 6 cycles of chemoradiotherapy in All 20 patients were assessable for response and survival. compliance with the trial’s protocol. One month after the At 6 months, 18 patients (90%) had progressive disease. end of chemoradiotherapy, his tumor exhibited a partial One year after week 12, the median duration of disease response with a volume shrinking to 64% as well as a drop stabilization was 139 days (range: 125 - 378). The best in CA 19-9 marker count from 3000 to 30. In regard to this response observed was complete response (CR) (1 pt, con- remarkable result subsequent resective surgery was firmed by surgery), partial response (PR) (1 pt, confirmed proposed. by a second evaluation) and disease stabilization (DS) (10 Left splenopancreatectomy was performed with tumor pts) with an objective response (2 confirmed responses) margin-free en bloc resection of the pancreas body and tail rate of 10% (95% CI, [0-23%]). The disease control rate, and cholecystectomy for gallstones. The en-bloc resected partial responses (2 pts) or stable disease (10 pts), mea- piece was 10 cm long for 5 cm in diameter at the level of sured at week 12 was 60% (95%CI, [38-81%]). No progres- the resection margin. The result of the extemporaneous sion was observed during treatment. Nineteen patients resection margin examination was suspect (presence of (95%) died afterwards, all from their cancer within 17 non-neoplasic dystrophic lesions) and two additional trans- months. Median overall survival time was 10 months verse cuts were necessary to obtain a free resected margin. (range: [3 - 69] months) (Figure 2). Six- and 12-month The eleven lymph nodes found were all negative (11N-/11). survival rate were 85% (95%CI, [64%-95%]) and 40% (95% One year after surgery the patient had recovered from a CI [22%-61%]) respectively. Median progression-free survi- weight loss of 15 kg. Sixty six (66) months after surgical val (PFS) was 4 months (range: [2 - 69] months) (Figure 2). resection of his tumor, the patient was still living and in PFS percentages at 3 and 6 months were 70% (95% CI, good health (complete remission). The thorax-abdomen- [48% - 85%]) and 15% (95% CI, [5% - 36%]), respectively. pelvis CT-scans that are performed every 6 months did not One patient is still alive and has been in complete remis- reveal any specific sign of disease locoregional relapse or sion since he underwent tumor resection 66 months ago. distant extension and the CA 19-9 markers remained per- Decision to stop inclusions in this study arm was subse- manently low. quently made, due to the lack of treatment efficacy. Discussion Long-term survival with complete remission In the face of the lack of progress observed during the We observed a long-term survival showing complete past two decades in the curative-intent treatment of response with an absence of progression and no Kaplan-Meier survival estimates Oberic et al. Radiation Oncology 2011, 6:124 Page 6 of 7 http://www.ro-journal.com/content/6/1/124 LAPC, the combined-modality treatment based on con- survival [25-27]. In those reported cases long-term survival current radiation therapy and chemotherapy remains the usually means survival prolonged for 1-3 years which commonly accepted treatment and the sole prospect for already represents a substantial victory, especially in improving disease outcome. However, the chemora- regards to the minimal expectations of the initial prog- diotherapy optimal schedule and whether it should be nosis. For patients undergoing curative resection, the administrated pre-operatively or post-operatively are yet prognosis appears to be determined by tumor biology rather than factors involved in the resection [6,28,29]. The to be determined. accurate proportion of complete remission, i.e. complete One essential reason to investigate neoadjuvant che- and permanent response without detectable signs of dis- moradiotherapy schedules relates to the possibility of gaining disease locoregional control in unresectable or ease relapse, is to our knowledge currently not available, borderline pancreatic cancer which represents a first step but seems to be extremely low (ca. 0.2% at 3 years) in his- toward curative intent. In a recent review, the results of tologically confirmed pancreatic carcinoma cases [30]. 13 phase II studies, published from year 2000 onwards, Further surgical and/or chemotherapeutic treatment of including 510 patients with unresectable LAPC treated metastases or second cancer is very frequent (> 50%) in 5- by standard radiotherapy and concurrent chemotherapy year and longer survival cases also characterized by high were compiled [19]. This study has shown that resection comorbidity [4]. Long-term complete remissions such as rates rangedfrom8to 64% andamong theoperated the one we report here should be given more scientific patients, 57 to 100% (median, 87.5%) had tumor resection attention and systematically collected for further re-exami- with negative margin (R0). Surprisingly, in patients with nation to help establish better prognostic and/or treatment unresectable tumor at presentation, median survival after schedules, as they prove that there is hope even in this surgery ranged from 16.4 to 32.3 months as compared most dreadful pathology [31]. with 9 to 13 months for concurrent chemoradiation with- out surgery. Thus, pre-operative chemoradiation can play Conclusions a beneficial role beyond palliative treatment of this type Despite good tolerance, concurrent 5-FU-docetaxel of tumor and the design of optimally successful schedules radiotherapy cannot be recommended as a standard of remains a relevant issue. care or even be tested in a subsequent phase III study. In our trial, 18 patients (90%) had progressive disease at Inclusions have continued in the 5-FU-cisplatin arm, the time of the intermediate analysis, with a median PFS final results are awaited. of only 4.8 months, and a median survival of 10.1 months. These results are not better than those achieved with Acknowledgements other treatment regimens for LAPC, including phase II The authors would like to thank the long surviving patient who gave written trials that combined radiotherapy and chemotherapy consent for the description of his clinical case. They also thank Valère Lounnas who provided medical writing services on behalf of FNCLCC and [20-22]. In compliance with the pre-established continua- Meredith Charpantier for editing grammar and syntax. We would like to tion/discontinuation rules of the trial, this protocol treat- thank the brave patients who participated in this study, and their families for ment (docetaxel + 5-FU + RT) was not deemed efficient their confidence. The trial was supported by Aventis and the French National League against enough to justify further investigations and advance to Cancer phase III trial. It was organized and followed by the Bureau d’Etudes Cliniques of the Pronounced toxicity side effects were observed during French Federation of Anti Cancer Centres treatment (12 pts) and in week 12 (7 pts) with a majority Author details of patients (75%) who have experienced grade 3-4 events, 1 2 Institut Gustave Roussy, Villejuif, France. Institut Paoli Calmettes, Marseille, 3 4 occurring predominantly in the gastrointestinal tract. France. Centre Val d’Aurelle, Montpellier, France. Centre René Gauducheau, 5 6 Nantes, France. Centre Oscar Lambret, Lille, France. Centre Alexis Vautrin, Hematological toxicity was mild and non-hematological 7 8 Nancy, France. Hôpital Lyon Sud, Lyon, France. Centre Paul Papin, Angers, symptoms were similar to those previously reported 9 10 France. FNCLCC, Paris, France. Université Paris Sud 11, Le Kremlin Bicetre, including significant fatigue, lack of appetite, abdominal France. pain, nausea and emesis [23,24]. Overall, tolerance was Authors’ contributions comparable with other chemoradiotherapy regimens and MD, PC, FV, and JPP conceived of the study and helped to draft the would not have hampered the treatment feasibility if it manuscript, JB and her team coordinated the study. JPP, CB, LO and MD participated in data analysis. FV, JB, CB, MY, FM, LO, PC, had had the expected efficacy. MD, JB participated in data collection. All authors read and approved the The concept that primarily unresectable pancreatic can- final manuscript. cer are amenable to surgery is further supported by a Competing interests number of published case reports, of dramatically Michel Ducreux has participated to advisory boards for Aventis during the advanced and/or metastatic primarily unresectable pan- accrual period of the study. creatic cancer leading to surgical resection and ‘long-term’ The (other) authors declare they have no competing interest.” Oberic et al. Radiation Oncology 2011, 6:124 Page 7 of 7 http://www.ro-journal.com/content/6/1/124 Received: 12 April 2011 Accepted: 26 September 2011 After Concurrent Chemoradiation in Primarily Unresectable Pancreatic Published: 26 September 2011 Cancer. Ann Surg Oncol 2010, 17:194-2005. 20. Rich T, Harris J, Abrams R, Erickson B, Doherty M, Paradelo J, Small W Jr, Safran H, Wanebo HJ: Phase II study of external irradiation and weekly References paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98- 1. Berrino F, Verdecchia A, Lutz JM, Lombardo C, Micheli A, Capocaccia R: 12. Am J Clin Oncol 2004, 27:51-56. Comparative cancer survival information in Europe, EUROCARE Working 21. Blackstock AW, Tepper JE, Niedwiecki D, Hollis DR, Mayer RJ, Tempero MA: Group. Eur J Cancer 2009, 45:901-8. Cancer and leukemia group B (CALGB) 89805: Phase II chemoradiation 2. Garcea Giuseppe: Survival Following Curative Resection for Pancreatic trial using gemcitabine in patients with locoregional adenocarcinoma of Ductal Adenocarcinoma. A Systematic Review of the Literature. JOP J the pancreas. Int J Gastrointest Cancer 2003, 34:107 116. Pancreas (Online) 2008, 9:99-132. 22. Haddock MG, Swaminathan R, Foster NR, Hauge MD, Martenson JA, 3. Keleg S, Büchler P, Ludwig R, Büchler MW, Friess H: Invasion and Camoriano JK, Stella PJ, Tenglin RC, Schaefer PL, Moore DF Jr, Alberts SR: metastasis in pancreatic cancer. Molecular Cancer 2003, 2:14. Gemcitabine, Cisplatin, and Radiotherapy for Patients With Locally 4. Jacobs NL, Que FG, Miller RC, Vege SS, Farnell MB, Jatoi A: Cumulative Advanced Pancreatic Adenocarcinoma: Results of the North Central morbidity and late mortality in long-term survivors of exocrine pancreas Cancer Treatment Group Phase II Study N9942. J Clin Oncol 2007, cancer. J Gastroinstestinal Cancer 2009, 40:46-50. 25:2567-2572. 5. Spinelli GP, Zullo A, Romiti A, Di Seri M, Tomao F, Miele E, Spalletta B, 23. Reyes-Gibby CC, Abbruzzese JL, Xiong HQ, Ho L, Evans DB, Varadhachary G, Eramo A, Hassan C, Tomao S: Long-Term Survival in Metastatic Pancreatic Bhat S, Wolf RA, Crane C: Patterns of self-reported symptoms in Cancer. A Case Report and Review of the Literature. JOP J Pancreas pancreatic cancer patients receiving chemoradiation. J Pain Symptom (Online) 2006, 7:486-491. Manage 2007, 34:244-252. 6. Cleary SP, Gryfe R, Guindi M, Greig P, Smith L, Mackenzie R, Strasberg S, 24. Schwartz AL, Nail LM, Chen S, Meek P, Barsevick AM, King ME, Jones LS: Hanna S, Taylor B, Langer B, Gallinger S: Prognostic factors in resected Fatigue patterns observed in patients receiving chemotherapy and pancreatic adenocarcinoma: analysis of actual 5-year survivors. J Am Coll radiotherapy. Cancer Invest 2000, 18:11-19. Surg 2004, 198:722-731. 25. Nagahama T, Ando M, Ohara T, Ganno H, Hataji K, Ami K, Fukuda A, 7. Moertel CG, Frytak S, Hahn RG, O’Connell MJ, Reitemeier RJ, Rubin J, Maruyama M: A case report of un-resectable pancreas body carcinoma Schutt AJ, Weiland LH, Childs DS, Holbrook MA, Lavin PT, Livstone E, successfully treated by chemoradiotherapy. Gan to Kagaku Ryoho 2009, Spiro H, Knowlton A, Kalser M, Barkin J, Lessner H, Mann-Kaplan R, 36:2425-2427. Ramming K, Douglas HO Jr, Thomas P, Nave H, Bateman J, Lokich J, 26. Hoshino H, Takeda Y, Nagano H, Nakamori S, Kobayashi S, Eguchi H, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW: Therapy of locally Marubashi S, Tanemura M, Kitagawa T, Umeshita K, Monden M, Doki Y, unresectable pancreatic carcinoma: a randomized comparison of high Mori M: A long-term survival case of pancreatic cancer with hepatic dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + metastasis after pancreaticoduodenectomy successfully treated by s-1 5-fluorouracil), and high dose radiation + 5-fluorouracil: The and gemcitabine combination chemotherapy. Gan To Kagaku Ryoho 2009, Gastrointestinal Tumor Study Group. Cancer 1981, 48:1705-1710. 36:2419-2421. 8. Abbott DE, Baker MS, Talamonti MS: Neoadjuvant Therapy for Pancreatic 27. Ohmura Y, Takeda Y, Nagano H, Nakamori S, Kobayashi S, Marubashi S, Cancer: A Current Review. J Surg Oncol 2010, 101:315-320. Eguchi H, Tanemura M, Kitagawa T, Monden M, Mori M, Doki Y: A case of 9. Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH, Zahurak ML, locally advanced pancreatic cancer with superior membrane artery Dooley WC, Coleman J, Sauter PK, Pitt HA, Lillemoe KD, Cameron JL: invasion successfully resected after gemcitabine-based Pancreaticoduodenectomy for pancreatic adenocarcinoma: chemoradiotherapy. Gan To Kagaku Ryoho 2009, 36:2428-2429. postoperative adjuvant chemoradiation improves survival. A prospective, 28. Peros G, Sakorafas GH, Giannopoulos GA, Manikis D, Vassiliu P, single-institution experience. Ann Surg 1997, 225:621-636. Brountzos EN: Successful Pancreaticoduodenectomy with Immediate 10. Saini A, Norman AR, Cunningham D, Chau I, Hill M, Tait D, Hickish T, Vascular Reconstruction in a Patient with Cancer of the Pancreatic Head Iveson T, Lofts F, Jodrell D, Ross PJ, Oates J: Twelve weeks of protracted and Celiac Artery Stenosis. A Case Report. JOP J Pancreas (Online) 2009, venous infusion of fluorouracil (5-FU) is as effective as 6 months of 10:667-670. bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer. Br 29. Ahmad NA, Lewis JD, Ginsberg GG, Haller DG, Morris JB, Williams NN, J Cancer 2003, 88:1859-1865. Rosato EF, Kochman ML: Long term survival after pancreatic resection for 11. Duffour J, Bouché O, Rougier P, Milan C, Bedenne L, Seitz JF, Buecher B, pancreatic adenocarcinoma. The American Journal of Gastroenterology Legoux JL, Ducreux M, Vetter D, Raoul JL, François E, Ychou M: Safety of 2001, 96:2609-2615. cisplatin combined with continuous 5-FU versus bolus 5-FU and 30. Connoly MM, Dawson PJ, Mhicelassi F, Moossa AR, Lowenstein F: Survival leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised in 1001 Patients with Carcinoma of the Pancreas. Ann of Surg 1987, trial). Anticancer Res 2006, 26:3877-3883. 206:366-370. 12. Pasetto LM, Jirillo A, Stefani M, Monfardini S: Old and new drugs in 31. Chen EL, Prinz RA: Long-term survival after pancreatic cancer treatment. systemic therapy of pancreatic cancer. Crit Rev Oncol Hematol 2004, Am J Surg 2007, 194:s127-s130. 49:135-151. 13. Trudeau ME: Docetaxel: a review of its pharmacology and clinical doi:10.1186/1748-717X-6-124 activity. Can J Oncol 1996, 6:443-457. Cite this article as: Oberic et al.: Docetaxel- and 5-FU-concurrent 14. Rougier P, Adenis A, Ducreux M, de Forni M, Bonneterre J, Dembak M, radiotherapy in patients presenting unresectable locally advanced Clouet P, Lebecq A, Baille P, Lefresne-Soulas F, Blanc C, Armand JP: A phase pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial’s II study: Docetaxel as first-line chemotherapy for advanced pancreatic pre-planned analysis and case report of a 5.5-year disease-free survival. adenocarcinoma. Eur J Cancer 2000, 36:1016-1025. Radiation Oncology 2011 6:124. 15. Mason K, Hunter N, Abbruzzese J: In vivo enhancement of tumor radio response by Taxotere (TXT). Proc Annu Meet Am Soc Clin Oncol 1997, 16:775a. 16. Choy H, Rodriguez F, Wilcox B: Radiation-sensitizing effects of taxotere. Proc Annu Meet Am Assoc Cancer Res 1992, 33:2991a. 17. Di Cosimo S, Ferretti G, Fazio N, Silvestris N, Carlini P, Alimonti A, Gelibter A, Felici A, Papaldo P, Cognetti F: Docetaxel in advanced gastric cancer: Review of the main clinical trials. Acta oncologica 2003, 42:693-700. 18. Fleming TR: One sample multiple testing procedure for phase II trials. Biometrics 1982, 38:143-205. 19. Morganti AG, Massaccesi M, La Torre G, Caravatta L, Piscopo A, Tambaro R, Sofo L, Sallustio G, Ingrosso M, Macchia G, Deodato F, Picardi V, Ippolito E, Cellini N, Valentini V: A Systematic Review of Resectability and Survival http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial's pre-planned analysis and case report of a 5.5-year disease-free survival

Loading next page...
 
/lp/springer-journals/docetaxel-and-5-fu-concurrent-radiotherapy-in-patients-presenting-WifoxBQcDy
Publisher
Springer Journals
Copyright
Copyright © 2011 by Oberic et al; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Oncology; Radiotherapy
eISSN
1748-717X
DOI
10.1186/1748-717X-6-124
pmid
21943032
Publisher site
See Article on Publisher Site

Abstract

Background: To explore possible improvement in the treatment of locally advanced pancreatic carcinoma (LAPC) we performed a randomized, non-comparative phase II study evaluating docetaxel - plus either daily continuous 5 FU or weekly cisplatin concurrent to radiotherapy. We report here the results of the docetaxel plus 5 FU regimen stopped according to the interim analysis. The docetaxel plus cisplatin arm was continued. Methods: Forty (40) chemotherapy-naive patients with unresectable LAPC were randomly assigned (1:1) to either 2 2 continuous fluorouracil (5-FU) 200 mg/m /day (protracted IV) and docetaxel (DCT) 20 mg/m /week or DCT 20 mg/ 2 2 m and cisplatin (CDDP) 20 mg/m , plus concurrent radiotherapy for a period of 6 weeks. The radiation dose to the primary tumor was 54 Gy in 30 fractions. The trial’s primary endpoint was the 6-month crude non-progression rate (NPR). Secondary endpoints were tolerance, objective response rate, and overall survival. Accrual was to be stopped if at 6 months more than 13 disease progressions were observed in 20 patients. Results: Eighteen (18) progressions occurred at 6 months in the 5-FU-DCT arm. Six-month NPR was 10% (95%CI: 0-23). Six and 12-month survivals were 85% (95%CI: 64-95) and 40% (95%CI: 22-61); median overall survival was 10.1 months. Median progression-free survival was 4.3 months. We report the case of one patient who was amenable to surgery and has been in complete response (CR) for 5.5 years. Toxicities grade ≥ 3 were reported in 75% of patients; no treatment-related death occurred. Severe toxicities were mainly vomiting (35%), abdominal pain (10%) and fatigue (10%). Conclusions: Combination of 5-FU, docetaxel and radiotherapy has inadequate efficacy in the treatment of LAPC despite good tolerance for the 5-FU-DCT regimen. Trial Registration: ClinicalTrials.gov: NCT00112697 Background diagnosis has remained unchanged, around (15%-20%), Pancreatic cancer (PC) is an extremely aggressive malig- over the past decades [2]. More than 50% of patients with th nancy and the 4 cause of all cancer deaths worldwide [1]. PC are unresectable because of the metastatic spread of Unfortunately, because of the typically late onset of symp- the disease at initial presentation, and the remaining 30% toms and the persistent lack of early detection, the rate of unresectable are due to local extension with vascular PC cases amenable to surgical resection at the time of involvement [3]. Overall, the acknowledged 5-year survival rate for exocrine pancreas adenocarcinoma is around 3% - * Correspondence: ducreux@igr.fr 5% [4,5]. In case of loco-regional disease development, Institut Gustave Roussy, Villejuif, France survival is relatively better. However, with a median Full list of author information is available at the end of the article © 2011 Oberic et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Oberic et al. Radiation Oncology 2011, 6:124 Page 2 of 7 http://www.ro-journal.com/content/6/1/124 survival of only 6 to 8 months the patient’s chances of sur- FNCLCC and the participating institutions. Trial registra- viving several years remain low. About 10%-15% of tion: Current Controlled Trials NCT00112697; resected patients survive more than 5 years and less than 5% more than 10 years [5,6]. Patient Population Compared to radiotherapy alone, 5-FU concurrent Patients of age > 18 years and < 75 years with pathologi- radiotherapy has become a widespread standard that can cally confirmed unresectable locoregional advanced ade- be used in locally advanced PC, either pre- or post-opera- nocarcinoma of the exocrine pancreas were eligible. tively [7]. In the pre-operative setting, chemoradiation is Other histological subtype of pancreatic tumors including used to gain locoregional control in the treatment of neuroendocrine tumor and ampulla of Vater were not border line resectable cancer [8]. Chemoradiation facili- eligible. Unresectability was defined by a surgeon and tates or makes the resection possible, especially when the evaluated after laparotomy or according to CT-scan and/ tumor is too large or if it makes contact with the vascular or endoscopic criteria, including vascular involvement. system. Post-operative chemoradiation is used to Measurable disease was required. Patients with clinical or improve survival [9]. Although there is no definite evi- radiologic diagnosis of metastases were excluded. No dence of the superiority of either its tolerance or efficacy prior chemotherapy was allowed; patients were required compared to bolus 5-FU, continuous (protracted) 5-FU to have a Karnofsky performance status (PS) higher than intravenous infusion, delivered with concurrent radio- 70, adequate baseline bone marrow function (i.e., neutro- therapy (RT), is of common use in the treatment of a philes count > 1,500/μL and platelets > 100,000/μL), nor- number of gastrointestinal cancers including pancreatic mal serum creatinine levels (< 120 μmol/l), and bilirubin and colorectal carcinoma [10,11]. Continuous infusion levels < 1.5 times the upper limit of normal (ULN) after insures a more constant concentration of radio-sensitiz- biliary drainage. Patients with prior history of another ing agent at the tumor site throughout the period of primary tumor within the last 10 years, except adequately radiotherapy. Although 5-FU-based chemoradiation has treated in situ carcinoma of the cervix uteri and basal or an acceptable response rate (20%) and a low toxicity, squamous cell skin carcinomas, and patients with grade the ideal schedule has not yet been established [12]. II peripheral neuropathy according to NCI-CTC criteria Docetaxel (DCT) is a semisynthetic taxane with a large were excluded. Written informed consent was obtained spectrum of antitumoral activity including pancreatic according to the French regulations. cancer [13]. The activity of this drug in first-line meta- static patients has been demonstrated as has its radiosen- Treatment Plan sitizing potential [14-16]. Several phase II and phase III Patients were randomly assigned to receive continuous 2 2 trials have shown that the addition of both cisplatin and 5-FU 200 mg/m /day and docetaxel (DCT) 20 mg/m / fluorouracil to docetaxel did not increase toxicity [17]. week (Figure 1) or weekly docetaxel and cisplatin. Treat- The Federation Nationale des Centres de Lutte contre ment was administered for at least six weeks unless dis- le Cancer (FNCLCC) has designed this randomized phase ease progression was documented, unacceptable toxicity, II study to explore the possibility of combining DCT with or patient refusal occurred. Premedication included ade- either cisplatin or 5-FU to improve concurrent chemo- quate antiemetic therapy, dexamethasone (IV) before and radiation therapy in the treatment of non resectable each docetaxel infusion and prophylactic granulocyte LAPC. We report here the study arm where docetaxel colony-stimulating factor (C-GSF) treatment in case of was combined to 5-FU and briefly discuss a long-term severe hematotoxicity. survival case. Dose adjustments were based on the worst toxicity observed during the previous cycle. Radiotherapy con- Methods sisted of an initial 54 Gy in 30 fractions (dose specified Patients participating in this non-comparative, multicen- at the isocenter) with minimum photon energy of 6 ter, phase II study were centrally randomized at the MeV. The initial field covered the gross tumor volume Gustave-Roussy Institute in Villejuif, France using mini- and regional nodes, including the celiac axis. mization on center, performance status and age. An interim analysis was planned after inclusion of 20 Response and Toxicity Evaluation patients in each arm. The results we report here are only Because evaluating tumor response in LAPC is difficult, for the 5-FU-docetaxel concurrent radiotherapy arm that we used progression instead of objective response as the was discontinued after the interim analysis. This research main study endpoint. Progressive disease (PD) was was carried out in compliance with the Helsinki Declara- defined as the appearance of a metastasis or protein-rich tion. The protocol was approved by the Ethical Commit- ascites or duodenal stenosis, and/or an increase > 30% of tee of Kremlin-Bicêtre, the review committees of the the lesion size calculated as the sum of the two longest Oberic et al. Radiation Oncology 2011, 6:124 Page 3 of 7 http://www.ro-journal.com/content/6/1/124 1 8 15 22 29 36 Day Radiotherapy 1.8 Gy/day Docetaxel IV 20 mg/m²/week 5FU IV 200 mg/m²/day Figure 1 Treatment schedule: 5-FU + docetaxel + radiotherapy. perpendicular diameters of the tumor. Tumors were eval- considered as active and stopped. Secondary endpoints uated with the modified RECIST scale at week 12 (i.e. 5 included adverse events, progression-free survival (PFS), weeks after the treatment’s end) and every 2 months overall survival (OS), and objective response (OR) thereafter until disease progression or patient’sdeath. according to the RECIST criteria. Adverse events were Toxicities were graded according to the NCICTC scale evaluated before each cycle of treatment. Overall and (version 2.0) for chemotherapy, and according to the progression-free survivals were estimated using the RTOG criteria for radiotherapy. Kaplan-Meier method. Overall survival was defined as the time from randomization to the date of death or to Statistical Design the date of lost follow-up and progression-free survival as The primary endpoint was the 6-month crude non-pro- the time from randomization to disease progression or gression rate (NPR). All eligible patients who initiated death, whatever its cause, or last follow-up. study treatment were included in the primary endpoint Written informed consent was obtained from the analysis. Considering a 35% control rate, the trial power patient for publication of this case report and accompa- to detect a 6-month crude NPR of 60% was 93% with a nying images. A copy of the written consent is available type I error of 4% based on a Fleming design [18]. An for review by the Editor-in-Chief of this journal.’ interim analysis was planned after the first 20 enrolled patients experienced the treatment protocol for 6 Results months. Enrollment was to be continued with 20 addi- Results are reported only for arm A which was closed tional patients if between 8 and 12 cases of non-progres- prematurely, i.e. continuous infusion of 5-FU plus doce- sion were observed at 6 months. With 7 patients or less, taxel and radiotherapy. the regimen would be considered non efficient and the corresponding arm terminated. Conversely with more Patient characteristics than 13 out of 20 patients exhibiting non progressive Between November 2003, and August 2005, 20 patients diseases, the experimental arm would therefore be were included in 6 centers. Patient characteristics are Oberic et al. Radiation Oncology 2011, 6:124 Page 4 of 7 http://www.ro-journal.com/content/6/1/124 listed in Table 1. Median age was 62 years, and all Chemotherapy patients had PS between 80 and 100. The primary Median treatment duration was 6 cycles (range: [3 - 7]). tumor location was mainly the head of the pancreas, in Two patients received more than 130 mg/m of DCT or 70% of the enrolled patients. One patient presented 8750 mg/m of 5-FU:one becausehereceivedone 1.8 lesions in both pancreas head and body. T3 and T4 Gy fraction of radiotherapy on week 7, the other one because of weight gain during treatment. Two patients tumors represented the majority of cases, 40% and 35% received less than 120 mg/m : one because of non respectively. hematologic toxicity (hyperglycemia during cycle 4, grade 4 vomiting and low blood pressure at cycle 6) and Treatment Duration and Dose-Intensity All 20 patients received chemotherapy and radiotherapy one received a decreased dose of DCT (106 mg/m )for (CTRT). 6 weeks. The median relative dose-intensity was 99% of the theoretical dose (83%-106%) for DCT, and 98% (12%-106%) for 5-FU. Overall no treatment was stopped. Table 1 Patient and tumor characteristics Patients % Radiotherapy The median number of treatment sessions was 30 [26 - Sex 31]. Fifteen patients (75%) received the planned dose of Female 9 45% radiotherapy,i.e.54Gyin30fractions.Onlyone devia- Male 11 55% tion was observed with respect to the protocol with a Age case of non-toxicity-related prolongation of treatment ≤ 60 years 9 45% where the patient received 31 fractions of 1.8 Gy, i.e. 55.8 > 60 year 11 55% Gy in total. Four patients (20%) received less than 54 Gy. Median [min - max] 62 [44 - 74] - Three patients received 28 fractions in 7 weeks, i.e. 50.4 Performance status Gy. Causes of treatment delay were mainly maintenance 80% 7 35% of radiotherapy machines and bank holidays. One patient 90% 7 35% suffered also from a pelvis fracture at week 4 and another 100% 6 30% experienced an unspecified toxicity at week 7. One Diagnostic method patient received only 26 fractions in 6 weeks, i.e. 46.8 Gy. Histologic 7 35% At week 6, he received only one instead of 5 fractions Cytologic 13 65% because of grade 4 vomiting and hypotension; 5-FU che- Tumor differentiation motherapy and radiotherapy were subsequently inter- Well 7 35% rupted. Overall, the median number of administered Moderately 1 5% cycles was 6; there were no interruptions of treatment, Poorly or not 6 30% and the dose intensity was 98% of the theoretical dose. Missing 6 30% Median dose of radiotherapy was 54 Gy; only 3 patients TNM classification* received less than the theoretical dose. T2N0 1 5% T3N0 4 20% Toxicity T3N1 4 20% All patients were evaluated for adverse events (Table 2). T4N0 3 15% Twelve patients (60%) experienced grade 3-4 toxicities T4N1 4 20% during CTRT treatment. There were no treatment-related Missing** 4 20% deaths. The most relevant severe toxicity involved the gas- Localization trointestinal tract in 17 patients (85%) including vomiting Head and body 1 5% (35%), nausea (20%), abdominal pain (10%), anorexia (5%), Head alone 14 70% diarrhea (5%), stomatitis (5%) and dyspepsia (5%). Grade 3 Body alone 4 20% fatigue was observed in two patients. Grade 4 low blood Tail alone 1 5% pressure (1 pt) and gastrointestinal bleeding (1 pt) related Size of lesions (mm)*** to tumor progression occurred in two distinct patients. Primitive 39 [10 - 79] Five patients experienced grade 2 weight loss. At week 12 Primitive + lymph nodes 42 [10 - 79] (i.e., 5 weeks after radiochemotherapy treatment comple- Total 20 100% tion), toxicities of any grades affected 16 patients (80%) *All tumors were M0. and ranged from general (10 pts), hematologic (10 pts) ** Missing: 1 T3Nx (1), T4Nx (2) and TxNx (1). and gastrointestinal (9 pts) for those with highest occur- *** Median size and range for the longest tumoral diameter, data missing for rence rates to hepatic (4 pts), cardiovascular (1 pt) and one patient. Oberic et al. Radiation Oncology 2011, 6:124 Page 5 of 7 http://www.ro-journal.com/content/6/1/124 Table 2 Description of toxicities during CTRT 100% overall Type of toxicity Grade 3 Grade 4 progression-free N (%) N (%) 80% Vomiting 5 (25%) 2 (10%) Fatigue 2 (10%) - 60% Hypokalemia 2 (10%) - Anorexia 1 (5%) - 40% Diarrhea 1 (5%) - Nausea 4 (20%) - 20% Stomatitis 1 (5%) - Abdominal pain 1 (5%) 1 (5%) Dyspepsia 1 (5%) - 0% 48 12 16 20 Hyperglycemia 1 (5%) - months Deterioration of general condition 1 (5%) - Figure 2 Overall and progression-free survival. Hypotension - 1 (5%) Gastrointestinal bleeding - 1 (5%) detectable disease for a period of 66 months following tumor resection. The patient, aged 55 years, was included in the treatment protocol less than a month dermal (1 pt) for the less frequent ones. Most of them after he was diagnosed as having pancreatic cancer. were grades 1 or 2. However, the following toxicities Ultrasound examination revealed a tumoral lesion of sorted by increasing severity are to be noted: grade 2 alo- TNM grade US T3N0Mx located in the pancreas body pecia and cutaneous reaction of the hands and feet (1 pt); with no peripheral adenopathy detected. Two biopsies grade 3 hepatic toxicity (bilirubin 1 pt, GGT 1 pt) and weretaken showing thepresenceofan exocrinepan- grade 4 pulmonary emboli and cardiac complication (1 pt). creatic adenocarcinoma, and no criterion indicating the possibility of tumor surgical resection was observed. Response and Survival The patient received 6 cycles of chemoradiotherapy in All 20 patients were assessable for response and survival. compliance with the trial’s protocol. One month after the At 6 months, 18 patients (90%) had progressive disease. end of chemoradiotherapy, his tumor exhibited a partial One year after week 12, the median duration of disease response with a volume shrinking to 64% as well as a drop stabilization was 139 days (range: 125 - 378). The best in CA 19-9 marker count from 3000 to 30. In regard to this response observed was complete response (CR) (1 pt, con- remarkable result subsequent resective surgery was firmed by surgery), partial response (PR) (1 pt, confirmed proposed. by a second evaluation) and disease stabilization (DS) (10 Left splenopancreatectomy was performed with tumor pts) with an objective response (2 confirmed responses) margin-free en bloc resection of the pancreas body and tail rate of 10% (95% CI, [0-23%]). The disease control rate, and cholecystectomy for gallstones. The en-bloc resected partial responses (2 pts) or stable disease (10 pts), mea- piece was 10 cm long for 5 cm in diameter at the level of sured at week 12 was 60% (95%CI, [38-81%]). No progres- the resection margin. The result of the extemporaneous sion was observed during treatment. Nineteen patients resection margin examination was suspect (presence of (95%) died afterwards, all from their cancer within 17 non-neoplasic dystrophic lesions) and two additional trans- months. Median overall survival time was 10 months verse cuts were necessary to obtain a free resected margin. (range: [3 - 69] months) (Figure 2). Six- and 12-month The eleven lymph nodes found were all negative (11N-/11). survival rate were 85% (95%CI, [64%-95%]) and 40% (95% One year after surgery the patient had recovered from a CI [22%-61%]) respectively. Median progression-free survi- weight loss of 15 kg. Sixty six (66) months after surgical val (PFS) was 4 months (range: [2 - 69] months) (Figure 2). resection of his tumor, the patient was still living and in PFS percentages at 3 and 6 months were 70% (95% CI, good health (complete remission). The thorax-abdomen- [48% - 85%]) and 15% (95% CI, [5% - 36%]), respectively. pelvis CT-scans that are performed every 6 months did not One patient is still alive and has been in complete remis- reveal any specific sign of disease locoregional relapse or sion since he underwent tumor resection 66 months ago. distant extension and the CA 19-9 markers remained per- Decision to stop inclusions in this study arm was subse- manently low. quently made, due to the lack of treatment efficacy. Discussion Long-term survival with complete remission In the face of the lack of progress observed during the We observed a long-term survival showing complete past two decades in the curative-intent treatment of response with an absence of progression and no Kaplan-Meier survival estimates Oberic et al. Radiation Oncology 2011, 6:124 Page 6 of 7 http://www.ro-journal.com/content/6/1/124 LAPC, the combined-modality treatment based on con- survival [25-27]. In those reported cases long-term survival current radiation therapy and chemotherapy remains the usually means survival prolonged for 1-3 years which commonly accepted treatment and the sole prospect for already represents a substantial victory, especially in improving disease outcome. However, the chemora- regards to the minimal expectations of the initial prog- diotherapy optimal schedule and whether it should be nosis. For patients undergoing curative resection, the administrated pre-operatively or post-operatively are yet prognosis appears to be determined by tumor biology rather than factors involved in the resection [6,28,29]. The to be determined. accurate proportion of complete remission, i.e. complete One essential reason to investigate neoadjuvant che- and permanent response without detectable signs of dis- moradiotherapy schedules relates to the possibility of gaining disease locoregional control in unresectable or ease relapse, is to our knowledge currently not available, borderline pancreatic cancer which represents a first step but seems to be extremely low (ca. 0.2% at 3 years) in his- toward curative intent. In a recent review, the results of tologically confirmed pancreatic carcinoma cases [30]. 13 phase II studies, published from year 2000 onwards, Further surgical and/or chemotherapeutic treatment of including 510 patients with unresectable LAPC treated metastases or second cancer is very frequent (> 50%) in 5- by standard radiotherapy and concurrent chemotherapy year and longer survival cases also characterized by high were compiled [19]. This study has shown that resection comorbidity [4]. Long-term complete remissions such as rates rangedfrom8to 64% andamong theoperated the one we report here should be given more scientific patients, 57 to 100% (median, 87.5%) had tumor resection attention and systematically collected for further re-exami- with negative margin (R0). Surprisingly, in patients with nation to help establish better prognostic and/or treatment unresectable tumor at presentation, median survival after schedules, as they prove that there is hope even in this surgery ranged from 16.4 to 32.3 months as compared most dreadful pathology [31]. with 9 to 13 months for concurrent chemoradiation with- out surgery. Thus, pre-operative chemoradiation can play Conclusions a beneficial role beyond palliative treatment of this type Despite good tolerance, concurrent 5-FU-docetaxel of tumor and the design of optimally successful schedules radiotherapy cannot be recommended as a standard of remains a relevant issue. care or even be tested in a subsequent phase III study. In our trial, 18 patients (90%) had progressive disease at Inclusions have continued in the 5-FU-cisplatin arm, the time of the intermediate analysis, with a median PFS final results are awaited. of only 4.8 months, and a median survival of 10.1 months. These results are not better than those achieved with Acknowledgements other treatment regimens for LAPC, including phase II The authors would like to thank the long surviving patient who gave written trials that combined radiotherapy and chemotherapy consent for the description of his clinical case. They also thank Valère Lounnas who provided medical writing services on behalf of FNCLCC and [20-22]. In compliance with the pre-established continua- Meredith Charpantier for editing grammar and syntax. We would like to tion/discontinuation rules of the trial, this protocol treat- thank the brave patients who participated in this study, and their families for ment (docetaxel + 5-FU + RT) was not deemed efficient their confidence. The trial was supported by Aventis and the French National League against enough to justify further investigations and advance to Cancer phase III trial. It was organized and followed by the Bureau d’Etudes Cliniques of the Pronounced toxicity side effects were observed during French Federation of Anti Cancer Centres treatment (12 pts) and in week 12 (7 pts) with a majority Author details of patients (75%) who have experienced grade 3-4 events, 1 2 Institut Gustave Roussy, Villejuif, France. Institut Paoli Calmettes, Marseille, 3 4 occurring predominantly in the gastrointestinal tract. France. Centre Val d’Aurelle, Montpellier, France. Centre René Gauducheau, 5 6 Nantes, France. Centre Oscar Lambret, Lille, France. Centre Alexis Vautrin, Hematological toxicity was mild and non-hematological 7 8 Nancy, France. Hôpital Lyon Sud, Lyon, France. Centre Paul Papin, Angers, symptoms were similar to those previously reported 9 10 France. FNCLCC, Paris, France. Université Paris Sud 11, Le Kremlin Bicetre, including significant fatigue, lack of appetite, abdominal France. pain, nausea and emesis [23,24]. Overall, tolerance was Authors’ contributions comparable with other chemoradiotherapy regimens and MD, PC, FV, and JPP conceived of the study and helped to draft the would not have hampered the treatment feasibility if it manuscript, JB and her team coordinated the study. JPP, CB, LO and MD participated in data analysis. FV, JB, CB, MY, FM, LO, PC, had had the expected efficacy. MD, JB participated in data collection. All authors read and approved the The concept that primarily unresectable pancreatic can- final manuscript. cer are amenable to surgery is further supported by a Competing interests number of published case reports, of dramatically Michel Ducreux has participated to advisory boards for Aventis during the advanced and/or metastatic primarily unresectable pan- accrual period of the study. creatic cancer leading to surgical resection and ‘long-term’ The (other) authors declare they have no competing interest.” Oberic et al. Radiation Oncology 2011, 6:124 Page 7 of 7 http://www.ro-journal.com/content/6/1/124 Received: 12 April 2011 Accepted: 26 September 2011 After Concurrent Chemoradiation in Primarily Unresectable Pancreatic Published: 26 September 2011 Cancer. Ann Surg Oncol 2010, 17:194-2005. 20. Rich T, Harris J, Abrams R, Erickson B, Doherty M, Paradelo J, Small W Jr, Safran H, Wanebo HJ: Phase II study of external irradiation and weekly References paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98- 1. Berrino F, Verdecchia A, Lutz JM, Lombardo C, Micheli A, Capocaccia R: 12. Am J Clin Oncol 2004, 27:51-56. Comparative cancer survival information in Europe, EUROCARE Working 21. Blackstock AW, Tepper JE, Niedwiecki D, Hollis DR, Mayer RJ, Tempero MA: Group. Eur J Cancer 2009, 45:901-8. Cancer and leukemia group B (CALGB) 89805: Phase II chemoradiation 2. Garcea Giuseppe: Survival Following Curative Resection for Pancreatic trial using gemcitabine in patients with locoregional adenocarcinoma of Ductal Adenocarcinoma. A Systematic Review of the Literature. JOP J the pancreas. Int J Gastrointest Cancer 2003, 34:107 116. Pancreas (Online) 2008, 9:99-132. 22. Haddock MG, Swaminathan R, Foster NR, Hauge MD, Martenson JA, 3. Keleg S, Büchler P, Ludwig R, Büchler MW, Friess H: Invasion and Camoriano JK, Stella PJ, Tenglin RC, Schaefer PL, Moore DF Jr, Alberts SR: metastasis in pancreatic cancer. Molecular Cancer 2003, 2:14. Gemcitabine, Cisplatin, and Radiotherapy for Patients With Locally 4. Jacobs NL, Que FG, Miller RC, Vege SS, Farnell MB, Jatoi A: Cumulative Advanced Pancreatic Adenocarcinoma: Results of the North Central morbidity and late mortality in long-term survivors of exocrine pancreas Cancer Treatment Group Phase II Study N9942. J Clin Oncol 2007, cancer. J Gastroinstestinal Cancer 2009, 40:46-50. 25:2567-2572. 5. Spinelli GP, Zullo A, Romiti A, Di Seri M, Tomao F, Miele E, Spalletta B, 23. Reyes-Gibby CC, Abbruzzese JL, Xiong HQ, Ho L, Evans DB, Varadhachary G, Eramo A, Hassan C, Tomao S: Long-Term Survival in Metastatic Pancreatic Bhat S, Wolf RA, Crane C: Patterns of self-reported symptoms in Cancer. A Case Report and Review of the Literature. JOP J Pancreas pancreatic cancer patients receiving chemoradiation. J Pain Symptom (Online) 2006, 7:486-491. Manage 2007, 34:244-252. 6. Cleary SP, Gryfe R, Guindi M, Greig P, Smith L, Mackenzie R, Strasberg S, 24. Schwartz AL, Nail LM, Chen S, Meek P, Barsevick AM, King ME, Jones LS: Hanna S, Taylor B, Langer B, Gallinger S: Prognostic factors in resected Fatigue patterns observed in patients receiving chemotherapy and pancreatic adenocarcinoma: analysis of actual 5-year survivors. J Am Coll radiotherapy. Cancer Invest 2000, 18:11-19. Surg 2004, 198:722-731. 25. Nagahama T, Ando M, Ohara T, Ganno H, Hataji K, Ami K, Fukuda A, 7. Moertel CG, Frytak S, Hahn RG, O’Connell MJ, Reitemeier RJ, Rubin J, Maruyama M: A case report of un-resectable pancreas body carcinoma Schutt AJ, Weiland LH, Childs DS, Holbrook MA, Lavin PT, Livstone E, successfully treated by chemoradiotherapy. Gan to Kagaku Ryoho 2009, Spiro H, Knowlton A, Kalser M, Barkin J, Lessner H, Mann-Kaplan R, 36:2425-2427. Ramming K, Douglas HO Jr, Thomas P, Nave H, Bateman J, Lokich J, 26. Hoshino H, Takeda Y, Nagano H, Nakamori S, Kobayashi S, Eguchi H, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW: Therapy of locally Marubashi S, Tanemura M, Kitagawa T, Umeshita K, Monden M, Doki Y, unresectable pancreatic carcinoma: a randomized comparison of high Mori M: A long-term survival case of pancreatic cancer with hepatic dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + metastasis after pancreaticoduodenectomy successfully treated by s-1 5-fluorouracil), and high dose radiation + 5-fluorouracil: The and gemcitabine combination chemotherapy. Gan To Kagaku Ryoho 2009, Gastrointestinal Tumor Study Group. Cancer 1981, 48:1705-1710. 36:2419-2421. 8. Abbott DE, Baker MS, Talamonti MS: Neoadjuvant Therapy for Pancreatic 27. Ohmura Y, Takeda Y, Nagano H, Nakamori S, Kobayashi S, Marubashi S, Cancer: A Current Review. J Surg Oncol 2010, 101:315-320. Eguchi H, Tanemura M, Kitagawa T, Monden M, Mori M, Doki Y: A case of 9. Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH, Zahurak ML, locally advanced pancreatic cancer with superior membrane artery Dooley WC, Coleman J, Sauter PK, Pitt HA, Lillemoe KD, Cameron JL: invasion successfully resected after gemcitabine-based Pancreaticoduodenectomy for pancreatic adenocarcinoma: chemoradiotherapy. Gan To Kagaku Ryoho 2009, 36:2428-2429. postoperative adjuvant chemoradiation improves survival. A prospective, 28. Peros G, Sakorafas GH, Giannopoulos GA, Manikis D, Vassiliu P, single-institution experience. Ann Surg 1997, 225:621-636. Brountzos EN: Successful Pancreaticoduodenectomy with Immediate 10. Saini A, Norman AR, Cunningham D, Chau I, Hill M, Tait D, Hickish T, Vascular Reconstruction in a Patient with Cancer of the Pancreatic Head Iveson T, Lofts F, Jodrell D, Ross PJ, Oates J: Twelve weeks of protracted and Celiac Artery Stenosis. A Case Report. JOP J Pancreas (Online) 2009, venous infusion of fluorouracil (5-FU) is as effective as 6 months of 10:667-670. bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer. Br 29. Ahmad NA, Lewis JD, Ginsberg GG, Haller DG, Morris JB, Williams NN, J Cancer 2003, 88:1859-1865. Rosato EF, Kochman ML: Long term survival after pancreatic resection for 11. Duffour J, Bouché O, Rougier P, Milan C, Bedenne L, Seitz JF, Buecher B, pancreatic adenocarcinoma. The American Journal of Gastroenterology Legoux JL, Ducreux M, Vetter D, Raoul JL, François E, Ychou M: Safety of 2001, 96:2609-2615. cisplatin combined with continuous 5-FU versus bolus 5-FU and 30. Connoly MM, Dawson PJ, Mhicelassi F, Moossa AR, Lowenstein F: Survival leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised in 1001 Patients with Carcinoma of the Pancreas. Ann of Surg 1987, trial). Anticancer Res 2006, 26:3877-3883. 206:366-370. 12. Pasetto LM, Jirillo A, Stefani M, Monfardini S: Old and new drugs in 31. Chen EL, Prinz RA: Long-term survival after pancreatic cancer treatment. systemic therapy of pancreatic cancer. Crit Rev Oncol Hematol 2004, Am J Surg 2007, 194:s127-s130. 49:135-151. 13. Trudeau ME: Docetaxel: a review of its pharmacology and clinical doi:10.1186/1748-717X-6-124 activity. Can J Oncol 1996, 6:443-457. Cite this article as: Oberic et al.: Docetaxel- and 5-FU-concurrent 14. Rougier P, Adenis A, Ducreux M, de Forni M, Bonneterre J, Dembak M, radiotherapy in patients presenting unresectable locally advanced Clouet P, Lebecq A, Baille P, Lefresne-Soulas F, Blanc C, Armand JP: A phase pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial’s II study: Docetaxel as first-line chemotherapy for advanced pancreatic pre-planned analysis and case report of a 5.5-year disease-free survival. adenocarcinoma. Eur J Cancer 2000, 36:1016-1025. Radiation Oncology 2011 6:124. 15. Mason K, Hunter N, Abbruzzese J: In vivo enhancement of tumor radio response by Taxotere (TXT). Proc Annu Meet Am Soc Clin Oncol 1997, 16:775a. 16. Choy H, Rodriguez F, Wilcox B: Radiation-sensitizing effects of taxotere. Proc Annu Meet Am Assoc Cancer Res 1992, 33:2991a. 17. Di Cosimo S, Ferretti G, Fazio N, Silvestris N, Carlini P, Alimonti A, Gelibter A, Felici A, Papaldo P, Cognetti F: Docetaxel in advanced gastric cancer: Review of the main clinical trials. Acta oncologica 2003, 42:693-700. 18. Fleming TR: One sample multiple testing procedure for phase II trials. Biometrics 1982, 38:143-205. 19. Morganti AG, Massaccesi M, La Torre G, Caravatta L, Piscopo A, Tambaro R, Sofo L, Sallustio G, Ingrosso M, Macchia G, Deodato F, Picardi V, Ippolito E, Cellini N, Valentini V: A Systematic Review of Resectability and Survival

Journal

Radiation OncologySpringer Journals

Published: Sep 26, 2011

References