A randomised trial comparing 5-FU with 5-FU plus cisplatin in advanced pancreatic carcinoma

M. Ducreux1,+, P. Rougier1,2, J.-P. Pignon1, J.-Y. Douillard3, J.-F. Seitz4, R. Bugat5, J.-F. Bosset6, Y. Merouche6, J.-L. Raoul7, M. Ychou8, A. Adenis9, F. Berthault-Cvitkovic10 and M. Luboinski1,§

1 Institut Gustave Roussy, Villejuif; 2 Hôpital Ambroise Paré, Boulogne; 3 Centre René Gauducheau, Nantes; 4 Institut Paoli Calmettes, Marseille; 5 Centre Claudius Régaud, Toulouse; 6 CHU Besançon; 7 Centre Eugène Marquis, Rennes; 8 Centre Val d’Aurelle, Montpellier; 9 Centre Oscar Lambret, Lille; 10 Centre René Huguenin, Saint-Cloud, France

Received 24 September 2001; revised 29 November 2001; accepted 19 December 2001


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Background:

Chemotherapy is moderately efficient as a treatment for pancreatic adenocarcinoma, but patient survival and quality of life has improved with this modality in some trials. In a previous phase II trial, 5-fluorouracil (5-FU) plus cisplatin (FUP) yielded a 26.5% response rate and a 29% survival rate at 1 year. The present study aimed to compare FUP with 5-FU alone, which was the control arm in former Mayo Clinic trials.

Patients and methods:

Patients with untreated cytologically or histologically proven metastatic or locally advanced adenocarcinoma of the pancreas were deemed measurable or evaluable. Chemotherapy regimens consisted of a control FU arm (5-FU 500 mg/m2/day for 5 days) and the investigational FUP arm (continuous 5-FU 1000 mg/m2/day for 5 days plus cisplatin 100 mg/m2 on day 1 or day 2). In both arms, chemotherapy was repeated at day 29.

Results:

Two-hundred and seven patients from 18 centres were randomised: 103 in the FU arm and 104 in FUP arm. Treatment arms were balanced with respect to performance status grade 0–1 (83% versus 86%, respectively) and the presence of metastases (92% versus 89%, respectively). The median number of cycles administered was two in both arms (range 0–14). Five patients did not receive any chemotherapy and 45 received only one cycle. Toxicity (WHO grade 3–4) was lower with FU than with FUP (20% versus 48%, P <0.001), as was neutropenia (6% versus 23%), vomiting (4% versus 17%) and toxicity-related deaths (one versus four early in the trial). The response rate was low in both arms, but superior in the FUP arm: 12% versus 0% (intention-to-treat analysis, P <0.01). The survival rates at 6 months were 28% and 38% for the FU and FUP arms, respectively, and 1-year survival rates were 9% and 17% (log-rank test, P = 0.10). One-year progression-free survival was 0% with FU versus 10% with FUP (log-rank test, P = 0.0001).

Conclusions:

In advanced pancreatic carcinomas with a poor prognosis, FUP was superior to FU in terms of response and progression-free survival, but not in terms of overall survival. The low response rate is partly related to the number of patients who received only one cycle of chemotherapy. A more effective, better tolerated version of this FUP combination is needed.

Key words: chemotherapy, metastatic disease, pancreatic neoplasm


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Pancreatic adenocarcinoma is the fifth most common cause of cancer-related death in the USA [1] and France [2]. Cure is only possible if the primary tumour is resected, but this is achieved in only 5–10% of patients in practice. The prognosis remains very poor, and of all cancers pancreatic cancer has one of the worst 5-year survival rates: 3% in some population-based studies [3, 4] and <25% in large surgical studies [57]. As virtually all patients develop metastases, meaningful improvements are expected with enhanced systemic therapies. Although a mammoth effort has been deployed to test new active drugs against this cancer, the results obtained to date with cytotoxic chemotherapy have been very disappointing.

There is currently no consensus regarding a standard chemotherapy regimen. Two recent studies have demonstrated that chemotherapy can improve overall survival without impairing the patient’s quality of life [8, 9], but two different schedules were employed. The FAM regimen [5-fluorouracil (5-FU) plus adriamycin plus mitomycin C] used in the first study has never been proven to be superior to 5-FU alone in a well conducted phase III trial [10]. In the latter study, the protocols used combined 5-FU plus folinic acid with or without etoposide, which is not commonly used in metastatic pancreatic carcinoma. 5-FU alone therefore remains one of the standard treatments in this disease and could be used in a control arm in randomised trials. On the other hand, single-agent cisplatin has shown promising activity in metastatic pancreatic carcinoma, with a 17% response rate reported in a recent, rigorously evaluated, phase II trial [11]. In a previous single-centre study, we used a 5-day continuous infusion of 5-FU plus cisplatin in 40 patients with advanced disease. A response rate of 26% was achieved and median survival at 7 months exceeded that expected in this population [12]. These results prompted our decision to perform a phase III trial comparing 5-FU alone (FU arm) with 5-day continuous infusion 5-FU plus cisplatin (FUP arm) in metastatic carcinoma of the pancreas.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Patient selection and randomisation
Eligibility criteria stipulated histological or cytological proof of ductal or undifferentiated adenocarcinoma of the pancreas. Disease was also to be either locally advanced or metastatic, and lesions were to be measurable or evaluable. Patients with ampulloma were also deemed eligible. Other eligibility criteria were: a life expectancy of at least 2 months, a WHO performance status (PS) of <3, age <75 years, no previous chemotherapy, no hormonotherapy during the previous 3 months, and no radiotherapy treatment of indicator lesions. Adequate hepatic, renal and bone marrow functions were required of all patients. Ineligibility criteria included leukopenia (<4000 cells/ml), thrombocytopenia (<130 000 cells/ml), elevated serum creatinine (>110 µmol/l), hyperbilirubinemia (>34 µmol/l), active heart disease and any known previous second primary malignant disease.

Informed consent was obtained from all patients and the local ethics committee approved the protocol.

Patients were stratified by centre, the presence of measurable disease and cancer of the pancreas or ampulloma using minimisation. They were then randomised to receive either 5-FU alone or FUP.

Treatment regimens
In the FU arm, 5-FU was administered alone in a rapid infusion (<1 h) in 250–500 ml of 5% dextrose at a dosage of 500 mg/m2/day for 5 consecutive days. Courses were repeated every 4 weeks.

In the FUP arm, 5-FU was given in 5% dextrose or isotonic saline by continuous infusion over 5 consecutive days (120 h). The system used for continuous infusion was at the discretion of the physician and could be a portable pump or a conventional system. 5-FU was given at a dose of 1000 mg/m2/day. Cisplatin was administered in a 2–3-h intravenous infusion in 500 ml hypertonic or isotonic normal saline together with mannitol. Prehydration with 2 l of isotonic normal saline followed by posthydration with an additional 2 l of isotonic normal saline preceded the cisplatin infusion. A parenteral supply of magnesium was recommended. Cisplatin was given at a dose of 100 mg/m2 on the first or second day of each cycle. Courses of the two drugs were repeated every 4 weeks.

Treatment was continued until disease progression in all patients. In the FUP arm, cisplatin could be stopped if renal, neurological or otological toxicity precluded further administration. In case of stabilisation or response, treatment was continued with a 5-day continuous infusion of 5-FU alone. Appropriate dosage adjustments were made if excessive toxicity was encountered during the preceding cycle.

When a good response was achieved, local treatment was allowed (radiation therapy or surgery).

Evaluation
Tumour response was determined by computed tomography (CT) scan and/or ultrasonography. Pleural effusion and ascites were not included in the response assessment criteria, except in the case of complete responses. Patients were evaluated for toxicity after each cycle and for response every two cycles. Toxicity and response were graded according to WHO criteria. Complete responses were defined as the disappearance of all tumour masses. Partial responses were defined as a reduction of >50% in the sum of the products of the two largest perpendicular dimensions of the target tumours, and no new lesions. Stabilisation was defined as a reduction of <50% in the size of the target tumours, and no new lesions. Tumour progression was defined as an increase of >25% in the target tumours, and/or a new tumour. If a response or stabilisation was documented, treatment was continued until progression. If there was evidence of progressive disease, treatment was discontinued. Clinical benefit was assessed indirectly, and was based on the patient’s weight and on the presence or absence of pain at each cycle. Quality of life was assessed before chemotherapy and after 2, 4 and 6 months of treatment using Spitzer’s index [13].

Statistical analysis
Our primary study end point was survival measured from the day of randomisation to the day of death. This study, comparing FUP with 5-FU alone, was designed to detect an increase from 10% to 25% in 1-year survival with a power of 0.90 using a two-sided log-rank test, for which a P value of 0.05 was considered significant. An interim analysis was performed after the inclusion of 131 patients (118 deaths observed) and its results were presented to an independent data monitoring committee in March 1996, which proposed that the trial be pursued. The Peto–Haybittle method was used to take into account this interim analysis [14]. Cox’s proportional hazards model [15] was used for all multivariate analyses and all tests were two-sided.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Two-hundred-and-seven patients were entered into this study between December 1992 and January 1998. No patients were excluded from the analysis and none were lost to follow-up. There were 16 protocol violations. Eight patients, most of whom were from the same centre, were included without histologically or cytologically proven disease (five in the FU arm, three in the FUP arm). Five of these eight patients had CA 19-9 levels that reached 20 times the upper normal value together with a pancreatic mass and hepatic metastases, so that the diagnosis of metastatic adenocarcinoma of the pancreas was strongly suggested. The other three patients had CA 19-9 levels between the normal level and seven times its upper normal limit, and a pancreatic mass and/or hepatic metastases; all three died within 5 months of inclusion (on days 3, 49 and 142). Furthermore, in the centre with the highest number of ineligible patients, the duration of survival did not differ from that achieved in the other centres. Six patients (three in the FU arm and three in the FUP arm) were included although their bilirubin levels were five-fold greater than the upper normal limit. Two patients (one in the FU arm, one in the FUP arm) were included despite a poor PS (WHO performance status 3). Table 1 details patient characteristics. In summary: the study comprised 134 men and 73 women; the mean age of the patient population was 60 years; PS was good (WHO 0 or 1) in 176 patients (85%); most patients had hepatic metastases (72%) but extra-abdominal spread was uncommon (10%); of 207 patients, 196 were evaluable for response; five patients in the FU arm and six in the FUP arm had only evaluable lesions (ascites or pleural effusion); and among patients with measurable disease, 9% (18/196) had only pancreatic sites of disease and 91% had metastatic lesions.


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Table 1.  Patient characteristics according to treatment arm
 
Treatment results
A total of 267 cycles were administered in the FU arm with a median of two cycles per patient (range 0–12) and a total of 316 cycles were administered in the FUP arm with a median of two cycles per patient (range 0–14). Five patients did not receive any chemotherapy (one in the FU arm and four in the FUP arm) due to an early tumour-related complication, 45 patients received only one course (23 in the FU arm, 22 in the FUP arm), also due to an early tumour-related complication or rapid progression. Among the 202 patients who received chemotherapy, the median total dose of 5-FU received was 5 g/m2 in the FU arm and 10 g/m2 in the FUP arm. The median mean dose per cycle was 2.5 g/m2 in the FU arm and 4.94 g/m2 in the FUP arm, which was very close to the planned dose. In the FUP arm, two patients never received cisplatin. The median mean dose of cisplatin per cycle was 100 mg/m2.

Tumour response
Only 10 of the 196 patients with measurable disease experienced an objective tumour regression: 0% with FU and 10% with FUP (95% confidence interval 4% to 16%), including one patient with an ampulloma (duration of response 317 days). The median response duration was long, 324 days (range 134–631), with a prolonged response of >12 months in two patients (seven for >9 months). Twelve and 19 patients experienced disease stabilisation with FU and FUP, respectively.

Symptoms and performance status after 2 months of treatment
A change in bodyweight of 2.3 kg in the FU arm and 2.5 kg in the FUP arm (n = 133; not significant, P = 0.52 Wilcoxon’s test) was observed between the pre-randomisation evaluation and after 2 months of treatment. Moderate or intense pain after 2 months was experienced by 47% and 33% of patients in the FU and the FUP arm, respectively (n = 144; P = 0.08). The WHO PS did not differ significantly after 2 months of treatment. Early death was the main reason for missing data (n = 51).

Quality of life
Spitzer’s index values assessing quality of life were initially available at 1 and 2 months for 114 patients. Values was missing initially in 16% of patients. Mean index values in the FU group were 7.1 (initially), and 6.6 and 5.9 at 1 and 2 months, respectively (n = 54). For the FUP group values were 7.6, 7.4 and 7.0, respectively (n = 56). Analysis of variance for repeated measures showed a significant treatment effect in favour of the FUP regimen (P = 0.03) and a significant time effect (P <0.0001) without interaction between treatment and time (P = 0.17).

Survival
A comparison of the duration of survival times from the date of randomisation is presented in Figure 1. One hundred patients in the FU arm and 103 patients in the FUP arm had died at the time of this report. Median survival was 102 days in the FU arm and 112 days in the FUP arm, and there was no difference in the relative risk of death between treatment arms (log-rank test 0.10). However, the percentage of survivors at 1 year was 17.3% in the FUP arm compared with 8.7% in the FU arm (P = 0.07). Table 2 shows survival in relation to certain patient characteristics. Statistically significant predictors of survival were: absence of metastases, ampulloma, the number of target lesions and eligibility. Survival in the treatment groups was compared after adjustment for these prognostic factors and stratification by centre using Cox’s regression analysis. The FUP regimen was not significantly superior to the FU regimen in terms of survival (P = 0.08) (Table 3).



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Figure 1. Survival according to treatment group. P = 0.10 for the comparison between the two treatment arms. CDDP, cisplatin.

 

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Table 2.  Duration of survival according to patient characteristics (univariate analysis)
 

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Table 3.  Multivariate analysis
 
Progression-free survival
Figure 2 depicts progression-free survival according to the treatment arm. The median duration of progression free-survival was 59 days with FU and 73 days with FUP. At 6 months, 4% of patients in the FU arm and 19% in the FUP arm were free from progression. At 1 year, seven patients in the FUP arm were free from progression compared with none in the FU arm. The benefit in favour of FUP was statistically significant (P = 0.0001, log-rank test). The benefit was even greater when adjustment was made with respect to centre (P = 0.00007).



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Figure 2. Progression-free survival, according to treatment group. P = 0.0001 for the comparison between the two treatment arms. CDDP, cisplatin.

 
Toxicity
Toxic reactions according to the treatment arm are detailed in Table 4. As might have been expected from the constituent single agents and their relative dosages, nausea and vomiting were more frequent and intense with the FUP regimen. Antiemetic therapy was not standardised but most of the investigators used HT3 inhibitors plus steroids. Neutropenia was more frequent with FUP, but severe sepsis did not occur frequently. There was a greater frequency of stomatitis with FUP but severe diarrhoea was roughly comparable between the treatment arms. Nephrotoxicity was limited to a transient and mild increase in serum creatinine. Peripheral neuropathy was very infrequent but severe ototoxicity, documented once with FUP, led to discontinuation of cisplatin. Overall, 48% and 20% of patients in the FUP arm and the FU arm, respectively, experienced WHO grade 3–4 toxic reactions. These adverse effects were partially responsible or the main reason for interruption of treatment in 12 patients on FUP, while such was the case in only seven patients on FU.


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Table 4.  Toxic reactions according to treatment group
 
Four toxicity-related deaths occurred in the FUP arm, and one in the FU arm, all during the first half of the accrual period.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Adenocarcinoma of the pancreas is a very aggressive and poorly chemosensitive tumour. This study is one of the largest to compare the efficacy of two chemotherapy schedules in advanced adenocarcinoma of the pancreas. Moreover, for the first time, a combination regimen appears to yield a benefit in these patients. FUP was superior to FU in terms of response and more beneficial to the patients in terms of progression-free survival. Although not confirmed as significant by the log-rank test, a trend towards a better 1-year survival rate was observed in the FUP arm. This is not surprising, as this test reflects an overall comparison of the survival curves, which did not separate before 3 months. The post hoc power was 80% to detect a 10% difference in 1-year survival, i.e. 7% to 17% at 1 year. It is also noteworthy that a subgroup of patients was found to be completely refractory to chemotherapy; these patients died very rapidly from tumour dissemination and complications (thromboembolism, haemorrhage) before receiving adequate chemotherapy (25% of cases).

Previous phase III trials comparing combination regimens with 5-FU alone were very disappointing. In 1979, combination of 5-FU and streptozotocin was compared with 5-FU alone in 176 patients. The objective response rate was 12% in both arms and median survival was similar. Cullinan et al. [10] have conducted two important trials. In the first one they compared the FAM regimen and 5-FU plus adriamycin with 5-FU alone, as in our trial. The number of evaluable patients was small. No clear benefit was obtained in favour of either combination schedule and so they were abandoned [10]. In the second study, 184 patients were randomised to three arms: (i) 5-FU alone; (ii) 5-FU plus adriamycin plus cisplatin (FAP regimen); and (iii) 5-FU plus methotrexate plus vincristine plus cyclophosphamide followed by 5-FU and mitomycin C (Mallinson regimen). There were slight differences in the response rate obtained with the different schedules but no difference was observed in terms of survival. On the other hand, the multidrug regimens were far more toxic with notable quality of life impairment [16].

Our results, which argue in favour of the FUP arm, confirm previous phase II reports suggesting interesting objective response rates (22–25%) and a promising median survival when cisplatin and 5-FU are combined for various schedules [1720]. The objective response rate in the FUP arm was, however, rather disappointing, but it should be borne in mind that 50 patients received two or less courses of chemotherapy.

Recent results have demonstrated the superiority of weekly gemcitabine over weekly 5-FU in terms of clinical benefit and overall survival, but not in terms of objective response [21]. The magnitude of the effect observed with FUP compared with 5-FU alone does not appear to be very different from that obtained with gemcitabine compared with 5-FU in the above-mentioned study [21]. Furthermore, the follow-up of patients in our study was much longer and survival curves for the two trials are very similar. It is possible that a longer follow-up in the gemcitabine trial would have led to non-significant results in terms of survival. Considering all these restrictions on the gemcitabine trial, which was published 6 months before the end of the planned accrual period, we decided not to abandon the trial prematurely.

Clinical benefit, a new criterion used to evaluate gemcitabine, was not assessed in our study, but its assessment would have been limited to a subgroup of patients representing only 50% of our population. There was, however, a non-significant trend towards a decline in the percentage of patients experiencing moderate or intense pain in the FUP arm. WHO PS and weight loss were not modified according to the treatment arm, even though FUP was more toxic. Information concerning quality of life was not available for all patients, but it was clear that there was an improvement in patient quality of life during the treatment period in the FUP arm, while it worsened in the FU arm.

Although more effective than 5-FU alone, the combination of 5-FU plus cisplatin caused frequent and sometimes severe nausea and vomiting, even with adequate prophylactic antiemetic therapy. These adverse side effects compromised both the patients’ quality of life and their compliance. Four toxicity-related deaths occurred in the FUP arm compared with only one in the FU arm. The higher toxicity is clearly due to the adjunction of cisplatin to 5-FU, but may also have been dose-dependent: the scheduled doses of 5-FU in the FUP arm were twice that of 5-FU in the FU arm. Cisplatin is nonetheless active when given alone as a treatment for pancreatic adenocarcinoma [11], but more recent combinations of 5-FU plus leucovorin plus cisplatin using a bimonthly schedule have yielded more encouraging results in terms of toxicity [22, 23].

The most significant poor prognostic factors identified by multivariate analysis were the presence of metastases and pancreatic carcinoma rather than ampulloma. These results were keenly awaited as it was known that metastatic adenocarcinoma of the pancreas carries a very poor prognosis, with a median survival of 4 months compared with 6–8 months for locally advanced disease. Ampulloma is known to carry a better prognosis than pancreatic carcinoma when surgically resectable [24]. Little is known about locally advanced or metastatic ampulloma, although this tumour seems less aggressive than pancreatic carcinoma. The prognostic value of ineligibility shows that ineligible patients had a poorer prognosis than eligible ones. The high proportion of ineligible patients with a very poor prognosis partially explains why survival curves did not separate before 3 months. The prognostic analysis was an additional argument in favour of the FUP regimen, which was of borderline prognostic significance after adjustment for other prognostic factors.

Taken together, our results clearly demonstrate that combination 5-day continuous-infusion 5-FU and cisplatin is more effective than 5-FU alone, but is more toxic. Recently published reports and the present study demonstrate that bolus 5-FU alone is ostensibly ineffective and can no longer be considered the standard treatment [21, 25]. Different directions need to be considered for future research. Less toxic 5-FU and cisplatin schedules should be explored, such as combination bolus 5-FU plus continuous infusion plus folinic acid for 2 days every 15 days plus cisplatin 50 mg/m2 every 15 days, or weekly 24-h continuous infusion 5-FU plus folinic acid combined with the same doses of cisplatin [22, 26]. Another potential avenue of research would be to test the recent drug gemcitabine combined with cisplatin. A randomised multicentre phase II study of 103 patients has already been conducted with weekly cisplatin 25 mg/m2. The combination arm appears to be more effective than gemcitabine alone, but neutropenia and thrombocytopenia were more frequent in this arm [27].


    Conclusion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Combination 5-FU plus cisplatin is slightly more effective than 5-FU alone for the treatment of advanced pancreatic adenocarcinoma, with benefits afforded in terms of response and progression-free survival, but with no gain in terms of overall survival. However, the FUP regimen is more toxic than 5-FU alone. Further trials are warranted to search for a better 5-FU administration schedule in order to improve tolerance thresholds with combination 5-FU plus cisplatin. Regimens combining gemcitabine and cisplatin or 5-FU, gemcitabine and cisplatin should also be evaluated. New drugs are urgently needed for treatment of this very aggressive tumour.


    Acknowledgements
 
We are indebted to Bernard Asselain, Gilles Pelletier and Thierry Conroy for their participation in the Data Monitoring Committee of the trial, and Lorna Saint Ange for editing.

Members of the Groupe Digestif of the Fédération Nationale des Centres de Lutte Contre le Cancer: M. Ducreux, P. Rougier, J.-P. Pignon, M. Luboinski, (Institut Gustave Roussy, Villejuif); J.-Y. Douillard, (Centre René Gauducheau, Nantes); J.-F. Seitz, M. Giovannini (Centre Paoli Calmettes, Marseille); R. Bugat, (Centre Claudius Régaud, Toulouse); J.-F. Bosset, Y. Merouche, (CHU Jean Minmoz, Besançon); J.-L. Raoul, (Centre Eugène Marquis, Rennes); M. Ychou, (Centre Val d’Aurelle, Montpellier); A. Adenis, (Centre Oscar Lambret, Lille); F. Berthault-Cvitkovic, (Centre René Huguenin, Saint Cloud); A. Ben Bouali (Centre Paul Papin, Angers); Y. Becouarn (Fondation Bergonié, Bordeaux); J. Jacob (Centre François Baclesse, Caen); B. Coudert, P. Fargeot (Centre Georges-François Leclerc, Dijon); T. Conroy (Centre Alexis Vautrin, Nancy); E. François (Centre Antoine Lacassagne, Nice); S. Nasca (Institut Jean Godinot, Reims); P. Haegele (Centre Paul Strauss, Strasbourg); P. Burtin (CHU, Angers); P. Rougier (Hôpital Ambroise Paré, Boulogne).

Study promotor: The French Federation of Anticancer Centres (FNCLCC, Fédération Nationale des Centres de Lutte Contre le Cancer); study coordinator: P. Rougier; statistician: J.-P. Pignon; data manager: M. Luboinski; data monitoring committee: Bernard Asselain, Thierry Conroy and Gilles Pelletier.


    Footnotes
 
+ Correspondence to: Dr M. P. Ducreux, Institut Gustave Roussy, Service d’Oncologie Digestive, Rue Camille Desmoulins, 94805 Villejuif, France. Tel: +33-1-42-11-43-08; Fax: +33-1-42-11-52-28; E-mail: ducreux@igr.fr Back

§ Members of the GDFNCLCC are listed in Acknowledgements. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
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