Annals of Oncology Advance Access originally published online on October 14, 2008
Annals of Oncology 2009 20(2):244-250; doi:10.1093/annonc/mdn638
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gastrointestinal tumors |
Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer
1 Department of Medicine, Royal Marsden Hospital, London and Surrey, UK
2 Medical University bej Chemotherapy Szpital Akademii Medycznej im, M. Kopernika, Oddzial Chemioterapii, ul. Paderewskiego, Lodz, Poland
3 Comprehensive Cancer Centre, Maria Sklodowska-Curie Memorial Institute, Branch Gliwice, Wybrze
e Armii Krajowej, Gliwice, Poland
4 Wielkopolskie Centrum Onkologii, Klinika Chemioterapii, Garbary, Poznan, Poland
5 Department of Radiotherapy, Mount Vernon Hospital, Northwood, UK
6 Rydygier Memorial Hospital, Krakow-Nowa Huta, Poland
7 Department of Medical Oncology, North Middlesex Hospital, London, UK
8 Mater Health Services, Mater Adult Hospital, South Brisbane, Australia
9 Department of Clinical Oncology, Hammersmith Hospital, London, UK
10 Department of Surgery, Chang Gung University, Chang Gung Memorial Hospital, Sec. West, Jiapu Rd., Puzih City, Ciayi County, Taiwan(R.O.C.)
11 Central Clinical Hospital of Military Medical Academy, Klinika Onkologii, CSK WAM SP ZOZ, ul. Szaszerow, Warsaw, Poland
12 Southern Medical Day Care Centre, Wollongong, NSW, Crown St, Wollongong, NSW, Australia
13 Department of Clinical Oncology, Queen Mary Hospital, Pokfulam, Hong Kong
14 Global Oncology, sanofi-aventis, Paris, France
15 Department of Medical Oncology, Cancer Research UK, University of Glasgow, Scotland, UK
* Correspondence to: Prof. D. Cunningham, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-20-8661-3156; Fax: +44-20-8643-9414; E-mail: david.cunningham{at}rmh.nhs.uk
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Background: Oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (LV) are standard first-line treatments for patients with metastatic colorectal cancer (mCRC). The aim of this multicentre, open-label, phase IIIb study was to assess the addition of oxaliplatin to two different 5-FU regimens.
Patients and methods: Patients with previously untreated mCRC were randomised to arm A [two-weekly oxaliplatin 85 mg/m2 + either continuous intravenous infusion (CIV) of 5-FU without LV or two-weekly bolus and CIV 5-FU + LV (LV5FU2)] or arm B (5-FU CIV or LV5FU2 alone). Irinotecan monotherapy was planned on progression.
Results: A total of 725 patients were enrolled. After a fixed follow-up of 2 years for each patient, 2-year survival rates were 27.3% and 24.8% in arms A and B, respectively (hazard ratio 0.93; 95% confidence interval 0.78–1.10). The addition of oxaliplatin significantly improved response rates (54.1 versus 29.8%; P < 0.0001) and median progression-free survival (7.9 versus 5.9 months; P < 0.0001). The most common grade 3–4 toxic effects were neutropenia (arm A, 33%; arm B, 5%), diarrhoea (arm A, 14%; arm B, 8%), and fatigue (arm A, 9%; arm B, 8%).
Conclusions: Despite improved rates of tumour control, these results failed to demonstrate a survival benefit from the addition of oxaliplatin to infused 5-FU and lend further support to the use of sequential monotherapy in some patients with mCRC.
Key words: colorectal cancer, 5-fluorouracil, leucovorin, metastatic, oxaliplatin, phase III
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introduction |
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The treatment of patients with metastatic colorectal cancer (mCRC) has evolved significantly over the last 10 years. For
40 years, the fluoropyrimidine 5-fluorouracil (5-FU) was the only agent used for advanced metastatic disease [1]. However, since the mid-1990s, with the introduction and approval of several new chemotherapy (oxaliplatin, irinotecan) and biologic agents (cetuximab, panitumumab, bevacizumab), available treatment options have widened significantly and overall survival (OS) has improved considerably [2–7]. A recent meta-analysis of current clinical practice has shown that patients receiving all three classes of drugs, i.e. fluoropyrimidines, oxaliplatin, and irinotecan have better survival compared with those receiving 5-FU and leucovorin alone, and the addition of biologic agents further improves outcomes [8]. However, such analyses may be confounded by patients with biologically less aggressive disease, who are better candidates for multiple lines of therapy. In 2000, when the current study was commenced, standard treatment for most patients worldwide was first-line 5-FU-based treatment followed, on progression, by irinotecan. Continuous intravenous infusion (CIV) of 5-FU without LV was also a common regimen used in UK at that time. For patients with mCRC, 5-FU + LV increases response rates (RR) compared with 5-FU alone (21% versus 11%) and confers a small but significant (11.7 versus 10.5 months) survival benefit [9]. Likewise, CIV 5-FU increases response rates versus bolus 5-FU (22% versus 14%), improves survival by a small increment, and has less haematological toxicity [10, 11].
The present trial was designed to evaluate two 5-FU regimens ± oxaliplatin followed by irinotecan on progression, with the primary objective of demonstrating an improvement in survival on addition of oxaliplatin. Results from our study are presented here and discussed within the context of recently published trials.
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patients and methods |
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patients
Patients had histologically proven CRC with distant metastases (excluding central nervous system metastases). Main eligibility criteria were age
18 years; no prior chemotherapy for metastatic disease; World Health Organisation (WHO) performance status (PS) 
2; no major biochemical/haematologic abnormalities; unidimensionally measurable lesions; and completion of any previous adjuvant chemotherapy (not containing oxaliplatin and/or irinotecan) 6 months before study entry. Patients were excluded if they had resectable disease; unresolved bowel obstruction/diarrhoea; peripheral neuropathy (National Cancer Institute Common Toxicity—Criteria Version 2.0 grade 1); prior malignancies; history of hypersensitivity; or intolerance to previous 5-FU. Pregnant/lactating females were excluded.
treatment
This was a phase IIIb, randomised, open-label, parallel-group study. Patients were randomly allocated to one of two main treatment arms (arm A or arm B), each of which was further divided into two subgroups, resulting in four treatment groups (A1, A2, B1, B2). Patients in arm A1 received oxaliplatin once every 2 weeks (85 mg/m2 2-h i.v. infusion on D1) + 5-FU 250 mg/m2/day CIV given continuously without interruption for the 2-week duration of the treatment cycle (oxaliplatin + 5-FU CIV). Patients in arm A2 had the same oxaliplatin regimen as patients in arm A1 and received 5-FU (400 mg/m2 bolus + 600 mg/m2 22-h CIV on D1, 2) + LV (200 mg/m2 2-h i.v. infusion on D1, 2) (FOLFOX4). Patients in arm B1 received 5-FU 300 mg/m2/day CIV (5-FU CIV) without interruption. Patients in arm B2 received 5-FU (400 mg/m2 bolus + 600mg/m2 22-h CIV on D1, 2) + LV (200 mg/m2 2-h i.v. infusion D1, 2) (LV5FU2). [12] Cycles were repeated every 2 weeks until disease progression or unacceptable toxicity.
As there was no consensus on a first-line 5-FU regimen at the time of the study, participating institutions selected either a 5-FU CIV regimen or LV5FU2 [12]. The same 5-FU regimen was given to all patients treated at the same institution. Randomisation was stratified according to WHO PS (0/1 versus 2), metastatic sites (1 versus 2), alkaline phosphatase (grade 0/1 versus 2), and centre. Owing to the large number of centres that were expected to participate in the study, the statistical analyses were not stratified by centre.
Premedication for allergies, nausea, and vomiting was recommended; analgesics and antiemetics were administered as required. To minimise the imbalance of second-line treatment, all eligible patients were planned to receive irinotecan 350 mg/m2 three-weekly at disease progression after a washout period of at least 4 weeks. Patients not eligible for irinotecan could receive other non-oxaliplatin therapy.
Dose modifications were made according to worst toxicity observed during the previous cycle. Treatment was delayed until full recovery of stomatitis or diarrhoea, recovery to grade 2 skin or other toxicity, and recovery of neutrophils >1 x 109/l and platelets >75 x 109/l. For patients receiving CIV 5-FU, dose reduction (DR) by 50, 100, and 150 mg/m2 for grades 2, 3, and 4 toxic effects, respectively, was planned for grade 2 stomatitis, hand–foot syndrome, and diarrhoea. For grades 3–4 diarrhoea or stomatitis, despite 150 mg/m2 DR for 5-FU, oxaliplatin was to be reduced to 75 mg/m2. Among patients receiving FOLFOX, DRs (to 300, 500, 75 mg/m2 for 5-FU bolus, 5-FU CIV, oxaliplatin, respectively) were planned for grades 3–4 neutropenia/thrombocytopenia and grade 4 diarrhoea/stomatitis. 5-FU, but not oxaliplatin reduction, was required for grade 3 diarrhoea or stomatitis. Grade 3 paraesthesias and dysaesthesias lasting >7 days required oxaliplatin DR to 75 mg/m2. Oxaliplatin was discontinued for grade 4 paraesthesia/dysaesthesia or persistent grade 3 paraesthesia/dysaesthesia unless there was improvement, in which case oxaliplatin was restarted at 75 mg/m2.
The study was conducted in accordance with the amended Declaration of Helsinki, and the protocol was approved by local Independent Ethics Committees or similar bodies. All patients provided written informed consent.
assessments and follow-up
Clinical response was determined by radiologic imaging [thoraco-abdomino-pelvic computed tomography (CT)] according to Response Evaluation Criteria In Solid Tumors [13] at baseline, cycle six and every fourth cycle thereafter, at end of treatment (28 days post last chemotherapy cycle), and every 3 months during follow-up. These were graded as complete response (CR the disappearance of all target lesions), partial response (PR at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter), progressive disease (PD at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions), or stable disease (SD neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.). All responses (CR and PR) were confirmed after 4 weeks. Complete responses were confirmed if determined by two observations no less than 4 weeks apart. No external review of response was carried out.
Toxic effects were assessed using NCI-CTC v2 before the start of each cycle, and scored based on worst grade/patient. The incidence, time to onset, and duration of neurotoxicity was assessed in all treatment groups. Standard laboratory tests [haematology, serum chemistry, carcinoembryonic antigen (CEA)] and physical examinations, including neurologic assessment, were carried out at baseline, start of each cycle (until cycle six, then every fourth cycle thereafter for CEA), and at end of treatment. A new baseline CT scan within 5 weeks for second-line therapy was to be conducted documenting progression.
statistical analysis
The primary end point of survival was defined as the percentage of patients alive at 2 years. Secondary end points included response rate, progression-free survival (PFS), time-to-treatment failure (TTF), and safety. The primary efficacy analysis was conducted in the intention-to-treat (ITT) population, comprising all patients who met the entry criteria and were randomised. Safety was assessed in all patients who received any study drug.
For the primary analysis, patients who were alive 2 years after being randomised were censored at 24 months. A secondary analysis was conducted based on the follow-up for 2 years after randomisation of the last patient. A stratified (based on the baseline factors balanced at randomisation) log-rank test was used to determine statistical significance of survival comparisons. A sample size of 700 patients (350/arm) was required to provide 90% power to detect a difference between the two arms using a two-sided log-rank test at the 0.05 level, on the basis of the assumption that 2-year survival would be 30% in arm A and 20% in arm B.
OS was calculated from the date of randomisation until death. Survival curves were plotted using Kaplan–Meier methodology and the primary end point was analysed using a two-sided log-rank test. [14] Response rate was defined as the number of patients with CRs or PRs divided by the number of patients randomised. PFS was defined as the time from randomisation until death or disease progression. TTF was defined as the time from randomisation until disease progression or study discontinuation owing to toxicity, death, or patient/physician decision. PFS and TTF were analysed using the stratified log-rank test with a fixed follow-up of 2 years after the date of randomisation for each patient. Response rates were analysed using a 
2 test.
These data have previously been presented at American Society of Clinical Oncology meeting. [15]
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patients
In all, 725 patients were enrolled and randomised onto the study (ITT population). The safety population comprised 720 patients (Figure 1). Five patients were not treated: two physician decision, one intercurrent medical problem, one voluntary withdrawal, and one death before treatment. In total, 362 patients (50%) were randomised to arm A [oxaliplatin + 5-FU CIV, 58 (16%); FOLFOX4, 304 (84%)] and 363 (50%) were randomised to arm B [5-FU CIV, 62 (17%); LV5FU2, 301 (83%)]. Patient flow chart is shown in Figure 1. Baseline characteristics were well balanced between the two treatment arms (Table 1).
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The main reason for treatment discontinuation was progressive disease (52%) followed by patient/physician decision (29%), toxicity (11%), concomitant medical problem (4%), death (3%), and noncompliance (1%). Reasons for withdrawal were similar between treatment arms, with the exception of progressive disease, which was more common in arm B (61%) than in arm A (43%) and treatment-limiting toxicity (arm A, 17%; arm B, 5%).
treatment administered
A total of 7908 cycles were administered to 720 patients, with a median of 10 cycles per patient. Patients in arms A1, A2, B1 and B2, respectively, received means of 78.3%, 83.6%, 76.7%, and 91.0% of the planned 5-FU dose intensity. Patients in arms A1 and A2, respectively, received means of 77.0% and 83.0% of the planned oxaliplatin dose intensity. Among patients who received one or more cycle of treatment, DRs for 5-FU were more common with the CIV regimen (arm A, 61%; arm B, 69%) than the two-weekly regimen (arm A, 41%; arm B, 16%). In arm A, reductions in oxaliplatin dose were required in 34% of patients in the oxaliplatin + 5-FU CIV group and in 39% of FOLFOX4 patients. Sixty-six patients required oxaliplatin DR because of haematologic toxicity, 65 of whom were in the FOLFOX4 group. Treatment delays (one or more cycle) were least common in patients who received LV5FU2 (52%) and occurred in similar proportions of patients who received oxaliplatin + 5-FU CIV (75%), FOLFOX4 (74%), or 5-FU CIV (76%). In both treatment arms, DR and delays because of haematologic toxicity were more commonly associated with biweekly 5-FU than with the CIV regimen.
Second-line chemotherapy was received by 196 patients (54.1%) in arm A and 220 (60.6%) in arm B. Irinotecan was received by 150 patients (41.4%) in arm A and 177(48.8%) in arm B (median treatment duration 2.1 months in both arms). Other second-line therapy was received by 44 patients (12.2%) in arm A and 43 (11.8%) in arm B.
efficacy
For the primary efficacy analysis, 2-year survival rates were similar between the two treatments: 27.3% in arm A and 24.8% in arm B. Median OS was 15.9 months [95% confidence interval (CI) 15.0–17.3] in arm A and 15.2 months (95% CI 14.0–16.1) in arm B. The hazard ratio (HR) for survival was 0.93 (95% CI 0.78–1.10; P = 0.155). One-year survival rates were 62.6% (95% CI 57.6% to 67.7%) and 61.5% (95% CI 56.5% to 66.5%) in arms A and B, respectively. A numerically greater probability of survival was observed in arm A compared with arm B at all time points (Figure 2). A subsequent survival analysis (follow-up for 2 years after last patient randomised) showed no significant difference between the two groups, HR 0.92 (95% CI 0.78–1.08; P = 0.106). Survival analysis by stratification variables (Cox proportional hazards) indicated that OS was higher for patients on oxaliplatin compared with 5-FU ± LV alone (RR 0.93; 95% CI 0.79–1.09) and for patients who received the 5-FU CIV regimen compared with LV5FU2 (RR 0.84; 95% CI 0.67–1.05). In addition, a retrospective analysis showed that median OS appeared to be longer, particularly in arm A, in centres where >50% of patients received second-line irinotecan (19.9 months in arm A versus 16.4 in arm B) (Figure 3).
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The overall response rate (CR + PR) was significantly higher in arm A (54.1%; 95% CI 48.9% to 59.45) than in arm B (29.8%; 95% CI 25.1% to 34.7%; P < 0.0001) (Table 2).
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Median PFS was significantly longer in arm A (7.9 months; 95% CI 7.3–9.0) than in arm B (5.9 months; 95% CI 5.1–6.8) (HR 0.67; 95% CI 0.58–0.79; P < 0.0001). The probability of being alive without disease progression was greatest in arm A at all time points (Figure 4). Median TTF was 5.5 months in arm A (95% CI 5.2–6.1) and 4.9 in arm B (95% CI 4.7–5.3) (HR 0.90; 95% CI 0.77–1.04; P = 0.053).
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Safety
Oxaliplatin versus non-oxaliplatin
More patients in arm A than in arm B experienced at least one episode of grades 3–4 toxicity (77% versus 51%, respectively). Grade 3–4 toxic effects with a higher incidence in arm A than in arm B included neutropenia, sensory neuropathy, and diarrhoea (Table 3). Treatment was discontinued owing to toxicity in 17% of patients in arm A and 5% in arm B. Rates of febrile neutropenia (arm A, 3%; arm B, 1%) and toxic death (arm A, 0.8%; arm B, 0.3%) were similar.
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Overall, 267 patients (75%) in arm A experienced neurosensory toxicity [grade
2 in 124 (35%) and grade 3 in 47 (13%)], of whom 100 (37%) had resolution of symptoms within 8 weeks. Neurosensory toxicity any grade was reported in 69 patients (19%) in arm B, with 5 (1%) experiencing grades 3–4 neurosensory symptoms.
CIV versus two-weekly schedule
In arm A, the incidence of several grade 3–4 toxic effects differed according to the administered 5-FU schedule (oxaliplatin + 5-FU CIV versus FOLFOX4, respectively) including diarrhoea (28% versus 11%), neutropenia (2% versus 39%), febrile neutropenia (0% versus 3%), infection without neutropenia (19% versus 6%), skin exfoliation (11% versus 1%), fatigue (4% versus 10%), and vomiting (12% versus 5%). In arm B, the incidence of grade 3–4 toxic effects was similar for the two 5-FU regimens, with exception of skin exfoliation, which was more common with the 5-FU CIV regimen than LV5FU2 (15% versus 1%).
Serious adverse events (SAEs)
Overall, the total number of SAEs leading to hospitalisation, prolonged hospitalisation, death, or considered medically important was 424 for arm A and 310 for arm B. A total of 40 patients died between the date of randomisation and 30 days after completion of chemotherapy (oxaliplatin + 5-FU CIV 4; FOLFOX4 16; 5-FU CIV 2; LV5FU2 18), most commonly owing to disease progression. The reported causes of death were study drug toxicity for three patients receiving FOLFOX4 (neutropenic sepsis in two, acute on chronic renal failure in one) and one patient receiving LV5FU2 (neutropenic sepsis with perforated viscus). The number of patients requiring hospitalisation during the study was 146 (40%) in arm A and 125 (34%) in arm B.
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discussion |
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This study was designed with OS as a primary end point to evaluate the benefit of adding oxaliplatin to 5-FU followed by irinotecan. There was no planned cross-over, which should have optimised the ability to evaluate the true impact of adding oxaliplatin to first-line chemotherapy in mCRC. However, although the addition of oxaliplatin led to improved tumour control with better response rates and PFS, which were comparable to previously published results (Table 4), we did not observe a statistically significant OS benefit. Contrary to other studies designed to assess response rate or PFS as the primary end point but lacking the optimum number of patients [16–18], our study design was on the basis of the hypothesis that the 2-year survival rate would be 20% in the non-oxaliplatin arm; in fact, 24.8% of patients were alive at 2 years in this arm. The higher than expected survival in the comparator arm may have decreased the power of this study to detect survival differences, although the OS observed in the present study is somewhat lower than that reported for recent studies of first-line oxaliplatin-based chemotherapy in mCRC [19–22]. These recent studies reported median OS rates of 18.9 months (OXAFAFU) [22], 19.7 months (FUFOX) [20], 19.5 months (FOLFOX4) [19], and 20.6 months (FOLFOX6) [21]. The shorter survival in the current study may be due to relative under-use of irinotecan or alternative therapies [arm A, 54.1% (41.4% irinotecan); arm B, 60.6% (48.8% irinotecan)], as well as the specific exclusion of patients with potentially resectable metastatic disease. Of note, survival is similar to that reported in the MRC FOCUS study for the oxaliplatin combination arm (15.4 months) which also specifically targeted patients with inoperable disease [23]. Median OS may be correlated with exposure to all three cytotoxic agents (5-FU/LV, oxaliplatin, irinotecan) during treatment [24]. In other first-line studies of oxaliplatin-based chemotherapy, use of second-line, predominantly irinotecan-based, chemotherapy ranged from 72% to 81% [19–21]. In the current study, for centres where >50% of patients received second-line irinotecan, median survival among patients who received oxaliplatin with 5-FU ± LV was 19.9 months, which is similar to that reported in these other studies.
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Another factor that may have contributed to shorter OS in this study was treatment compliance. In the de Gramont study, 11% of patients withdrew from oxaliplatin [16], whereas in our study 17% of patients withdrew from oxaliplatin, 34%–39% had oxaliplatin DR, and 41% of the FOLFOX4 group had 5-FU DR versus 61% on the CIV regimen.
There were no unexpected toxic effects. The safety profiles of oxaliplatin combined with 5-FU ± LV and 5-FU ± LV alone were similar to previous reports [6, 17, 19, 20]. With the addition of oxaliplatin, more patients (77% versus 51%) reported one or more grade 3–4 toxic effects (Table 3). As observed previously, oxaliplatin-associated neurotoxicity increased with increasing cumulative dose and usually resolved over time [25]. FOLFOX4 appeared to have a slightly more favourable safety profile than oxaliplatin + 5-FU CIV. DRs and treatment delays because of haematologic toxicity were commonly seen with the two-weekly schedule.
Three large randomised trials are evaluating the staged-sequenced approach to treating mCRC patients who do not fulfil the criteria for treatment with curative intent (CAIRO, FOCUS, and FFCD 2000-05). Two of these recently published trials have shown that within the context of palliative treatment, using initial 5-FU/capecitabine alone and reserving combination chemotherapy for second-line treatment, does not compromise survival or quality of life [23, 26]. Our study also shows that for patients receiving non-curative treatment, using 5-FU alone upfront is a possibility and would allow scheduling of drugs in a sequenced fashion for future use. On the other hand, upfront combination chemotherapy has consistently resulted in high response rates compared with fluoropyrimidine alone and therefore may be preferable in symptomatic patients or those with metastatic disease that is potentially resectable either upfront or after downstaging.
In conclusion, our study showed that adding oxaliplatin to 5-FU ± LV improved response rates and PFS as first-line treatment of mCRC. The combination of oxaliplatin with biweekly 5-FU/LV (FOLFOX4) resulted in a moderately improved efficacy/toxicity profile compared with oxaliplatin plus 5-FU CIV, supporting the use of FOLFOX4 as one of the standard treatment options for patients when the two-drug combination is considered appropriate. However, in light of this and other sequential versus combination chemotherapy studies, it may be argued that a staged-sequential approach could also be considered for some patients.
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Prof. DC has received in the past honoraria for attending advisory boards and giving presentations/lectures at National and International meetings and has received research funding from Sanofi-Aventis. Dr BS has received honoraria from Sanofi-Aventis to attend educational meetings. Dr RG-J has sat on advisory boards for Sanofi-Aventis and has received funding to attend International meeting in the past 2 years from Sanofi-Aventis. Dr HW has received honoraria for Advisory Boards and invited talks from Sanofi-Aaventis. IT-F is an Employee of Sanofi-Aventis.
Received for publication May 12, 2008. Revision received July 16, 2008. Accepted for publication August 22, 2008.
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