The feasibility of triple-drug chemotherapy combination in older adult patients with oesophagogastric cancer: A randomised trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65+)

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Abstract

Background

We evaluated the feasibility and tolerability of triple- versus double-drug chemotherapy in elderly patients with oesophagogastric cancer.

Methods

Patients aged 65 years or older with locally advanced or metastatic oesophagogastric cancer were stratified and randomised to infusional 5-FU, leucovorin and oxaliplatin without (FLO) or with docetaxel 50 mg/m2 (FLOT) every 2 weeks. The study is registered at ClinicalTrials.gov, identifier NCT00737373.

Findings

One hundred and forty three (FLO, 71; FLOT, 72) patients with a median age of 70 years were enrolled. The triple combination was associated with more treatment-related National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3/4 adverse events (FLOT, 81.9%; FLO, 38.6%; P < .001) and more patients experiencing a ⩾10-points deterioration of European Organization for Research and Treatment of Cancer Quality of Life (EORTC QoL) global health status scores (FLOT, 47.5%; FLO 20.5%; p = .011). The triple combination was associated with more alopecia (P < .001), neutropenia (P < .001), leukopenia (P < .001), diarrhoea (P = .006) and nausea (P = .029).). No differences were observed in treatment duration and discontinuation due to toxicity, cumulative doses or toxic deaths between arms. The triple combination improved response rates and progression-free survival in the locally advanced subgroup and in the subgroup of patients aged between 65 and 70 years but not in the metastatic group or in patients aged 70 years and older.

Interpretation

The triple-drug chemotherapy was feasible in elderly patients with oesophagogastric cancer. However, toxicity was significantly increased and QoL deteriorated in a relevant proportion of patients.

Funding

The study was partially funded by Sanofi-Aventis.

Introduction

The global incidence of oesophagogastric cancer was estimated to be nearly 1.5 million in 2008.1 The majority of these patients, nearly two-thirds, are over the age of 65 years; however, older patients are generally underrepresented in clinical trials, and many elderly patients do not receive effective combination therapies most probably due to concerns with tolerability.2

Systemic chemotherapy as palliative treatment of patients with advanced oesophagogastric cancer is widely accepted. Doublet combinations with a fluoropyrimidine and a platinum have been considered standard treatment based on improved survival and response rates for many years.3 The addition of docetaxel to cisplatin and 5-FU (DCF regimen) has been shown to improve efficacy in a recent phase III trial.4 The improvement, however, was achieved on the cost of substantial toxicity. National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3/4 neutropenia and complicated neutropenia were observed in 82% and 29% of patients receiving DCF, respectively, and severe stomatitis, diarrhoea and lethargy were in the 20% range.4 Median age was 55 years, with only 24% of patients aged ⩾65 years.4 This has raised doubts about whether older patients will be able to tolerate a docetaxel-based triplet.5

Oxaliplatin has been shown to be more tolerable than cisplatin,6 especially in older patients,7, 8 and has proven efficacy in combination with fluorouracil.6, 7, 8, 9 In a randomised phase III trial of 220 patients with previously untreated advanced adenocarcinoma of the stomach or oesophagogastric junction, the combination of 5-FU, leucovorin and oxaliplatin (FLO) every two weeks was associated with significantly less adverse events compared to 5-FU, leucovorin and cisplatin (FLP) with comparable efficacy.8 Furthermore, elderly patients treated with FLO had significantly higher ORR (41.3% versus 16.7%; P = .012), median PFS (6.0 versus 3.1 months; P = .029) and a trend towards an improved OS (13.9 versus 7.2 months) compared to those treated with FLP.

The addition of docetaxel at 50 mg/m2 every two weeks to the FLO regimen was shown to be active and tolerable in a cohort of 59 patients with a median age of 60 years, with metastatic gastric or oesophagogastric junction cancer, yielding a response rate of 58%.9 Grade 3/4 neutropenia occurred in 48% of patients, but febrile neutropenia in only 3.8%, which were favourable compared to DCF.4

The aim of this present study was to determine if the docetaxel-based triplet regimen FLOT is feasible in elderly patients. Since information on tolerability and feasibility of FLOT was required for both, the locally advanced and metastatic setting, patients with locally advanced or metastatic disease were eligible to enrol in this phase II trial after prospective stratification.

Section snippets

Patient eligibility

Patients aged ⩾65 years with histologically confirmed and measurable locally advanced or metastatic adenocarcinoma of the stomach or oesophagogastric junction were eligible. Patients with locally advanced disease (as determined by CT scans and endoscopic ultrasound) had to have lymph node involvement (>2 cm) in order to enable adequate response evaluation. Patients must have had no prior chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, sufficient bone marrow and

Patient characteristics

Between August 2007 and October 2008, 143 patients (FLOT, 72; FLO, 71) were recruited from 28 centres in Germany. One patient was excluded from the safety analysis because of consent withdrawal before study treatment. Therefore, all 143 patients (FLOT, 72; FLO, 71) were eligible for the efficacy analysis on an intent-to-treat basis and 142 patients (FLOT, 72; FLO, 70) were eligible for the safety analysis (Fig. 1). The treatment arms were well balanced for pretreatment characteristics (Table 1).

Discussion

We report the results of a randomised phase II trial specifically assessing the tolerability, feasibility and QoL of the addition of docetaxel to the duplet-drug combination 5-FU/leucovorin and oxaliplatin (FLO) in older adult patients with gastric cancer.

The addition of docetaxel to 5-FU/leucovorin and oxaliplatin (FLOT) resulted in significant increases in individual toxicities such as neutropenia, leukopenia, diarrhoea and nausea. The rates and types of adverse events observed were

Contributors

S.E.A. had the idea for and designed the study. S.E.A., C.P., N.H., J.T.H., M.M., S.P., V.R., J.S.-W., N.P., S.H., C.B., R.M., R.D.H., K.L., F.K. and E.J. provided study materials, obtained data and interpreted the results. S.E.A. and C.P. analysed data. S.E.A. and C.P. wrote the report. All authors reviewed, amended and approved the report.

Conflict of interest statement

S.E.A. has received research grants and honoraria for advisory role from Sanofi Aventis. All other authors declare that they have no conflicts of interest.

Acknowledgments

We thank Karin Scheffler (MCA, Berlin, Germany) for study monitoring. We thank Michael Scholz and Martina Güntner (Trium Analysis Online GmbH) for the statistical analysis.

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The study data has been presented in part in the poster discussion session (abstract 4013) at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO).

o

Current address: Klinikum Wolfsburg, Sauerbruchstr. 7, 38440 Wolfsburg, Germany.

p

Current address: Universitätsklinikum Kiel, Christian-Albrechts-University, Germany.

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