Annals of Oncology Advance Access originally published online on July 31, 2008
Annals of Oncology 2008 19(11):1882-1887; doi:10.1093/annonc/mdn403
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gastrointestinal tumors |
Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie
1 Klinik für Onkologie und Hämatologie, Krankenhaus Nordwest, Frankfurt
2 Department of Medical Oncology, Hematology, Immunology, Rheumatology and Pulmology South West Cancer Center, Eberhard-Karls-University, Tuebingen
3 Department of Medicine III, Universitätsklinikum Mannheim
4 Department of Medicine I, University of Lübeck
5 Department of Hematology and Oncology, Katholisches Krankenhaus, Hagen
6 Department of Hematology and Oncology, Städtische Kliniken, Bielefeld
7 Department of Internal Medicine I, Universitätsklinikum Carl Gustav Carus, Dresden
8 Department of Medicine I, Mutterhaus der Borromäerinnen, Trier
9 Krankenhaus Bad Cannstatt, Stuttgart
10 Gemeinschaftspraxis für Hämatologie und Internistische Onkologie, Bad Soden
11 Medical Oncology, Sanofi Aventis Deutschland GmbH, Berlin, Germany
* Correspondence to: Dr S.-E. Al-Batran, Klinik für Onkologie und Hämatologie, Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt am Main, Germany. Tel: +496976013788; Fax: +496976013655; E-mail: albatran{at}aol.com
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Abstract |
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Background: The combination of docetaxel (Taxotere), cisplatin, and fluorouracil improved efficacy in gastric cancer, but was associated with substantial toxicity. This study was designed to incorporate docetaxel into a tolerable biweekly (once every 2 weeks) oxaliplatin-based chemotherapy regimen.
Patients and methods: Patients with measurable, metastatic adenocarcinoma of the stomach or esophagogastric junction and no prior chemotherapy received oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24-h infusion in combination with docetaxel 50 mg/m2 (FLOT) on day 1 every 2 weeks. Prophylactic growth factors were not administered.
Results: Fifty-nine patients were enrolled; 54 received treatment. Patients had a median age of 60 years (range 29–76) and most (93%) of them had metastatic disease. Objective responses were observed in 57.7% of patients with a median time to treatment response of 1.54 months. Median progression-free survival (PFS) and overall survival were 5.2 and 11.1 months, respectively. Twenty-five percent of patients experienced prolonged (>12 months) PFS. Frequent (>10%) grade 3 or 4 toxic effects included neutropenia in 26 (48.1%), leukopenia in 15 (27.8%), diarrhea in 8 (14.8%), and fatigue in 6 (11.1%) patients. Complicated neutropenia was observed in two (3.8%) patients, only.
Conclusions: Biweekly FLOT is active and has a favorable safety profile.
Key words: docetaxel, esophageal, FLOT, gastric, oxaliplatin
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introduction |
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Systemic chemotherapy is widely accepted as palliative treatment of patients with advanced gastric cancer, leading to objective responses, improved quality of life, and prolonged survival time [1]. On the basis of favorable response rates, fluorouracil (FU)- and cisplatin-containing combinations were considered as a standard therapy for patients with advanced gastric cancer, even though randomized trials failed to show an improvement over the previous regimens in terms of survival [2].
A recent phase III trial has shown that the addition of docetaxel (Taxotere, Sanofi-Aventis, Berlin, Germany) to cisplatin and FU (DCF) was superior to cisplatin and FU alone (CF) in terms of quality of life, response rate, time to progression, and overall survival [3–5]. These improvements were, however, achieved at the cost of substantial toxicity. National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 or 4 neutropenia and complicated neutropenia were observed in 82% and 29% of patients, respectively. Other frequent NCI-CTC grade 3 or 4 side-effects included stomatitis (21%), diarrhea (19%), lethargy (19%), and nausea or vomiting (14%). This prompted many investigators to explore alternative docetaxel-based regimens for gastric cancer within clinical trials.
Oxaliplatin, a third generation platinum compound, has been proved to be at least as effective as cisplatin in the treatment of esophagogastric cancer [6, 7]. Several oxaliplatin-based doublets have been evaluated for gastric cancer within clinical trials. Among those, a biweekly (once every 2 weeks) combination of infusional FU (24 h), leucovorin, and oxaliplatin (FLO) represents the most intensively investigated regimen [7–9]. A recent phase III trial has randomly assigned 220 patients with previously untreated advanced gastric cancer to receive FLO or a similar cisplatin-based regimen, consisting of weekly infusional FU (24 h), leucovorin, and biweekly cisplatin [7]. In the FLO arm, NCI-CTC grade 3 or 4 leukopenia occurred in <5% of patients, and FLO was associated with significantly less nausea, leukopenia, anemia, alopecia, fatigue, renal toxicity, and thromboembolic events, as compared with the cisplatin-based regimen.
These results raised interest in whether the risk/benefit ratio of DCF could be improved by the use of FLO as a backbone for docetaxel, instead of the classical CF regimen. In the present study, we combined FLO with docetaxel at a dose of 50 mg/m2 every 2 weeks within a phase II trial in untreated patients with adenocarcinoma of the stomach or esophagogastric junction (EGJ).
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patients and methods |
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patient eligibility
Patients with histologically confirmed locally advanced, recurrent or metastatic adenocarcinoma of the stomach or EGJ were eligible. Further criteria were measurable disease, no prior palliative chemotherapy, age >18 years, Eastern Cooperative Oncology Group (ECOG) performance status of two or less, sufficient bone marrow function, creatinine clearance >40 ml/min, no concurrent uncontrolled medical illness, and no other current or previous malignancy within the past 5 years (with the exception of squamous cell carcinoma of the skin treated by surgery). Patients were excluded from the study if they had peripheral neuropathy of NCI grade
2 at baseline, brain metastases, inflammatory bowel disease, coronary heart disease, cardiac insufficiency NYHA II–IV, known hypersensitivity to FU, leucovorin, oxaliplatin, or docetaxel, or were pregnant or breast feeding. Women of childbearing potential were advised to take adequate precautions to prevent pregnancy. Participants gave written informed consent before they entered the study, which was approved by the ethics committees of the participating institutions.
treatment
Patients received oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and docetaxel 50 mg/m2, each as a 1- to 2-h i.v. infusion followed by FU 2600 mg/m2 as a 24-h continuous infusion. The drugs were given on day one of two weekly cycles. Antiemetic prophylaxis was given according to local protocols. Prophylactic dexamethasone 8 mg was administered orally (days 0 to 3) to prevent fluid retention and allergic reactions. The prophylactic use of growth factors was not permitted. Treatment was continued until disease progression, unacceptable toxicity, patient's refusal, physician's decision, or until eight cycles were completed. The administration of more than eight cycles was permitted in the absence of relevant toxic effects and if the investigator decided that it was in the best interest of the patient. The dose of FU and docetaxel was reduced by 25% for diarrhea or mucositis exceeding NCI-CTC grade 2. In cases of paresthesia or dysesthesia persisting between cycles, oxaliplatin was reduced by 25%. In cases of paresthesia or dysesthesia accompanied by pain or functional impairment, oxaliplatin was reduced by 50% (if lasting between 7 and 14 days) or omitted in further cycles until recovery (if persisting between cycles). Treatment was continued if blood leukocytes were 3000/µl independent of the granulocyte count and in the absence of thrombocytopenia or any other non-hematological toxicity >NCI-CTC grade 1.
toxicity assessment
Toxic effects were graded according to NCI-CTC version 3. Peripheral sensitive neuropathy was graded according to an oxaliplatin-specific scale as described previously [10].
evaluation of efficacy outcomes
Responses were classified according to the World Health Organization (WHO) [11] criteria. Computed tomography scans of the chest, abdomen, and pelvis were carried out within 3 weeks before the start of the treatment and those of the target areas were repeated every 6 weeks. Patients who discontinued the study were evaluated every 2 months. Median time to treatment response was measured from the time of treatment start to the first observation of a partial or complete response. Progression-free survival (PFS) was measured from the date of random assignment until disease progression or death of any cause. Overall survival (OS) was measured from date of random assignment until death of any cause.
statistical analysis
The primary end point was the response rate as assessed in the efficacy population, which included all patients with eligible disease who received treatment. The treatment was considered active if the clinical response rate exceeded 40%. Conversely, the treatment was considered inactive if the response rate was <25%. On the basis of a one-step Fleming [12] design (power 80%; significance level 0.05), a sample size of 42 assessable patients was calculated. Five additional patients were to be included to address potential dropouts (n = 47). Because recruitment was faster than expected, the protocol was amended, increasing the sample size by 12 additional patients in order to improve the statistical power.
The conduct of the study was externally monitored according to the International Conference on Harmonisation/WHO Good Clinical Practice standards and data were reviewed by an independent safety board.
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patients
From March to October 2006, a total of 59 patients were recruited from 10 centers in Germany. Two patients, who had ineligible disease (pancreatic carcinoma and lung cancer), were excluded from the efficacy population. Five patients never received the study treatment because of rapid deterioration of performance status (one patient), screening failure (two patients), and death (three patients). These patients were excluded from the safety and the efficacy population. Therefore, 52 patients were eligible for the efficacy analysis and 54 patients for the safety analysis.
Median age was 60 years and median ECOG performance status was one. The majority (93.2%) of the patients had metastatic disease and 33.9% of them had peritoneal involvement. The baseline characteristics are shown in Table 1.
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safety and toxicity
The median number of cycles administered was 7 (range 1-14) and median treatment duration was 3.7 months (range 0.43–9.77 months). The median cumulative doses per patient for FU, oxaliplatin, and docetaxel were 15581.6, 503.1, and 323 mg/m2, respectively.
The treatment was generally well tolerated. The most common NCI-CTC grade 3 or 4 non-hematological toxic effects were diarrhea (14.8%), fatigue (11.1%), and peripheral neuropathy (9.3%). NCI-CTC grade 3 or 4 hematological toxic effects included neutropenia, leukopenia, and thrombocytopenia observed in 26 (48.1%), 15 (27.8%), and 1 (1.9%) patients, respectively. Complicated neutropenia (febrile neutropenia or neutropenic infection) was observed in two (3.8%) patients. Serious adverse events considered at least possibly related to the treatment were documented in 12 (22.2%) patients. There were no treatment-related deaths. Toxic effects are summarized in Table 2.
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Dose reductions of docetaxel were carried out in 18.5% of patients and dose reductions of any drug were required in 33.3% of patients. Reasons for treatment discontinuation were disease progression (33.3%), patient request (14.8%), toxicity (9.3%), surgery (3.7%), and other reasons (1.9%).
efficacy
Fifty-two patients received at least one chemotherapy administration and had eligible disease. Of these patients, 2 [3.8%; 95% confidence interval (95% CI) 0% to 9.1%] experienced a complete and 28 (53.8%; 95% CI, 40.3% to 67.4%) a partial response, adding to an overall response rate of 57.7% (95% CI 44.3% to 71.1%). Stable disease was observed in 12 (23.1%; 95% CI 11.6% to 34.5%) and progressive disease in 6 (11.5%; 95% CI 2.9% to 20.2%) patients. Four (7.7%; 95% CI 0.5% to 14.9%) patients were not assessable for response. The majority of the objective responses were achieved at the first tumor assessment carried out 6 weeks after the start of the treatment. As a result, the median time to treatment response was 1.54 months. Response rates are shown in Table 3.
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The median follow-up of surviving patients was 18.1 months. Forty-six (88.5%) patients had experienced progressive disease and 34 (65.4%) patients had died. Median PFS and OS were 5.2 (95% CI 4.4–8.4) and 11.1 (95% CI 9.3–17.3) months, respectively. The corresponding PFS rates at 6 and 12 months were 42% (95% CI 28.6% to 55.4%) and 25% (95% CI 13.2% to 36.77%), respectively, and the 1-year survival rate was 42% (95% CI 28.6% to 55.4%). Survival data were assessed in the Kaplan–Meier analysis shown in Figure 1. Second-line chemotherapy was carried out in 50% of the patients. Irinotecan plus a fluoropyrimidine (FU or capecitabine) represented the most common type of second-line treatment (n = 11). Other second-line regimens were capecitabine, FU, or mitomycin C.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Our study aimed at evaluating a biweekly docetaxel-oxaliplatin-FU-based triplet therapy for patients with untreated adenocarcinoma of the stomach or EGJ. The new regimen was investigated as an alternative to the DCF regimen, which has been proved effective, but was associated with significant toxic effects.
The response rate achieved in our trial was 57.7%, surpassing by far the expected rate that had been used for the sample size calculation. The rate of disease progression as best response was 11.5%. Median PFS and OS were 5.2 and 11.1 months, respectively, and the corresponding 1-year survival rate was 42%. Within the limitations of a cross-study comparison, these results seem at least comparable to those reported from the V325 trial, using DCF in metastatic gastric cancer (response rate 37%; progressive disease 17%; median time to progression 5.6 months; median OS 9.6 months; 1-year survival rate 40%; [3]). Notably, the objective responses in our trial were achieved after a median of 1.54 months. This is in line with previous findings [13], indicating rapid tumor shrinkage after docetaxel-based triplet therapies.
The rates and types of adverse events observed in our patients were consistent with those expected from docetaxel, oxaliplatin, and FU. The predominant toxicity was hematological, with grade 3 or 4 neutropenia observed in 48.1% of patients. In many cases, the patients experienced isolated neutropenia, since the rate of grade 3 or 4 leukopenia was relatively low (27.8%), and complicated neutropenia occurred in two (3.8%) patients, only. Therefore, again compared with DCF (grade 3 or 4 neutropenia, 82%; grade 3 or 4 leukopenia, 65%; complicated neutropenia, 29%; [3]), the hematological toxicity profile of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) can be considered as favorable. FLOT was also associated with reduced rates of non-hematological side-effects. The only grade 3 or 4 gastrointestinal toxicity that exceeded the 10% rate was diarrhea (14.8%). The rate of peripheral neuropathy was relatively low (9.3%), indicating that docetaxel did not enhance this dose-limiting toxicity of oxaliplatin. Notably, FLOT contains cumulative doses of docetaxel that are comparable to those used within the DCF regimen (50 mg/m2, qd15 versus 75 mg/m2 qd21, respectively). The improved tolerability (versus DCF) in our study may, therefore, be best explained by the less toxic chemotherapy backbone to which docetaxel was added. FLO is a biweekly combination of infusional FU (24 h), leucovorin, and oxaliplatin. It is different from the classical FOLFOX-regimen in that it does not contain bolus FU and is, therefore, associated with markedly reduced rates of hematological side-effects as compared with other regimens such as FOLFOX6 or CF (grade 3 or 4 neutropenia 11.6% [7] versus 28% [14] versus 57% [3], respectively). Overall, weekly or biweekly schedules of FU that were adapted from colorectal cancer seem to be associated with lower rates of hematological and gastrointestinal toxic effects as compared with the 5-day infusion of FU [15], which is often used within the CF regimen in the United States.
Several trials have been recently conducted to evaluate modifications of DCF; some of them are published in abstract form. For instance, a phase I study of escalated doses of docetaxel up to 50 mg/m2 combined with oxaliplatin 85 mg/m2 and FU 2200 mg/m2 via 48-h infusion administered every 2 weeks (D-FOX regimen) in 36 patients was reported [16]. The maximum tolerated dose of docetaxel was not reached and grade 3 or 4 (first-cycle) toxic effects affected <5% of patients. Complicated neutropenia was not reported. The response rate assessed in cohorts with different docetaxel doses was 44%. Overall, the safety results were in line with those observed in our study. A recently reported trial investigated a cisplatin-based modification of DCF, using split-dose docetaxel and cisplatin (each 40 mg/m2 on days 1, 15, and 29 every 7 weeks) combined with weekly FU (2000 mg/m2) and leucovorin 200 mg/m2 (T-PLF regimen) [17]. In contrast to the hematological toxicity of DCF, the trial reported reduced grade 3 or 4 neutropenia (22%), febrile neutropenia (5%), and stomatitis (0%). The regimen was, however, associated with significant grade 3 or 4 diarrhea (20%) and lethargy (18%). Dose modifications were required in 65% of patients and the toxicity was the main reason for treatment discontinuation, despite a relatively low dose intensity of docetaxel. This raises doubt whether a simple splitting of the doses of docetaxel, cisplatin, and FU represents a substantial improvement in tolerability over DCF.
A further advantage of oxaliplatin-based modifications such as FLOT is the fact that they do not require hospitalization for pre- and post-cisplatin hydration. This issue may have particular relevance to the treatment of elderly patients, where cardiac and renal impairment are frequent comorbidities. Of note, in the present trial, NCI-CTC grades 2–4 creatinine elevations were not observed, while a grade 1 creatinine elevation was seen in one patient only.
In conclusion, the FLOT regimen has an acceptable toxicity profile while response rates and median survival of the patients are in range with those reported with DCF or in other studies using modern combination chemotherapy for the treatment of metastatic esophagogastric cancer. Therefore, FLOT warrants further investigation within a randomized clinical trial to evaluate whether it may represent a valuable treatment alternative to DCF. The results reported here may be improved within integrated treatment approaches, including surgery following preoperative FLOT, within sequential strategies for systemic treatment or by the addition of an active biological drug. A randomized trial comparing FLO versus FLOT in older adult patients (65 years) with locally advanced or metastatic esophagogastric cancer (FLOT65+ study) is currently recruiting patients and two additional phase II trials using FLOT in the neo-adjuvant setting are planned.
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The study was supported by a scientific grant provided by Sanofi-Aventis, Germany.
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We thank Yvonne Kolassa and Kristina Steinmetz for their help in the study coordination. We thank Karin Scheffler (MCA, Berlin, Germany) for study monitoring, and Axel Hinke, MD (Wissenschaftlicher Service Pharma GmbH, Langenfeld, Germany), and Michael Scholz (Trium Analysis Online GmbH) for the statistical analysis. We thank the members of the independent safety board: Dirk Arnold, MD (Halle), Markus Moehler, MD (Mainz), and Peter Thuss-Patience, MD (Berlin). We thank Anita Löw, MD and Rosemarie Kuhl, MD (both Sanofi-Aventis, Germany) for excellent cooperation. A preliminary analysis of the study was presented at the 2007 annual meeting of the American Society of Clinical Oncology.
Received for publication February 26, 2008. Revision received May 2, 2008. Accepted for publication May 15, 2008.
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