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Annals of Oncology Advance Access published July 31, 2008
Annals of Oncology Biweekly fluorouracil, leucovorin, oxaliplatin, anddocetaxel (FLOT) for patients with metastaticadenocarcinoma of the stomach or esophagogastricjunction: a phase II trial of the ArbeitsgemeinschaftInternistische Onkologie S.-E. Al-Batran1*, J. T. Hartmann2, R. Hofheinz3, N. Homann4, V. Rethwisch5, S. Probst6,J. Stoehlmacher7, M. R. Clemens8, R. Mahlberg8, M. Fritz9, G. Seipelt10, M. Sievert11,C. Pauligk1, A. Atmaca1 & E. Ja¨ger11Klinik fu¨r Onkologie und Ha¨matologie, Krankenhaus Nordwest, Frankfurt; 2Department of Medical Oncology, Hematology, Immunology, Rheumatology and PulmologySouth West Cancer Center, Eberhard-Karls-University, Tuebingen; 3Department of Medicine III, Universita¨tsklinikum Mannheim; 4Department of Medicine I, University of Lu¨beck; 5Department of Hematology and Oncology, Katholisches Krankenhaus, Hagen; 6Department of Hematology and Oncology, Sta¨dtische Kliniken, Bielefeld;7Department of Internal Medicine I, Universita¨tsklinikum Carl Gustav Carus, Dresden; 8Department of Medicine I, Mutterhaus der Borroma¨erinnen, Trier; 9KrankenhausBad Cannstatt, Stuttgart; 10Gemeinschaftspraxis fu¨r Ha¨matologie und Internistische Onkologie, Bad Soden; 11Medical Oncology, Sanofi Aventis Deutschland GmbH, Received 26 February 2008; revised 2 May 2008; accepted 15 May 2008 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 in8 (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 A recent phase III trial has shown that the addition of docetaxel (Taxotere, Sanofi-Aventis, Berlin, Germany) to Systemic chemotherapy is widely accepted as palliative treatment cisplatin and FU (DCF) was superior to cisplatin and FU alone of patients with advanced gastric cancer, leading to objective (CF) in terms of quality of life, response rate, time to responses, improved quality of life, and prolonged survival time progression, and overall survival [3–5]. These improvements [1]. On the basis of favorable response rates, fluorouracil were, however, achieved at the cost of substantial toxicity.
(FU)- and cisplatin-containing combinations were considered as National Cancer Institute Common Toxicity Criteria (NCI- a standard therapy for patients with advanced gastric cancer, CTC) grade 3 or 4 neutropenia and complicated neutropenia even though randomized trials failed to show an improvement were observed in 82% and 29% of patients, respectively. Other over the previous regimens in terms of survival [2].
frequent NCI-CTC grade 3 or 4 side-effects included stomatitis(21%), diarrhea (19%), lethargy (19%), and nausea or vomiting *Correspondence to: Dr S.-E. Al-Batran, Klinik fu¨r Onkologie und Ha¨matologie, (14%). This prompted many investigators to explore alternative Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt am Main, Germany.
Tel: +496976013788; Fax: +496976013655; E-mail: albatran@aol.com docetaxel-based regimens for gastric cancer within clinical trials.
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org Annals of Oncology Oxaliplatin, a third generation platinum compound, has oxaliplatin was reduced by 50% (if lasting between 7 and 14 days) or been proved to be at least as effective as cisplatin in the omitted in further cycles until recovery (if persisting between cycles).
treatment of esophagogastric cancer [6, 7]. Several oxaliplatin- Treatment was continued if blood leukocytes were ‡3000/ll independent based doublets have been evaluated for gastric cancer within of the granulocyte count and in the absence of thrombocytopenia or any clinical trials. Among those, a biweekly (once every 2 weeks) other non-hematological toxicity >NCI-CTC grade 1.
combination of infusional FU (24 h), leucovorin, andoxaliplatin (FLO) represents the most intensively investigated toxicity assessment regimen [7–9]. A recent phase III trial has randomly assigned Toxic effects were graded according to NCI-CTC version 3. Peripheralsensitive neuropathy was graded according to an oxaliplatin-specific scale 220 patients with previously untreated advanced gastric cancer as described previously [10].
to receive FLO or a similar cisplatin-based regimen, consistingof weekly infusional FU (24 h), leucovorin, and biweekly evaluation of efficacy outcomes cisplatin [7]. In the FLO arm, NCI-CTC grade 3 or 4 Responses were classified according to the World Health Organization leukopenia occurred in <5% of patients, and FLO was (WHO) [11] criteria. Computed tomography scans of the chest, abdomen, associated with significantly less nausea, leukopenia, anemia, and pelvis were carried out within 3 weeks before the start of the treatment alopecia, fatigue, renal toxicity, and thromboembolic events, as and those of the target areas were repeated every 6 weeks. Patients who compared with the cisplatin-based regimen.
discontinued the study were evaluated every 2 months. Median time to These results raised interest in whether the risk/benefit treatment response was measured from the time of treatment start to ratio of DCF could be improved by the use of FLO as the first observation of a partial or complete response. Progression-free a backbone for docetaxel, instead of the classical CF regimen.
survival (PFS) was measured from the date of random assignment until In the present study, we combined FLO with docetaxel at disease progression or death of any cause. Overall survival (OS) was a dose of 50 mg/m2 every 2 weeks within a phase II trial in measured from date of random assignment until death of any cause.
untreated patients with adenocarcinoma of the stomach oresophagogastric junction (EGJ).
statistical analysisThe primary end point was the response rate as assessed in the efficacypopulation, which included all patients with eligible disease who patients and methods received treatment. The treatment was considered active if the clinicalresponse rate exceeded 40%. Conversely, the treatment was considered patient eligibility inactive if the response rate was <25%. On the basis of a one-step Patients with histologically confirmed locally advanced, recurrent or Fleming [12] design (power 80%; significance level 0.05), a sample size metastatic adenocarcinoma of the stomach or EGJ were eligible. Further of 42 assessable patients was calculated. Five additional patients were to be criteria were measurable disease, no prior palliative chemotherapy, age >18 included to address potential dropouts (n = 47). Because recruitment years, Eastern Cooperative Oncology Group (ECOG) performance status of was faster than expected, the protocol was amended, increasing the two or less, sufficient bone marrow function, creatinine clearance >40 sample size by 12 additional patients in order to improve the statistical ml/min, no concurrent uncontrolled medical illness, and no other current or previous malignancy within the past 5 years (with the exception of The conduct of the study was externally monitored according to the squamous cell carcinoma of the skin treated by surgery). Patients were International Conference on Harmonisation/WHO Good Clinical Practice excluded from the study if they had peripheral neuropathy of NCI grade ‡2 standards and data were reviewed by an independent safety board.
at baseline, brain metastases, inflammatory bowel disease, coronary heartdisease, 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 informedconsent before they entered the study, which was approved by the ethics From March to October 2006, a total of 59 patients were committees of the participating institutions.
recruited from 10 centers in Germany. Two patients, whohad ineligible disease (pancreatic carcinoma and lung cancer), were excluded from the efficacy population. Five Patients received oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and patients never received the study treatment because of rapid docetaxel 50 mg/m2, each as a 1- to 2-h i.v. infusion followed by FU 2600 deterioration of performance status (one patient), screening mg/m2 as a 24-h continuous infusion. The drugs were given on day one of failure (two patients), and death (three patients). These patients two weekly cycles. Antiemetic prophylaxis was given according to local were excluded from the safety and the efficacy population.
protocols. Prophylactic dexamethasone 8 mg was administered orally (days Therefore, 52 patients were eligible for the efficacy analysis 0 to 3) to prevent fluid retention and allergic reactions. The prophylactic and 54 patients for the safety analysis.
use of growth factors was not permitted. Treatment was continued until Median age was 60 years and median ECOG performance disease progression, unacceptable toxicity, patient's refusal, physician's status was one. The majority (93.2%) of the patients had decision, or until eight cycles were completed. The administration of more metastatic disease and 33.9% of them had peritoneal than eight cycles was permitted in the absence of relevant toxic effects and if involvement. The baseline characteristics are shown in Table 1.
the investigator decided that it was in the best interest of the patient. Thedose of FU and docetaxel was reduced by 25% for diarrhea or mucositis safety and toxicity exceeding NCI-CTC grade 2. In cases of paresthesia or dysesthesiapersisting between cycles, oxaliplatin was reduced by 25%. In cases of The median number of cycles administered was 7 (range 1-14) paresthesia or dysesthesia accompanied by pain or functional impairment, and median treatment duration was 3.7 months (range 2 Al-Batran et al.
Annals of Oncology Table 1. Patient characteristics possibly related to the treatment were documented in 12(22.2%) patients. There were no treatment-related deaths.
Patient characteristics Toxic effects are summarized in Table 2.
Dose reductions of docetaxel were carried out in 18.5% of patients and dose reductions of any drug were required in Total no. of patients 33.3% of patients. Reasons for treatment discontinuation were Ineligible disease disease progression (33.3%), patient request (14.8%), toxicity (9.3%), surgery (3.7%), and other reasons (1.9%).
Fifty-two patients received at least one chemotherapy administration and had eligible disease. Of these patients, 2 Primary tumor site [3.8%; 95% confidence interval (95% CI) 0% to 9.1%] Esophagogastric junction 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.
The median follow-up of surviving patients was 18.1 No. of organs involved 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 Organs involved (primary tumor excluded) 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.
ECOG, Eastern Cooperative Oncology Group; NK, not known.
aSurgery was carried out in curative intent in 20 patients and in palliative intent in five patients.
b Our study aimed at evaluating a biweekly docetaxel-oxaliplatin- Bone (5), adrenal gland (3), pelvis (3), pancreas (3), ovary (2), diaphragm FU-based triplet therapy for patients with untreated (2), small intestine (1), duodenum (1), mesenterium (1), omentum major adenocarcinoma of the stomach or EGJ. The new regimen was (1), truncus coeliacus (1).
investigated as an alternative to the DCF regimen, which hasbeen proved effective, but was associated with significanttoxic effects.
0.43–9.77 months). The median cumulative doses per patient The response rate achieved in our trial was 57.7%, surpassing for FU, oxaliplatin, and docetaxel were 15581.6, 503.1, and 323 by far the expected rate that had been used for the sample size calculation. The rate of disease progression as best The treatment was generally well tolerated. The most response was 11.5%. Median PFS and OS were 5.2 and 11.1 common NCI-CTC grade 3 or 4 non-hematological toxic months, respectively, and the corresponding 1-year survival effects were diarrhea (14.8%), fatigue (11.1%), and peripheral rate was 42%. Within the limitations of a cross-study neuropathy (9.3%). NCI-CTC grade 3 or 4 hematological toxic comparison, these results seem at least comparable to those effects included neutropenia, leukopenia, and reported from the V325 trial, using DCF in metastatic gastric thrombocytopenia observed in 26 (48.1%), 15 (27.8%), and 1 cancer (response rate 37%; progressive disease 17%; median (1.9%) patients, respectively. Complicated neutropenia (febrile time to progression 5.6 months; median OS 9.6 months; 1-year neutropenia or neutropenic infection) was observed in two survival rate 40%; [3]). Notably, the objective responses in (3.8%) patients. Serious adverse events considered at least our trial were achieved after a median of 1.54 months. This is in Annals of Oncology Table 2. Toxic effects according to National Cancer Institute Common Toxicity Criteria Version 3 All grades (n = 54) Grades 3–4 (n = 54) Median PFS, 5.2 months 1-year PFS rate, 25% Hematological toxicity Febrile neutropeniaa Infection in neutropenia – PFS months
Patients at risk (l = censored subject) Neurosensory toxicityc Median OS, 11.1 months Renal (creatinine) 1-year survival rate, 42% Data for events with suspected relation to the study drugs. AST indicates aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkalinephosphatase; NCI-CTC, National Cancer Institute Common Toxicity aFever (‡38C) with concomitant NCI-CTC grade 3 or 4 neutropenia.
OS months
bAntiemetic prophylaxis was given according to local protocols.
c Patients at risk (l = censored subject) Neurosensory toxicity was graded according to an oxaliplatin specific dNCI-CTC grade 2 alopecia affected 20.4%.
Figure 1. Kaplan–Meier survival curves demonstrating progression-free(A) and overall (B) survival for patients receiving first-line chemotherapywith the fluorouracil, leucovorin, oxaliplatin, and docetaxel regimen.
Table 3. Response rates according to WHO criteria 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 WHO, world health organization; CR, complete response; PR, partialresponse; SD, stable disease; PD, progression of disease; NE, not evaluable; neutropenia, 82%; grade 3 or 4 leukopenia, 65%; complicated CI, confidence interval.
neutropenia, 29%; [3]), the hematological toxicity profile of aThree patients died and one patient was lost to follow-up before the first fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) can assessment of response.
be considered as favorable. FLOT was also associated with 4 Al-Batran et al.
Annals of Oncology reduced rates of non-hematological side-effects. The only grade studies using modern combination chemotherapy for the 3 or 4 gastrointestinal toxicity that exceeded the 10% rate was treatment of metastatic esophagogastric cancer. Therefore, diarrhea (14.8%). The rate of peripheral neuropathy was FLOT warrants further investigation within a randomized relatively low (9.3%), indicating that docetaxel did not enhance clinical trial to evaluate whether it may represent a valuable this dose-limiting toxicity of oxaliplatin. Notably, FLOT treatment alternative to DCF. The results reported here may contains cumulative doses of docetaxel that are comparable to be improved within integrated treatment approaches, including those used within the DCF regimen (50 mg/m2, qd15 versus surgery following preoperative FLOT, within sequential 75 mg/m2 qd21, respectively). The improved tolerability (versus strategies for systemic treatment or by the addition of an active DCF) in our study may, therefore, be best explained by the less biological drug. A randomized trial comparing FLO versus toxic chemotherapy backbone to which docetaxel was added.
FLOT in older adult patients (‡65 years) with locally advanced FLO is a biweekly combination of infusional FU (24 h), or metastatic esophagogastric cancer (FLOT65+ study) is leucovorin, and oxaliplatin. It is different from the classical currently recruiting patients and two additional phase II trials FOLFOX-regimen in that it does not contain bolus FU and is, using FLOT in the neo-adjuvant setting are planned.
therefore, associated with markedly reduced rates ofhematological 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 The study was supported by a scientific grant provided by or biweekly schedules of FU that were adapted from colorectal cancer seem to be associated with lower rates of hematologicaland gastrointestinal toxic effects as compared with the 5-day infusion of FU [15], which is often used within the CFregimen in the United States.
We thank Yvonne Kolassa and Kristina Steinmetz for their help Several trials have been recently conducted to evaluate in the study coordination. We thank Karin Scheffler (MCA, modifications of DCF; some of them are published in abstract Berlin, Germany) for study monitoring, and Axel Hinke, MD form. For instance, a phase I study of escalated doses of (Wissenschaftlicher Service Pharma GmbH, Langenfeld, docetaxel up to 50 mg/m2 combined with oxaliplatin 85 mg/m2 Germany), and Michael Scholz (Trium Analysis Online GmbH) and FU 2200 mg/m2 via 48-h infusion administered every 2 for the statistical analysis. We thank the members of the weeks (D-FOX regimen) in 36 patients was reported [16]. The independent safety board: Dirk Arnold, MD (Halle), Markus maximum tolerated dose of docetaxel was not reached and Moehler, MD (Mainz), and Peter Thuss-Patience, MD (Berlin).
grade 3 or 4 (first-cycle) toxic effects affected <5% of We thank Anita Lo¨w, MD and Rosemarie Kuhl, MD (both patients. Complicated neutropenia was not reported. The Sanofi-Aventis, Germany) for excellent cooperation. A response rate assessed in cohorts with different docetaxel doses preliminary analysis of the study was presented at the 2007 was 44%. Overall, the safety results were in line with those annual meeting of the American Society of Clinical Oncology.
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6 Al-Batran et al.

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Bulletin of Pharmaceutical Research 2014;4(1):1-8 An Official Publication of Association of Pharmacy Professionals ISSN: 2249-6041 (Print); ISSN: 2249-9245 (Online) RESEARCH ARTICLE FORMULATION AND EVALUATION OF TOPICAL GEL CONTAINING HAIR GROWTH PROMOTERS FOR THE TREATMENT OF ANDROGENIC ALOPECIA Eby George* and Manju Maria Mathews Dept. of Pharmaceutics, Nirmala College of Pharmacy, Muvattupuza-686 673, Ernakulam, Kerala, India