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Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer†
Version of Record online: 27 JAN 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 6, pages 1446–1453, 15 March 2010
How to Cite
Overman, M. J., Kazmi, S. M., Jhamb, J., Lin, E., Yao, J. C., Abbruzzese, J. L., Ho, L., Ajani, J. and Phan, A. (2010), Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer. Cancer, 116: 1446–1453. doi: 10.1002/cncr.24925
Presented previously in abstract form at the 2008 American Society of Clinical Oncology Annual Meeting (Abstract 15525), Chicago, IL, May 30-June 3; and at the 2009 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (Abstract 68), San Francisco, CA, January 15-17.
- Issue online: 3 MAR 2010
- Version of Record online: 27 JAN 2010
- Manuscript Accepted: 22 JUL 2009
- Manuscript Received: 5 JUN 2009
- Manuscript Revised: 14 JUL 2005
- gastric cancer;
- esophageal cancer;
Docetaxel, cisplatin, and 5-flurouracil (DCF) administered every 3 weeks produces a high rate of treatment-related adverse events. The objective of the current study was to evaluate the efficacy and tolerability of a weekly formulation of DCF.
Data from 117 patients treated at The University of Texas M. D. Anderson Cancer Center from 2002 to 2006 with a weekly formulation of DCF were retrospectively collected. A total of 95 patients received front-line therapy with 20 mg/m2 of cisplatin, 350 mg/m2 of 5-fluorouracil, and 20 mg/m2 of docetaxel administered once weekly for 6 consecutive weeks followed by a 2-week break.
Ninety-five patients (median age, 62 years [range, 33 to 87 years], with an Eastern Cooperative Oncology Group performance status of 1 or 2 in 67%) received a median of 10 weeks of DCF treatment (range, 3-41 weeks). Grade 3 or 4 hematologic toxicity (assessed according to National Cancer Institute Common Toxicity Criteria [version 3.0]) included granulocytopenia (4 patients) and anemia (9 patients). None of the patients developed a febrile neutropenic infection, but grade 3 or 4 non-neutropenic infections occurred in 8 patients. Eighty patients had measurable disease with an objective response rate determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria of 34% (95% confidence interval [95% CI], 24-45%). The median follow-up was 9 months, with a median time to disease progression of 4.1 months (95% CI, 3.6-5.7 months) and a median overall survival of 8.9 months (95% CI, 7.7-10.8 months).
In patients with advanced gastric and esophageal cancer who were not candidates for every-3-week DCF, a weekly formulation of DCF demonstrated modest activity with minimal hematologic toxicity, suggesting that weekly DCF is a reasonable treatment option for such patients. Cancer 2010. © 2010 American Cancer Society.
Gastric, gastroesophageal junction, and esophageal carcinoma are aggressive malignancies in which survival remains dismal. The 5-year overall survival rate is 24% for gastric cancer and 19% for esophageal cancer.1 For patients with metastatic disease, the median survivals for those who received chemotherapy in recent large phase 3 studies are approximately 8 to 11 months.2, 3
In 2006, the US Food and Drug Administration (FDA) approved docetaxel to be used in combination with cisplatin and infusional 5-fluorouracil every 3 weeks as first-line therapy for advanced gastric and gastroesophageal junction cancers. In the randomized phase 3 trial that compared every-3-week therapy with docetaxel at a dose of 75 mg/m2 on Day 1, cisplatin at a dose of 75 mg/m2 on Day 1, and infusional 5-fluorouracil at a dose of 750 mg/m2/day on Days 1 to 5 (DCF) with every-4-week cisplatin plus infusional 5-fluorouracil (CF), the median time to tumor progression (TTP) and median overall survival (OS) were found to be significantly higher with every-3-week DCF.3 With longer follow-up, a subsequent analysis demonstrated that deterioration in quality of life was delayed for those patients on the DCF arm of the study.4, 5 However, among DCF-treated patients, 82% had grade 3 or 4 neutropenia and febrile neutropenia developed in 29%. In addition, common toxicities reported with every-3-week DCF were anemia, thrombocytopenia, and other nonhematologic toxicities including diarrhea, nausea or vomiting, and stomatitis. In all, 69% of patients developed treatment-related grade 3 adverse events. Thus, the higher rate of objective response and improvement in the median OS with the addition of docetaxel came at high price. Furthermore, 1 of the biggest criticisms of the trial was that the cohort of patients enrolled was much younger, with a median age of 55 years. Although the authors concluded that every-3-week DCF should be considered as the front-line therapy for all patients with metastatic or advanced unresectable gastric or gastroesophageal cancers, the high rate of treatment-related toxicity limits the applicability of this regimen to all patients, particularly those who are elderly or have a poor performance status.6
Several modifications of the every-3-week schedule of DCF have been investigated in an attempt to minimize the toxicity noted with this regimen. The primary focus of these modifications has been to alter the dose and frequency of the cytotoxic agents to allow further applicability of an otherwise proven effective chemotherapy combination. At the University of Texas M. D. Anderson Cancer Center (MDACC), patients with gastroesophageal carcinomas who were not considered candidates for a clinical trial or every-3-week DCF administration were given a modified weekly formulation of DCF. Herein, we report our experience with weekly DCF as front-line therapy for their metastatic or advanced gastric, gastroesophageal, or esophageal carcinomas.
MATERIALS AND METHODS
From January 2000 to March 2007, we identified all patients who had both a diagnosis of gastric, gastroesophageal junction, or esophageal carcinoma from the MDACC Tumor Registry and received weekly DCF chemotherapy from the MDACC Pharmacy Database.
A total of 117 patients with the aforementioned diagnoses treated between November 2002 and October 2006 were identified, but our analysis only included 95 patients who met the following inclusion criteria: 1) received weekly DCF as first-line therapy for either metastatic or locally advanced unresectable disease; 2) received no other concomitant targeted therapy such as bevacizumab or cetuximab; 3) had a histologically confirmed diagnosis of gastric, gastroesophageal, or esophageal carcinoma at MDACC; 4) received at least 3 weekly doses of DCF; and 5) had documented follow-up with a physician visit and a radiographic tumor evaluation. The interval between each restaging evaluation was determined by the treating physician, and was generally conducted every 8 weeks. Patients who initially received DCF every 3 weeks before weekly administration were excluded. Patients with either evaluable or measurable disease were included. This retrospective analysis was approved and performed in accordance with the ethical standards described by the MDACC Institutional Review Board.
All medical records were reviewed for information regarding demographic data, tumor characteristics, treatment toxicities, and laboratory values. Hematologic toxicity was assessed according to National Cancer Institute Common Toxicity Criteria (NCICTC) (version 3.0) and reported as the maximum grade anytime during the weekly DCF therapy. Due to the difficulty with retrospective grading of nonlaboratory toxicity, such toxicity was recorded as either present or absent as reported by the patients. Tumor responses were determined retrospectively by 2 authors (S.K. and M.O.) using Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0).7
Weekly DCF was administered according to a standardized order set using cisplatin at a dose of 20 mg/m2 given intravenously (iv) over 1 hour, 5-fluorouracil at a dose of 350 mg/m2 iv bolus administered over 15 minutes, and docetaxel at a dose of 20 mg/m2 iv given over 30 minutes, each administered every week for 6 consecutive weeks followed by a 2-week break (an overall 8-week cycle). Eight of the patients included in this analysis started with and received a slightly modified administration schedule, with 6 patients receiving weekly DCF for 3 consecutive weeks every 4 weeks and 2 patients receiving DCF for 2 consecutive weeks every 3 weeks.
The primary objective of the current study was to assess the therapeutic efficacy by objective response rate (ORR). Secondary objectives were to assess the toxicity of weekly DCF, in particular hematologic toxicity; median OS; and median TTP. The Kaplan-Meier product-limit method, calculated from the initiation of of chemotherapy to death or disease progression, was used to generate the survival and TTP curves. Disease progression was defined as either clinical deterioration requiring early termination, objective radiographic progression, or death within 12 weeks after last tumor assessment. For TTP analysis, the data are reported with and without censoring for patients who underwent subsequent anticancer therapy. Patients who received new anticancer therapy (such as radiotherapy, surgical resection, or additional chemotherapy) before disease progression were censored at the date of their last tumor assessment before the new anticancer therapy was initiated. To study the effects of explanatory covariates on OS, Cox proportional hazards regression models were used to assess the hazards ratios (HR). In univariate Cox regression, the effects of variables were modeled individually. All variables were then included into an initial multivariate Cox proportional hazards model, and a stepwise model selection procedure was performed with equal entering and staying probabilities of 0.1. All computations were performed on DELL PCs using the Windows NT operating system in SAS (SAS institute Inc, Cary, NC) and S-plus 8.0 (Insightful Corp., Seattle, Wash) statistical software.
Overall, we identified 117 patients with gastric, gastroesophageal junction, or esophageal carcinoma who were treated with weekly DCF at MDACC between November 2002 and October 2006. Twenty-two patients who did not meet the inclusion criteria for this analysis were excluded: 7 patients received weekly DCF as a second-line regimen, 8 patients received <3 weeks of therapy, 2 patients received therapy in the adjuvant or neoadjuvant setting, 2 patients received additional targeted therapy along with weekly DCF, and 3 patients lacked adequate follow-up for toxicity and response assessment. The final analysis included 95 patients.
Patients and Treatment
Baseline characteristics are presented in Table 1. The median patient age was 62 years (range, 33-87 years) with 22% of the population (21 patients) aged ≥70 years. Approximately 19% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. The majority of patients had metastatic disease (66%) and adenocarcinoma histology (82%).
|Characteristic||No. of Patients (%)|
|Median age (range), y||62 (33-87)|
|Male gender||71 (74)|
|ECOG performance statusa|
|Median albumin (range), g/dL||3.9 (2.3-3.5)|
|Median hemoglobin (range), g/dL||12.6 (8.7-15.8)|
|Gastroesophageal junction||37 (39)|
|Squamous cell carcinoma||17 (18)|
|Poorly differentiated||67 (72)|
|Moderately differentiated||26 (28)|
|Locally advanced, unresectable||32 (34)|
|Location of metastases|
|Distant lymph nodes||32 (33)|
|Perioperative chemotherapy||1 (1)|
|Surgical resection||5 (5)|
The median number of weeks that DCF was administered was 10 (range, 3-41 weeks) with patients aged ≥70 years receiving a median of 10 weeks (range, 5-35 weeks). Patients with an ECOG PS of 2 received a median of 6 weeks (range, 3-24 weeks) of treatment.
Toxicity data are summarized in Table 2. Grade 3 or 4 anemia occurred in 9 patients (9%), grade 3 or 4 neutropenia occurred in 4 patients (4%), and no cases of grade 3 or 4 thrombocytopenia occurred. Primary prophylaxis with white blood cell growth factor support was not used in any patient. Furthermore, neutropenic fever was not observed, but 8 patients had non-neutropenic febrile illnesses. All 8 patients received antibiotic therapy, and in 4 cases, an infectious etiology was identified: pneumonia (1 patient), bacteremia (2 patients), and urosepsis (1 patient). No deaths related to treatment toxicity were identified.
|Toxicity||No. of Patients (%)|
|Grades 1 and 2||84 (88)|
|Grades 3 and 4||9 (9)|
|Grades 1 and 2||33 (34)|
|Grades 3 and 4||4 (4)|
|Grades 1 and 2||41 (43)|
|Grades 3 and 4||None|
|Non-neutropenic febrile illness||8 (8)|
|Dose reductions||8 (8)|
|Dose delays or dose omissions||19 (20)|
Fatigue, nausea or vomiting, and diarrhea were reported at least once during the treatment course by 53%, 54%, and 29% of patients, respectively. Twenty-two patients (23%) required hospitalization during their course of chemotherapy. The most common reasons for admission included dehydration (6 patients), non-neutropenic fever (7 patients), declining functional status (2 patients), symptomatic pulmonary embolism (2 patients), and inadequate pain control (2 patient). Eight patients had dose reductions, with the most common reason being nausea and vomiting (3 patients). Dose delays or dose omissions occurred in 19 patients, with the most common causes being neutropenia (5 patients), anemia (3 patients), and thrombocytopenia (3 patients).
Among the 80 patients with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria at baseline, the ORR was 34% (95% confidence interval [95% CI], 23-45%) with 1 complete response and 26 partial responses noted (Table 3). The overall TTP was 5.3 months (95% CI, 3.9-6.1 months) (Fig. 1).
|Outcome Measure||No.||%||95% CI|
|Overall survival, mo||8.9||7.7-10.8|
|Time to disease progression, mo|
|Censored for subsequent therapy||4.1||3.6-5.7|
Twenty-seven (28%) patients with either stable or responding disease underwent subsequent cancer-directed therapy before progression on DCF. For this group of patients, further therapy included chemoradiation in 23, chemoradiation followed by surgical resection in 3, and alternate chemotherapy in 1 patient. The TTP censored for subsequent anticancer therapy was 4.1 months (95% CI, 3.6-5.7 months) (Fig. 1). Of the 3 patients who underwent subsequent surgical resection, 2 had died from disease and 1 remained without evidence of disease recurrence at 35 months after surgical resection. Thirty-five patients went on to receive additional chemotherapy. Second-line chemotherapy was comprised of oxaliplatin-based treatment in 22 patients, irinotecan-based treatment in 7 patients, experimental protocol-based treatment in 4 patients, capecitabine monotherapy in 2 patients, and single‒agent gemcitabine in 1 patient.
The median follow-up was 9 months (range, 1-53 months), with 82 (86%) patients dead at the time of last follow‒up. The median OS survival was 8.9 months (95% CI, 7.7-10.8 months), and the 1-year and 2-year survival rates were 36% (95% CI, 22-49%) and 13% (95% CI, 3-33%), respectively (Fig. 1).
Patients aged ≥70 years had a median TTP of 6.8 months (95% CI, 4.1-10.9 months) and median OS of 10.9 months (95% CI, 6.8-13.2 months). Patients with an ECOG PS of 2 demonstrated a worse outcome, with a median TTP of 1.6 months (95% CI, 1.5-4.5 months) and a median OS of 5.59 months (95% CI, 3.3-8.3 months). On multivariate survival analysis, the only statistically significant factor was ECOG PS, with worse OS observed in patients with an ECOG PS of 2 (HR, 2.88; 95% CI, 1.51-5.51 [P = .001]).
The weekly administration of DCF appears to be well-tolerated, with limited hematologic toxicities. Moreover, this weekly regimen demonstrated activity in patients who were generally believed to be poor candidates for the administration of DCF every 3 weeks, with a response rate of 34%, a median TTP of 4.1 months, and a median OS of 8.9 months. As a retrospective study, these results are hypothesis-generating and suggest that further examination of altered administration schedules of these 3 active chemotherapeutic agents in gastroesophageal cancer should continue.
A recent meta-analysis demonstrated a survival benefit for the use of combination chemotherapy compared with single-agent chemotherapy in patients with advanced gastric cancer.8 The benefit of a triplet combination over a doublet combination has been less well-established, although the addition of an anthracycline or taxane to the combination of 5-fluorouracil and a platinum compound has become common. The largest study to demonstrate the superiority of a triplet chemotherapy combination was the randomized phase 3 study comparing the addition of docetaxel to the combination of cisplatin and 5-fluorouracil.3 This addition resulted in statistically significant improvements in response rate (37% compared with 25%), median TTP (5.6 months compared with 3.7 months), and median OS (9.2 months compared with 8.6 months) in favor of the DCF treatment arm. Despite enrolling a young population (median age, 55 years) with good functional status (ECOG PS of 0-1), significant toxicity was observed with this triplet combination. Neutropenic infections occurred in 29% of patients, grade 3 or 4 neutropenia occurred in 82% of patients, and grade 3 or 4 gastrointestinal toxicity occurred in 49% of patients.
Weekly DCF, as studied in this report, results in low rates of hematologic toxicity with no neutropenic infections and a 4% rate of grade 3 or 4 neutropenia. Due to the retrospective nature of this study, grading of nonhematologic toxicities was not possible. Although 23% of patients were hospitalized for primarily nonhematologic toxicities, dose reductions and dose delays for nonhematologic toxicities were infrequent, occurring in <10% of patients. Despite the methodologic differences between this study and the phase 3 study of every-3-week DCF, the findings of the current study can at least propose that the weekly administration of DCF results in a lower rate of hematologic toxicity. This finding is not surprising given the improved hematologic tolerance of the weekly administration of docetaxel when compared with every-3-week administration in other cancer types.9-11
The 34% response rate reported with weekly DCF appears similar to the 37% response rate noted with every-3-week DCF.3 However, in contrast to this study, in which RECIST methodology was used, the response rate evaluation in the phase 3 study of every-3-week DCF used the World Health Organization response criteria, in which a partial response is defined as a decrease of ≥50% in the bidimensional size of a lesion. The median OS of 8.9 months is similar to the 9.2 months noted with the every-3-week DCF regimen, but the lower percentage of metastatic patients included in this study (66% in comparison with 97%) likely contributes to the high median OS noted in the current study. Because a large percentage of patients with locally advanced, unresectable cancer received consolidative chemoradiation before progressing on weekly DCF, a TTP censored for additional anticancer treatment before disease progression was calculated. This 4.1-month TTP is likely a more accurate comparator value to the 5.6-month TTP noted in the phase 3 study of every-3-week DCF.
A critical goal for the treatment of advanced gastroesophageal carcinoma is the fine balance between optimizing the treatment efficacy and improving quality of life. This becomes extremely important in this population of patients because the majority of patients will present with multiple comorbidities, significant weight loss, and diminished functional status.12 However, patients enrolled in phase 2 and 3 trials in gastroesophageal cancer represent a selected subset of patients with good physical and biochemical PS. For example, in the phase 2 GASTRO-TAX study of every-other-week DCF, the median patient age was 53 years, and 75% of patients had an ECOG PS of 0.13 In the phase 3 study of every-3-week DCF, the median patient age was 55 years, and 64% had an ECOG PS of 0.3 Information regarding the tolerability of newer chemotherapeutic combinations in more relevant and realistic populations of patients diagnosed with metastatic or advanced gastroesophageal cancers, particularly the elderly and less fit, is needed. In the current study, the median age of the patients was 62 years with an ECOG PS of 1 or 2 in 48% and 19% of patients, respectively. It is interesting to note that an analysis of the Surveillance, Epidemiology, and End Results (SEER) and Medicare registries has demonstrated that elderly patients are less likely to receive chemotherapy.14 Whether this decreased use of chemotherapy in the elderly is appropriate is not known, but the current phase 2 and phase 3 studies evaluating the young and fit will not answer this question.
In this report, the 21 patients who were aged ≥70 years demonstrated good tolerance of weekly DCF, received the same number of treatments, and had similar TTP and OS as patients aged <70 years. However, the 18 patients with an ECOG PS of 2 received less treatment and had worse outcomes. The median TTP for this group was 1.6 months and the median OS was 5.6 months, which is similar to the expected survival for untreated patients.15 Despite the improved tolerance of this regimen, this finding strongly suggests that patients with poor PS will not benefit from receiving combination chemotherapy.
Other studies have investigated alternative dose and administration schedules of DCF (Table 4). A phase 2 trial of a lower dosage of DCF administered every 3 weeks (docetaxel at a dose of 50 mg/m2, cisplatin at a dose of 80 mg/m2, and 5-fluorouracil as a continuous infusion of 1200 mg/m2 over 72 hours) reported a high rate of hematologic and gastrointestinal adverse events with grade 3 neutropenia reported in 68% of patients, febrile neutropenia in 28% of patients, and stomatitis in 21% of patients.16 The phase 2 GASTRO-TAX trial, which investigated every-other-week docetaxel at a dose of 40 mg/m2 and cisplatin at a dose of 40 mg/m2 combined with weekly 5-fluorouracial at a dose of 2000 mg/m2 over 24 hours, reported rates of grade 3 or 4 neutropenia of 23%, febrile neutropenia of 5%, and grade 3 or 4 diarrhea of 20%.13 A preliminary report of a multicenter phase 2 study with a modified DCF regimen of docetaxel at a dose of 30 mg/m2 on Days 1 and 8, cisplatin at a dose of 60 mg/m2 on Day 1, and 5-fluorouracil as a continuous infusion of 200 mg/m2/day for 21 days every 3 weeks demonstrated a 4% rate of febrile neutropenia and a 10% rate of grade 3 or 4 diarrhea.17 These various trials, along with the current study, illustrate the potential toxicity benefit from administration schedules other than every-3-week DCF.
|Study||Phase||No. of Patients||RR, %||TTP, Months||Febrile Neutropenia, %||Grade 3/4 Neutropenia, %|
|DCF every 3 wk (Van Cutsem 20063)||3||221||37||5.6||29||82|
|Docetaxel, 75 mg/m2 on D1|
|Cisplatin, 75 mg/m2 on D1|
|5-FU, 1000 mg/m2 on D1-5|
|Low-dose DCF every 3 wk (Park 200516)||2||47||40||4.6||26||68|
|Docetaxel, 50 mg/m2 on D1|
|Cisplatin, 80 mg/m2 on D1|
|5-FU, 1200 mg/m2 on D1-3|
|GASTRO-TAX, every 7 wk (Lorenzen 200713)||2||60||47||9.4||5||22|
|Docetaxel, 40 mg/m2 on D1, 15, and 29|
|Cisplatin, 40 mg/m2 on D1, 15, and 29|
|5-FU, 2000 mg/m2 wklya|
|ATTAX every 3 wk (Tebbutt 200717)||2||50||49||5.9b||4||NR|
|Docetaxel, 30 mg/m2 on D1 and 8|
|Cisplatin, 60 mg/m2 on D1|
|5-FU, 200 mg/m2/d|
|D-FOX, every 2 wk (Ajani 200718)||2||36||43||NR||0||NR|
|Docetaxel, 50 mg/m2 on D1|
|Oxaliplatin, 85 mg/m2 on D1|
|5-FU, 2200 mg/m2 on D1-2|
|FLOT, every 2 wk (Al-Batran 200819)||2||59||53||5.2b||2||48|
|Docetaxel, 50 mg/m2 on D1|
|Oxaliplatin, 85 mg/m2 on D1|
|5-FU, 2600 mg/m2 on D1c|
|Wkly DCF (current study)||Retrospective||95||34||4.1||0||4|
|Docetaxel, 20 mg/m2|
|Cisplatin, 20 mg/m2|
|5-FU, 350 mg/m2|
Another route to improve toxicity has been the substitution of oxaliplatin for cisplatin. In the phase 3 REAL-2 trial, the comparison of oxaliplatin combinations with cisplatin combinations demonstrated equivalent efficacy and a reduction in both neutropenia and renal toxicity with the use of oxaliplatin-based combinations.2 A phase 2 study of D-FOX (docetaxel at a dose of 50 mg/m2 on Day 1, oxaliplatin at a dose of 85 mg/m2 on Day 1, and 5-fluorouracil as a continuous infusion of 2200 mg/m2 over 48 hours on Days 1 to 2 every 2 weeks) demonstrated no episodes of febrile neutropenia in 36 treated patients.18
There are several limitations to this retrospective study, and our findings are only hypothesis-generating. The evaluation of toxicity, in particular nonhematologic toxicity, is limited in this study by its retrospective nature. The exact reason for the selection of this therapy by the treating physician could not be determined. The population studied in the current report is heterogeneous, and analysis of various subsets was severely limited by the small sample size. The response rate was determined retrospectively, although strict RECIST criteria were used. Finally, the impact of this therapy on quality of life could not be determined.
Weekly DCF, as studied in the current study, is a new and tolerable first-line palliative regimen for patients with advanced gastroesophageal cancer. Despite the improved tolerance, patients with an ECOG PS of 2 did not benefit from treatment. Further prospective study of alternate administration schedules of these active chemotherapeutic agents in gastroesophageal cancer should continue.
CONFLICT OF INTEREST DISCLOSURES
Dr. Overman received a research grant from Sanofi-Aventis. Dr. Phan has acted as a member of the Speakers Bureau for Sanofi-Aventis.
- 1http://seer.cancer.gov/csr/1975_2006/. Based on November 2008 SEER data submission. Accessed May 2009., , , et al. SEER Cancer Statistics Review, 1975–2006. National Cancer Institute. Bethesda, MD. Available at:
- 7New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92: 205-216., , , et al.
- 18Phase I/II trial of docetaxel plus oxaliplatin and 5-fluorouracil (D-FOX) in patients with untreated, advanced gastric or gastroesophageal cancer [abstract]. J Clin Oncol. 2007; 25: 4612., , , , , .
- 19Biweekly 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. Ann Oncol. 2008; 19: 1882-1887., , , et al.