Biweekly docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy for advanced esophageal squamous cell carcinoma: a phase I dose-escalation study

To be eligible for the study, patients had to be at least 18 years of age at the time of registration and have histologically or cytologically confirmed squamous cell carcinoma (SCC), which was surgically unresectable or recurrent. They also had to have an EOCG performance status of 0, 1, or 2, a life expectancy of >12 weeks, and adequate liver, bone marrow, renal and cardiovascular function (serum bilirubin ≤ 1.5 mg/dl; neutrophil count ≧1,500/mm³; serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ twice the upper limit of normal range; platelet count ≥10 × 10⁴/mm³; hemoglobin ≥8.0 g/dl; and creatinine ≤1.2 mg/dl (or creatinine clearance >60 ml/min). Patients previously treated with taxane therapy for recurrent disease or irradiation to major bone areas were excluded from the study. Finally, the last chemotherapeutic treatment had to be at least 4 weeks before trial enrollment. The major exclusion criteria included serious concomitant illness, symptomatic infectious disease, severe drug allergy, symptomatic peripheral neuropathy, or uncontrolled diabetes mellitus. All the participants had to sign an informed consent form approved by the Ethical Committee of Gifu University Hospital before study entry. Finally, 18 patients were entered, and all patients had fully undergone DCF therapy.

The primary objectives of this phase I study were to determine the MTD and toxicity of escalating doses of TXT combined with a fixed dose of CDDP and 5-FU in patients with advanced esophageal carcinoma. The secondary objective of the study was to obtain preliminary data regarding the clinical response.

At least three patients were entered at each TXT dose level. There was no dose-escalation within individual patients or within a dose level. All three patients at a given dose level completed the first two cycles of treatment without DLT before further patients were enrolled in the next dose level. In the absence of DLT, the next dose level was explored. Doses were escalated in sequential groups of three patients until the MTD was established or the highest intended dose levels were reached. If any of the three patients experienced DLT, an additional 3 patients were treated at the same dose level. If three or more of the six patients at a given dose level experienced DLT, the dose level was defined as the MTD. The level one step below was set as the RD for further evaluation in a phase II study.

Patients received TXT diluted in 250 ml of normal saline at the assigned dose. It was infused intravenously (iv) over 2 h, and a maintenance infusion was given for the next 2 h. Then CDDP was prepared in normal saline at a dose of 40 mg/m² and administered over 2 h on day 1.5-FU was prepared in normal saline at a dose of 400 mg/m² and administered continuously on days 1–5. TXT and CDDP were given on days 1 and 15, and 5-FU was given on days 1–5 and 15–19 of every 28-day cycle. The dose-escalation scheme is described in Table 1. The initial dose of TXT was 30 mg/m² (dose level I), and this was increased up to a maximum of 40 mg/m² in 5 mg/m²steps.

Supportive therapy for treatment and prophylaxis for expected side effects was performed. All patients were premedicated with granisetron 2 mg iv. Hypersensitivity reactions were treated with prophylactic use of dexamethasone 8 mg iv, which was infused 1 h prior to the administration of TXT. Further dexamethasone was prescribed at a dose of 4 mg orally for 2 days after administration of TXT to reduce the risk of hypersensitivity reaction and fluid retention. Diuretics were added at the discretion of the treating physician. Appropriate hydration was given before and after the cisplatin infusion. Antiemetics were recommended on subsequent days as needed.

To avoid severe mucositis, L-glutamine 8 g was administrated for all patients.

All patients underwent complete staging procedures to document disease extent, including EOCG performance status, medical history, and physical examination. Prestudy laboratory evaluation including a complete blood cell count; serum electrolytes; urea; creatinine and 24-h creatinine clearance; bilirubin; alkaline phosphatase and transaminases; CEA, SCC, CA19-9 and CYFRA measurements, and electrocardiogram was obtained within 1 week before initiation of treatment and at the start of each treatment cycle. Baseline computed tomography (CT) or magnetic resonance imaging (MRI) scans and positron emission tomography-CT were performed within 4 weeks prior to study entry. All patients had a complete blood count taken every week during therapy. Levels of electrolytes, serum creatinine, transaminases, alkaline phosphatase and bilirubin, and plasma urea were measured every 2 weeks during therapy. Medical history including toxicity, physical examination, and toxicity assessment was graded every 2 weeks during the study according to the Common Terminology Criteria for Adverse Events (v3.0). Tumor measurements were made from radiographic films or scans taken to document treatment response during therapy and were repeated at every second cycle of treatment or sooner if the patient appeared to show disease progression. Tumor response was assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria [14]. The response status of measurable lesions was evaluated by a barium meal study, endoscopy, ultrasonography and CT, or MRI.

A complete response was defined as complete disappearance of all clinically detectable malignant diseases. A partial response was defined as a ≥30% decrease in the sum of the perpendicular diameters of all measurable lesions lasting at least 4 weeks. Progressive disease was defined as ≥20% increase in the sum of products of measurable lesions over the smallest sum observed or appearance of new lesions. Stable disease did not qualify as complete response, partial response, or progressive disease.

Toxicity was evaluated and scored according to the Common Terminology Criteria for Adverse Events (v3.0). DLT was defined as febrile grade 3 neutropenia, grade 4 neutropenia lasting >7 days, grade 3 leucopenia, grade 4 thrombocytopenia, or grade 3 thrombocytopenia with bleeding tendency, or any grade 3–4 non-hematological toxicity with the exceptions of nausea, vomiting, diarrhea, and alopecia. If hematological toxicity ≥ grade 3 occurred, administration of the therapy was delayed until the platelet count was 10 × 10⁴/mm³ and absolute neutrophils were ≥2 × 10³. If gastrointestinal toxicity ≥ grade 3 occurred, the administration of chemotherapy was delayed until the optimum dose could be tolerated. Treatment was repeated every 4 weeks or as soon as a patient had recovered from the toxicity of the previous chemotherapy. However, if toxicities persisted for more than 2 weeks following the time of planned treatment, the patient was removed from the study. A delay longer than 2 weeks in administering the second cycle of therapy was also considered a DLT. Dose modifications for the next dose were based on the most severe toxicity observed since the previous treatment course. Treatment was interrupted until toxicity resolved to ≤ grade 1.