This trial was initiated and conducted within the NCCTG. The Institutional Review Boards at each site approved the protocol before patient enrollment, and all patients provided signed informed consent at the time of enrollment.
Eligibility and Exclusion Criteria
Eligibility criteria consisted of the following: 1) age ≥ 18 years; 2) histologic or cytologic evidence of squamous cell carcinoma or adenocarcinoma of the esophagus; 3) surgically resectable tumor, as deemed by a surgeon; 4) Eastern Cooperative Oncology Group (ECOG) performance score of 0–2; 5) anticipated life expectancy of ≥ 12 weeks; 7) the laboratory parameters < 14 days prior to registration of absolute neutrophil count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, total bilirubin ≤ 1.5 times the upper limit of normal, serum creatinine ≤ 1.5 times the upper limit of normal, asparatate aminotransferase ≤ three times the upper limit of normal.
Exclusion criteria consisted of the following: 1) uncontrolled infection; 2) prior chemotherapy for esophageal cancer; 3) pregnancy or unwillingness to utilize contraception if pregnancy was a possibility; 4) New York Heart Association classification III or IV; 5) other severe underlying illness that, in the opinion of the treating oncologist, would make the patient inappropriate for study entry; 6) prior radiation that would overlap anticipated radiation fields; 7) antihypertensive or diuretic medications that could not be safely discontinued, if necessary, for several days during study treatment.
The neoadjuvant treatment regimen consisted of both chemotherapy and radiation. Chemotherapy consisted of carboplatin with an area under the curve (AUC) of 4 to be given intravenously on days 1 and 22, paclitaxel 200 mg/m2 to be given intravenously on days 1 and 22, and 5-fluorouracil 225 mg/m2/day to be given by continuous intravenous infusion on days 1 through 42. In addition, amifostine was to be administered as a 500 mg flat dose subcutaneously immediately before each radiation treatment.
For evaluation purposes, a treatment "cycle" is defined by the administration of carboplatin and paclitaxel, where the initiation of these agents heralded the start of a new chemotherapy "cycle." In effect, cycle 1 occurred during days 1–21 of the treatment, and cycle 2 between days 22–42.
The protocol was written to allow for a dose increase of carboplatin to an AUC of 6 in the event that a planned interim toxicity analysis after the first 10 patients deemed this increase could be undertaken safely.
Radiation was prescribed at a total dose of 4500 centigray. Each fraction size was 180 centigray, and a total of 25 fractions were to be given.
Chemotherapy dose reductions were initiated based on toxicity. As determined by the National Cancer Institute's Common Toxicity Criteria (NCI CTC), version 2, Grade 3 or worse stomatitis, esophagitis, or diarrhea prompted holding 5-fluorouracil until symptoms were grade 2 or better. If treatment was held for diarrhea, the protocol called for resuming the continuous infusion 5-fluorouracil at 80% of the prior dose. 5-Fluorouracil that was held was not to be made up. Severe myelosuppression on weekly blood counts (absolute neutrophil count ≥ 0.5 × 109/L for greater than 2 days and/or platelet count ≤ 25 × 109/L) prompted a 25% dose reduction of both paclitaxel and carboplatin on day 22. Similarly, on day 22, the protocol mandated that paclitaxel and carboplatin be held until the absolute neutrophil count was ≥ 1.5 × 109/L and the platelet count ≥ 100 × 109/L. For grade 3 or worse esophagitis, the paclitaxel and carboplatin were held until the esophagitis resolved to grade 1 or less. Paclitaxel was also held for grade 3 or worse neuropathy. Re-treatment was permitted with a 30% dose reduction in the event the neuropathy resolved to grade 2 or better. For any grade 3 or 4 event attributable to amifostine, the amifostine was to be decreased to 300 mg and subsequently discontinued if the event recurred at the lower dose. Finally, radiation was to be held for myelosuppression (absolute neutrophil count < 1.0 × 109/L and/or the platelet count < 50 × 109/L) or for grade 4 esophagitis.
Aggressive supportive care measures were recommended throughout the neoadjuvant portion of the regimen. These measures included, but were not limited to, premedication with corticosteroids prior to paclitaxel, use of antiemetics before and during chemotherapy and before amifostine, and nutrition and hydration support, as needed.
An esophagectomy was to be performed within 4–8 weeks after completion of radiation for all patients still deemed to be operative candidates.
The protocol also included an optional, additional two cycles of post-operative chemotherapy with paclitaxel and carboplatin with dosing, for the most part, left to the discretion of the treating oncologist.
Pretreatment and Follow Up Evaluations
All patients underwent a history and physical examination within 21 days of trial registration. Other testing was performed within this time frame as well and included a complete hemogram, chemistry profile, computed tomography scan or magnetic resonance imaging of the chest and abdomen, chest radiograph, electrocardiogram, and an esophagoscopy. A bone scan was required if the alkaline phosphatase was two times the institution's upper limit of normal, and a bronchoscopy was required if the primary tumor was adjacent to the trachea or left main stem bronchus or if the patient was experiencing respiratory symptoms. Other testing was optional and included endoscopic ultrasound of the upper gastrointestinal tract and positron emission tomography scanning.
All patients were monitored throughout the period of radiation and chemotherapy administration with a weekly history and physical examination and weekly hemograms. History, physical examination, hemogram and chemistry profiles were mandated before days 1 and 22 of chemotherapy.
Tumor assessments were performed two weeks prior to surgery, and RECIST criteria, as recommended by the NCI http://www.nci.nih.gov/bip/RECIST.htm
, were used to determine tumor response [9
]. Additionally pathological response was assessed post-operatively.
Other testing, such as quality of life assessment and genotyping, were also obtained but will be reported at a later date.
The purpose of this study was to assess the safety of this treatment regimen for patients with locally advanced esophageal cancer. The protocol called for a three-stage phase II study design with a safety analysis in the first 10 patients. The first 10 patients received treatment, as described above, with a carboplatin AUC = 4. It was decided a priori that if more than two of the initial patients developed grade 4 or 5 non-hematologic adverse events during neoadjuvant therapy or died within 15 days of surgery, then the study would not permit a carboplatin dose increase to an AUC = 6.
All data on toxicity and response are presented descriptively in this initial 10-patient report on the first phase of this trial. Summary statistics, including means and median values, frequency tables, and graphical methods were used to describe the distributions of drug administration, clinical characteristics, and adverse event rates. Unless otherwise specified, all adverse event data are reported regardless of relationship to study treatment.