Paclitaxel, carboplatin, 5-fluorouracil, and radiation for locally advanced esophageal cancer: phase II results of preliminary pharmacologic and molecular efforts to mitigate toxicity and predict outcomes: North Central Cancer Treatment Group (N0044).
OBJECTIVE
Locally advanced esophageal cancer is challenging to treat. This study tested a 3-drug, multimodality approach. Chemotherapy dose reductions, the addition of amifostine, and pharmacogenetics were tested in an effort to mitigate toxicity and predict outcomes.


METHODS
This phase II trial tested chemotherapy (carboplatin area under the curve = 4 [lower dose than that from Meluch et al] on day 1 and 22, 5-fluorouracil 225 mg/m2 per day continuous infusion on days 1 to 42, and paclitaxel 200 mg/m2 on days 1 and 22) with concomitant radiation 4500 cG for locally advanced esophageal cancer. Esophagectomy was scheduled after radiation. Amifostine 500 mg subcutaneously before radiation was given to the first 19 patients.


RESULTS
Among 54 eligible patients, the pathologic complete response rate was 35% (95% confidence interval [CI], 23%-49%). Median survival was 21.2 months (95% CI, 13.6-37.6 months), and median time to cancer recurrence/progression 19 months (95% CI, 11.4-44.6 months). Nearly all patients (94%) suffered at least one grade 3 or worse adverse event, including 3 treatment-related deaths. Amifostine was discontinued because of one of these deaths. There was no statistically significant difference in the rates of severe adverse events among patients who received amifostine and those who did not. Genotyping for polymorphisms of dihydropyrimidine dehydrogenase, cytochrome P3A4, and glutathione-S-transferase did not predict tumor response or severe adverse events.


CONCLUSIONS
This 3-drug, multimodality approach yielded a pathologic complete response rate of 35%, but the severe adverse event rate was high. Utilizing amifostine to reduce toxicity or employing molecular approaches to predict outcomes did not show promise.
Jatoi
Aminah
A
Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. jatoi.aminah@mayo.edu
Martenson
James A
JA
Foster
Nathan R
NR
McLeod
Howard L
HL
Lair
Bradley S
BS
Nichols
Frank
F
Tschetter
Loren K
LK
Moore
Dennis F
DF
Fitch
Tom R
TR
Alberts
Steven R
SR
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D018579:Patient Selection; D011878:Radiotherapy / Q000009:adverse effects / Q000379:methods*; D012008:Recurrence; D016019:Survival Analysis; D017741:Survivors; D013997:Time Factors
D016190:Carboplatin; D017239:Paclitaxel; D005472:Fluorouracil