Preclinical and pilot clinical studies of docetaxel chemoradiation for Stage III non-small-cell lung cancer.
OBJECTIVE
Local and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for Stage III non-small-cell lung cancer. We conducted preclinical studies of docetaxel's cytotoxic and radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low-dose radiosensitizing docetaxel CRT.


METHODS
A preclinical study was conducted in human lung cancer cell lines NCI 520 and A549. Cells were treated with two concentrations of docetaxel for 3 h and then irradiated immediately or after a 24-h delay. A clonogenic survival assay was conducted and analyzed for cytotoxic effects vs. radiosensitizing effects of docetaxel. A pilot clinical study was designed based on preclinical study findings. Twenty-two patients were enrolled with a median follow-up of 4 years. Induction chemotherapy consisted of 75 mg/m(2) of docetaxel and 75 mg/m(2) of cisplatin on Day 1 and 150 mg/m(2) of recombinant human granulocyte colony-stimulating factor on Days 2 through 10. Concurrent CRT was started 3 to 6 weeks later with twice-weekly docetaxel at 10 to 12 mg/m(2) and daily delayed radiation in 1.8-Gy fractions to 64.5 Gy for gross disease.


RESULTS
The preclinical study showed potent cytotoxic effects of docetaxel and subadditive radiosensitizing effects. Delaying radiation resulted in more cancer cell death. The pilot clinical study resulted in a median survival of 32.6 months for the entire cohort, with 3- and 5-year survival rates of 50% and 19%, respectively, and a distant metastasis-free survival rate of 61% for both 3 and 5 years. A pattern-of-failure analysis showed 75% chest failures and 36% all-distant failures. Therapy was well tolerated with Grade 3 esophagitis observed in 23% of patients.


CONCLUSIONS
One-cycle full-dose docetaxel/cisplatin induction chemotherapy with recombinant human granulocyte colony-stimulating factor followed by pulsed low-dose docetaxel CRT is promising with regard to its antitumor activity, low rates of distant failure, and low toxicity, suggesting that this regimen deserves further investigation.
Chen
Yuhchyau
Y
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA. yuhchyau_chen@urmc.rochester.edu
Pandya
Kishan J
KJ
Hyrien
Ollivier
O
Keng
Peter C
PC
Smudzin
Therese
T
Anderson
Joy
J
Qazi
Raman
R
Smith
Brian
B
Watson
Thomas J
TJ
Feins
Richard H
RH
Johnstone
David W
DW
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy / Q000379:methods; D000077143:Docetaxel; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011994:Recombinant Proteins; D012074:Remission Induction / Q000379:methods; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D057170:Translational Research, Biomedical / Q000379:methods; D014410:Tumor Stem Cell Assay / Q000379:methods
D011838:Radiation-Sensitizing Agents; D011994:Recombinant Proteins; D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D002945:Cisplatin