A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer.
OBJECTIVE
This is a Phase I/II dose escalation study to determine the tolerable dose of tirapazamine (TPZ), and the toxicity of a regimen using TPZ with cisplatin, and radiotherapy in women with locally advanced cervical cancer.


METHODS
Eligible women for this study were those with a diagnosis of locally advanced cervix cancer, who were less than 75 years of age, having provided informed consent, and who had undergone the necessary prestudy investigations. External-beam radiotherapy (RT) was given to a minimum dose of 4500 cGy in 25 fractions (Day 1-35), and brachytherapy then delivered to bring the total dose at point A to 8500 cGy. The first dose level of the study used TPZ 190 mg/m(2) and cisplatin 75 mg/m(2) on Days 1, 15, and 29 of RT. TPZ 160 mg/m(2) alone was used on Days 8, 10, 12 and 22, 24, 26 of RT. A conventional dose-escalation step method was then used to determine the maximum tolerated dose (MTD) of TPZ.


RESULTS
Four patients were treated at Level 1, 6 at Level 2, and 5 at Level 3. Only 1 patient experienced a dose-limiting toxicity (DLT) at Level 2, but 2 of the 5 patients at Level 3 incurred DLTs. Level 2 was declared the MDT (TPZ 290 mg/m(2) on Days 1, 15, 29 and 220 mg/m(2) on Days 8, 10, 12 and 22, 24, 26). At 6 months, 13 of 15 patients had complete pelvic control of disease.


CONCLUSIONS
Level 2 of this regime was identified as the MDT. The use of TPZ with concurrent cisplatin and pelvic radiotherapy has acceptable toxicity and should be considered for further Phase 2 testing in view of the promising responses noted.
Craighead
P S
PS
Department of Oncology, University of Calgary, Alberta, Calgary, Canada. peterch@cancerboard.ab.ca
Pearcey
R
R
Stuart
G
G
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009367:Neoplasm Staging; D011879:Radiotherapy Dosage; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage / Q000009:adverse effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*
D014227:Triazines; D000077704:Tirapazamine; D002945:Cisplatin