Phase one dose finding study of capecitabine (Xeloda), radiotherapy and cisplatin in the treatment of locally advanced squamous cervical cancer.
OBJECTIVE
A dose escalation study was performed for patients with locally advanced squamous carcinoma of cervix to determine the maximum tolerated dose (MTD) of daily capecitabine when combined with weekly cisplatin and radiotherapy. MTD would be reached if at least 2 out of 6 at any particular dose level developed Grade 3 or 4 diarrhoea, mucositis, skin or bladder toxicity or Grade 4 neutropenia associated with fever lasting more than 7 days or Grade 3 or 4 thrombocytopenia. The secondary endpoints were to define the toxicity profile, compliance with treatment, late radiation effects and to determine the tumour responses.


METHODS
Thirteen patients were enrolled (7 Stage II(b), 6 Stage III(b)). Cisplatin was given weekly at 40 mg/m2 (maximum 70 mg) concurrently with radiotherapy. Two doses of capecitabine were studied 300 mg/m2 bid (cohort 1) and 450 mg bid (cohort 2).


RESULTS
One patient in cohort 1 developed Grade 3 diarrhoea and 2 patients had Grade 3 leucopenia. Two patients in cohort 2 developed Grade 4 leucopenia and neutropenic fever; one of these patients also had Grade 3 diarrhoea and thrombocytopenia. Only 1 patient had Grade 1 palmar-plantar erysthrodysesthesia. Three patients have developed late (RTOG/ECOG) Grade 3 toxicity bladder or vaginal mucosa at 6, 9 and 15 months. The MDT of continuous capecitabine, when given with pelvic radiotherapy and weekly cisplatin, is 450 mg m2 bid.


CONCLUSIONS
The recommended dose of capecitabine in this combination is 300 mg/m2 bid. The regimen was well tolerated and the compliance was high. Progression-free survival at 12 months was 69.2%, and at 24 months, it was 49.2% (SE 15.4%) with an overall survival of 57.7% (SE 15.0%) at 24 months. Further evaluation of this regimen in a phase II/III study is warranted.
Stokes
Zuzana
Z
Leicester Royal Infirmary, Leicester, UK.
Symonds
Paul
P
Habeshaw
Tim
T
Reed
Nick
N
Curto
Jorge
J
Joynson
Claire
C
Chan
Steve
S
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D000069287:Capecitabine; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006402:Hematologic Diseases / Q000139:chemically induced / Q000209:etiology; D006801:Humans; D008875:Middle Aged; D011878:Radiotherapy / Q000009:adverse effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*
D003841:Deoxycytidine; D000069287:Capecitabine; D002945:Cisplatin; D005472:Fluorouracil