Phase I/II study of alternating chemoradiotherapy using 5fu and nedaplatin for patients with high-risk group of cervical carcinoma; a comparison to the historical control group using pre-treatment MRI evaluation

Abstract

In previous manuscripts, we reported pre-treatment MRI had a great advantage for prediction of clinical outcome of patients with cervical carcinoma. With aid of MRI, patients with stage II disease could be divided into the favorable group (tumor size <50mm and negative pelvic node; expected disease-free survival (DFS) 93.2%) and the unfavorable group (tumor size ≥ 50mm or positive pelvic node; expected DFS 25–53.3%). To improve the clinical outcome of patients with high risk factor including stage III disease, we performed alternating chemoradiotherapy (ALCRT) using 5FU and nedaplatin (NDP). Previously untreated patients with histologically diagnosed as squamous cell carcinoma of uterine cervix were entered into this study. Eligible patient was defined as with high risk factor (stage I-II; tumor size ≥ 50mm or positive pelvic node, OR all stage III-IV disease); good PS, adequate organ function; aged 20–75; and informed consent. Before the start of treatment, patients underwent MRI to evaluate the tumor size/volume and the status of lymph node. Three courses of systemic chemotherapy with 5FU (700mg/m2 d1–5) and NDP (100–150 mg/m2 d6) combined with definitive radiotherapy were planned in alternating setting. A dose of NDP was escalated as follows: 100,120,140 and 150 mg/m2. Radiation therapy consisted of both 45.6–51.3Gy of external beam radiotherapy (EBRT) using two axial dynamic conformal technique and intracavitary brachytherapy (ICBT). Para-aortic irradiation of 36 Gy using dynamic conformal technique was added in case of positive pelvic node or stage III-IV disease. Clinical outcome was compared to the data of historical control group (N = 43) treated with radiation alone which was thought to be eligible for this criteria with pre-treatment evaluation by MRI. From 1998 to 2002, 32 patients were entered into this analysis, of which 2, 11,16 and 3 patients were diagnosed as stage I, II, III and IV disease, respectively. The median age was 55.5 years (range 39–78). The follow-up period for the 27 survivors ranged from 9.3 to 69.9 months (median 33.8months). The maximum tumor diameter was 35 mm to 100 mm (median 62mm). Twenty-two patients were diagnosed as positive pelvic lymph node. In the phase I portion, the maximum tolerated dose (MTD) of NDP among 18 patients was 150 mg/m2. The recommended dose of the phase II study was 140mg/m2. In the phase II portion, common toxicities were leucopenia, anemia, thrombocytopenia, and diarrhea with frequencies of grade 3 ≥ of 76.9, 46.2, 69.2 and 23%, respectively. Planned treatment was completed in 81.3% of 32 patients. The 3-year overall survival (OAS) and progression-free survival (PFS) rates of phase I/II proportion were 83% (95%CI = 69.3–96.7%) and 66.3% (95%CI = 47.3–85.3 %), respectively. Twenty-three patients lived without disease, while 9 patients developed treatment failures in this series. Six patients had failures at pelvic, 7 at distant, and 4 at both pelvic and distant sites. Four patients lived with disease and 5 patients died of cancer progression. In the historical group, the 3-year OAS and PFS rates were 67.4% (95%CI = 53.5–81.3%) and 48.8% (95%CI = 33.9–63.7 %), respectively. ALCRT showed a tendency for factor of better OAS (P = 0.083) and PFS (P = 0.055) by univariate analyses, however, it proved to be a significant prognostic factor of better PFS (P = 0.039) in multivariate analysis. ALCRT is efficacious and manageable in patients with high-risk group of cervical carcinoma. The MTD of NDP in ALCRT was 150 mg/m2. Improved PFS of this study in comparison with the historical control group was thought to be promising, considering the fact of large proportion of stage III disease in this cohort