Patient-Derived Xenograft Models of Epithelial Ovarian Cancer for Preclinical Studies.

PURPOSE: Patient-derived tumor xenografts (PDXs) can provide more reliable information about tumor biology than cell line models. We developed PDXs for epithelial ovarian cancer (EOC) that have histopathologic and genetic similarities to the primary patient tissues and evaluated their potential for use as a platform for translational EOC research. MATERIALS AND METHODS: We successfully established PDXs by subrenal capsule implantation of primary EOC tissues into female BALB/C-nude mice. The rate of successful PDX engraftment was 48.8% (22/45 cases). Hematoxylin and eosin staining and short tandem repeat analysis showed histopathological and genetic similarity between the PDX and primary patient tissues. RESULTS: Patients whose tumors were successfully engrafted in mice had significantly inferior overall survival when compared with those whose tumors failed to engraft (p=0.040). In preclinical tests of this model, we found that paclitaxel-carboplatin combination chemotherapy significantly deceased tumor weight in PDXs compared with the control treatment (p=0.013). Moreover, erlotinib treatment significantly decreased tumor weight in epidermal growth factor receptor-overexpressing PDX with clear cell histology (p=0.023). CONCLUSION: PDXs for EOC with histopathological and genetic stability can be efficiently developed by subrenal capsule implantation and have the potential to provide a promising platform for future translational research and precision medicine for EOC.

Platinum-based combination chemotherapy vs. weekly cisplatin during adjuvant CCRT in early cervical cancer with pelvic LN metastasis.

AIM: Adjuvant concurrent chemoradiation (CCRT) should be considered in surgically-treated patients with early-stage cervical cancer (ECC) who exhibit pelvic lymph node (LN) metastasis. Platinum-based chemotherapy is usually recommended during adjuvant CCRT, however, it is unclear which regimen has better prognostic outcomes. PATIENTS AND METHODS: We reviewed the electronic medical records to find patients with primary ECC (FIGO stages IB-IIA) who underwent type III radical hysterectomy and adjuvant CCRT due to pelvic LN metastasis at the Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, Korea, from November 1997 to September 2007. RESULTS: Among 75 patients, 34 received weekly cisplatin. Combination chemotherapy was performed without consolidation in 21 patients and with consolidation in 20 patients. The mean follow-up period was 59.0 months and the five-year survival rate was 84.4%. In multivariate analysis, combination chemotherapy with and without consolidation was associated with improved disease-free survival [hazard ratio (HR)=0.23, 95% confidence interval (CI)=0.06-0.88, p=0.032, and HR=0.29, 95% CI=0.09-0.91, p=0.034, respectively]; combination chemotherapy with consolidation significantly improved overall survival (HR=0.11, 95% CI=0.02-0.87, p=0.037) when compared to weekly cisplatin. CONCLUSION: We found that platinum-based combination chemotherapy during adjuvant CCRT after surgery promoted better survival than a weekly cisplatin regimen in ECC patients with pelvic LN metastasis.

A randomized phase II trial of maintenance therapy with Sorafenib in front-line ovarian carcinoma.

OBJECTIVES: Sorafenib, an oral multikinase inhibitor of the VEGFR/PDGFR/Raf/MEK/ERK pathway, has shown potential activity in patients with recurrent ovarian cancer (OC). One strategy to prolong disease control and survival in patients with OC is maintenance therapy after achieving a complete response. A double-blind, randomized, placebo-controlled, phase II study to assess the efficacy and safety of maintenance therapy with sorafenib in the treatment of OC is presented. METHODS: Patients with epithelial OC or primary peritoneal cancer in complete remission were randomized to sorafenib 400mg BID or matching placebo. The primary endpoint was progression-free survival (PFS). RESULTS: Of 246 randomized patients, 93% had OC; baseline characteristics were balanced between treatment arms. There was no significant difference between sorafenib and placebo arms for PFS (median 12.7 vs 15.7 months; hazard ratio 1.09; 95% CI 0.72-1.63), although there was a notable imbalance in early censoring. The most common ≥ grade 3 adverse events (AEs) were hand-foot skin reaction (39.0% vs 0.8%) and rash (14.6% vs 0%). More patients receiving sorafenib versus placebo required dose reductions (67.5% vs 30.1%), resulting in a lower than planned median daily dose (median 584.6 vs 800.0mg). Treatment with sorafenib was of shorter duration (median 17.6 vs 51.9 weeks) with more frequent discontinuations due to AEs (37.4% vs 6.5%). CONCLUSIONS: Sorafenib 400mg BID cannot be recommended as maintenance therapy for patients with OC in complete remission. Assessment of efficacy was limited by the high rate of dose reductions and early discontinuations.

The prognostic significance of tumor volume regression during radiotherapy and concurrent chemoradiotherapy for cervical cancer using MRI.

OBJECTIVE: The purpose of this study was to determine the prognostic significance of tumor volume regression rate during radiotherapy (RT) measured by three serial magnetic resonance imaging (MRIs) studies performed in patients treated with RT alone and compare the results with patients treated with concurrent chemoradiotherapy (CCRT). METHODS: We evaluated 81 patients with uterine cervical cancer who underwent three serial MR examinations, i.e., at the start of RT, at 36-45 Gy of external RT and 1 month after the end of RT. Forty-three patients were treated with RT alone and 38 patients were treated with CCRT. Pre-RT tumor volume (V1), the tumor volume regression rate measured during the fourth week of RT and residual tumor volume at 1 month after the end of RT (V3) were determined for each patient. The cut-off value used for the three parameters studied was the one that made the largest outcome difference. These volume parameters were analyzed to determine a difference in the treatment outcome. RESULTS: In the patients treated with CCRT, the mean value of the V1 was larger and the mean value of the V3 was smaller than in patients treated with RT alone. The mean value of the mid-RT regression rate was somewhat higher in patients treated with CCRT than in patients treated with RT alone; however, this difference was not statistically significant (79% vs. 69%). In both the RT alone and the CCRT group, the patients with a mid-RT regression >/=75% had 100% 5-year local control rates and a better disease free survival than the patients with mid-RT regression <75%. The patients with V3=0 cm(3) also had a better 5-year local control rate than the patients with a V3>0 cm(3), but statistical significance was found only in the patients treated with CCRT. CONCLUSIONS: The mid-RT tumor volume regression rate, at 36-45 Gy of external RT, was a predictor of local control rate in both RT and CCRT patient groups. However, in the patients who were treated with CCRT, the local control rate difference was even larger by post-RT residual volume than by the mid-RT tumor regression rate. Further studies on appropriate evaluation timing for mid-RT response in patients receiving CCRT are needed.

Phase II study of consolidation chemotherapy after concurrent chemoradiation in cervical cancer: preliminary results.

PURPOSE: Our aim was to determine the efficacy of consolidation chemotherapy after concurrent chemoradiation (CCRT) using high-dose-rate brachytherapy in patients with locally advanced cervical carcinoma. METHODS AND MATERIALS: Patients with cervical carcinoma (FIGO stage IB2-IVA) were treated with external beam radiation therapy to the whole pelvis (50.4 Gy) and high-dose-rate brachytherapy (24 Gy to point A). Cisplatin 60 mg/m(2) (Day 1) and 5-fluorouracil 1000 mg/m(2) (Days 1-5) were given every 3 weeks starting concurrently with the radiation and followed by 3 more cycles of consolidation for a total of 6 cycles. RESULTS: Thirty patients (94%) received 3 more cycles of post-CCRT consolidation chemotherapy and were evaluable for the toxicity and efficacy of consolidation. The most common toxicities of Grade 2 or higher were nausea or vomiting (47%) and anemia (33%). Late complications of the rectum and bladder occurred in 13% and 6% of the patients, respectively. The clinical complete response rate was 87% (95% CI, 75%-99%). During a median follow-up of 27 months (range, 6-58 months), 5 patients (17%) had recurrence; the sites of failure were 3 (10%) inside the radiation field and 2 (7%) outside the radiation field. The estimated 3-year progression-free survival rate was 83% (95% CI, 67%-99%) and overall survival rate was 91% (95% CI, 79%-100%). CONCLUSIONS: Consolidation chemotherapy after CCRT is well tolerated and effective in patients with locally advanced cervical carcinoma. A prospective randomized trial to compare this treatment strategy with standard CCRT seems to be worthwhile.