Rongyu Zang

Incorporation of Pazopanib in Maintenance Therapy of Ovarian Cancer

PURPOSE Pazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-β, and c-Kit. Preclinical and clinical studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy. PATIENTS AND METHODS Nine hundred forty patients with histologically confirmed cancer of the ovary, fallopian tube, or peritoneum, International Federation Gynecology Obstetrics (FIGO) stages II-IV, no evidence of progression after primary therapy consisting of surgery and at least five cycles of platinum-taxane chemotherapy were randomized 1:1 to receive pazopanib 800 mg once per day or placebo for up to 24 months. The primary end point was progression-free survival by RECIST 1.0 assessed by the investigators. RESULTS Maintenance pazopanib prolonged progression-free survival compared with placebo (hazard ratio [HR], 0.77; 95% CI, 0.64 to 0.91; P = .0021; median, 17.9 v 12.3 months, respectively). Interim survival analysis based on events in 35.6% of the population did not show any significant difference. Grade 3 or 4 adverse events of hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%) were significantly higher in the pazopanib arm. Treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%). CONCLUSION Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity (NCT00866697).

Secondary Cytoreductive Surgery for Patients with Relapsed Epithelial Ovarian Carcinoma: Who Benefits?

This study was performed to address patient selection criteria and the role of secondary cytoreductive surgery (SCR) in patients with epithelial ovarian carcinoma (EOC) who had relapsed tumors after a progression‐free interval ⩾ 3 months.

Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): Results of an international Intergroup trial (AGO-OVAR16).

LBA5503 Background: Pazopanib is an oral, multikinase inhibitor of VEGFR-1, -2, -3, PDGFR-α and -β, and c-Kit. Preclinical and clinical studies support VEGF(R) and PDGF(R) as targets for AEOC treatment. This study evaluated the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients who have not progressed after first-line chemotherapy for AEOC. METHODS Patients with histologically confirmed AEOC, FIGO II-IV, and no evidence of progression after surgery and ≥ 5 cycles of platinum-taxane chemotherapy were randomized 1:1 to receive 800 mg pazopanib once daily or placebo for up to 24 months. Primary endpoint was progression-free survival (PFS) by RECIST. Secondary endpoints included overall survival, PFS by GCIG criteria, safety, and quality of life. RESULTS Most of the 940 randomized patients had stage III/IV disease (91%) at initial diagnosis, and no residual disease after surgery (58%). The median time from diagnosis to randomization was 7.1 months in the placebo arm and 7.0 months in the pazopanib arm. The median follow-up was 24 months. Patients in the pazopanib arm had a prolonged PFS vs placebo (HR = 0.766; 95% CI: 0.64-0.91; p = 0.0021; medians 17.9 vs 12.3 months, respectively). Sensitivity and subgroup analyses of PFS, and analysis of PFS by GCIG criteria, were consistent with the primary analysis. The first interim analysis for OS (only 189 OS events = 20.1% of population) showed no difference between arms. Pazopanib mean exposure was shorter vs placebo (8.9 vs 11.7 months). Pazopanib treatment was associated with a higher incidence of adverse events (AEs) and serious AEs (26% vs 11%) vs placebo. The most common AEs were hypertension, diarrhea, nausea, headache, fatigue, and neutropenia. Fatal SAEs were reported in three patients on pazopanib and one patient on placebo. CONCLUSIONS Pazopanib maintenance therapy provided a statistically significant and clinically meaningful PFS benefit in patients with AEOC; OS data are not mature. The safety profile of pazopanib in this setting was consistent with its established profile. CLINICAL TRIAL INFORMATION NCT00866697.

Current status of gynecological cancer in China

The aim of this review is to examine the current status of gynecological cancer in China focusing on epidemiological data. Epidemiological data on gynecological cancer in China is sparse. Therefore, most of the data were estimated via extrapolation based on a few available datasets. Cervical cancer is relatively rare and the incidence and mortality rate are largely decreasing. However, in young women, the incidence and mortality rates are increasing. The overall and age-specific incidence rates of cervical cancer appear to be varied according to geographical areas. The overall prevalence rate of human papillomavirus (HPV) in China is similar with other eastern Asian countries, but the age-specific HPV prevalence showed sustained high HPV prevalence rates in elderly women. There is not yet an established national program for cervical cancer prevention. The incidence rate of corpus and ovarian cancers in China slightly increased between 2000 and 2005, but is still lower than Japan or Korea. There is no reliable, national-level data on mortality rates of corpus and ovarian cancer in China. Breast cancer is one of the most rapidly increasing cancers in China. The increase was sharper in young women than in elderly women. Both increased risk and change of population size/structure contributed to the increase of breast cancer.

Surgical treatment for patients with different origins of Krukenberg tumors: outcomes and prognostic factors.

AIMS We sought to investigate survival impacts of metastasectomy in women with Krukenberg tumors of the ovary and survival benefits in different origins (gastric cancer, colorectal cancer, or others). METHODS All patients diagnosed with Krukenberg tumors of the ovary who underwent surgical treatment at a single institution between 1997 and 2003 were retrospectively evaluated. Survival analyses and comparisons were performed using Kaplan-Meier method and log-rank test. RESULTS A total of 54 patients with Krukenberg tumors of the ovary were identified. The estimated 5-year survival was 12.1%. The median survival in patients with microscopic residual disease after metastasectomy was 29.6 months, compared to 10 months in those with visible residual disease (P<0.01). The median survival among patients with Krukenberg tumors of gastric origin, colon and rectum origin, and other origins were 13 months, 29.6 months, and 48.2 months, respectively (P=0.03). There was a significant difference in survival between patients with metastatic disease confined to the ovaries and those with extensive metastases, with an estimated median survival of 30.7 months and 10 months, respectively (P=0.02). Multivariate analysis suggested that the origin of ovarian metastatic carcinoma (P<0.01), residual disease after metastasectomy (P<0.01), and KPS (Karnofsky performance status) (P=0.03) were independent prognostic factors of survival. CONCLUSIONS Patients with Krukenberg tumors from colorectal cancer experience a better prognosis than those from gastric cancer and benefit more from metastasectomy. And metastasectomy significantly lengthens overall survival in patients with primary colorectal or breast cancer, higher KPS score, and those with optimal metastasectomy.

Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort

Background:This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer.Methods:Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model.Results:Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1–1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (⩽23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model.Conclusion:This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: recurrent disease

This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November 2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP-ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is > 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD).

Surgery in recurrent epithelial ovarian cancer: Benefits on survival for patients with residual disease of 0.1-1 cm after secondary cytoreduction

Recent retrospective trials stated that a benefit of surgery for recurrent ovarian cancer may be limited to patients in whom a complete cytoreduction (R0) could be achieved. Most of them pointed out there was no difference in survival between residual disease of 0.1–1 cm (R1) and >1 cm (R2). The aim of this study was to evaluate survival benefits from cytoreduction to R1.

Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women

Ovarian cancer is the leading cause of death from gynaecological malignancies worldwide. Here we perform a three-stage genome-wide association study (GWAS) in Han Chinese women to identify risk genetic variants for epithelial ovarian cancer (EOC). We scan 900,015 single-nucleotide polymorphisms (SNPs) in 1,057 EOC cases and 1,191 controls in stage I, and replicate 41 SNPs (P(meta)<10(-4)) in 960 EOC cases and 1,799 controls (stage II), and an additional 492 EOC cases and 1,004 controls (stage III). Finally, we identify two EOC susceptibility loci at 9q22.33 (rs1413299 in COL15A1, P(meta) = 1.88 × 10(-8)) and 10p11.21 (rs1192691 near ANKRD30A, P(meta) = 2.62 × 10(-8)), and two consistently replicated loci at 12q14.2 (rs11175194 in SRGAP1, P(meta) = 1.14 × 10(-7)) and 9q34.2 (rs633862 near ABO and SURF6, P(meta) = 8.57 × 10(-7)) (P<0.05 in all three stages). These results may advance our understanding of genetic susceptibility to EOC.

Association between XPF Polymorphisms and Cancer Risk: A Meta-Analysis

Background Xeroderma pigmentosum complementation group F (XPF or ERCC4) plays a key role in DNA repair that protects against genetic instability and carcinogenesis. A series of epidemiological studies have examined associations between XPF polymorphisms and cancer risk, but the findings remain inconclusive. Methodology/Principal Findings In this meta-analysis of 47,639 cancer cases and 51,915 controls, by searching three electronic databases (i.e., MEDLINE, EMBASE and CNKI), we summarized 43 case-control studies from 29 publications on four commonly studied polymorphisms of XPF (i.e., rs1800067, rs1799801, rs2020955 and rs744154), and we did not find statistical evidence of any significant association with overall cancer risk. However, in stratification analyses, we found a significant association of XPF-rs1799801 with a reduced cancer risk in Caucasian populations (4,845 cases and 5,556 controls; recessive model: OR = 0.87, 95% CI = 0.76–1.00, P = 0.049, P = 0.723 for heterogeneity test, I2 = 0). Further genotype-phenotype correlation analysis showed that the homozygous variant CC genotype carriers had higher XPF expression levels than that of the TT genotype carriers (Student’s t test for a recessive model: P = 0.046). No publication bias was found by using the funnel plot and Egger’s test. Conclusion This meta-analysis suggests a lack of statistical evidence for the association between the four XPF SNPs and overall risk of cancers. However, XPF-rs1799801 may be associated with cancer risk in Caucasian populations, which needs to be further validated in single large, well-designed prospective studies.