1 A Study Of Efficacy And Its Correlation With Plasma Biomarkers For Platinum-Resistant Recurrent Ovarian Cancer Patients Treated With PLD Combined With Apatinib Or PLD Alone 2 An Exploratory Analysis About Cycles Of Adjuvant Chemotherapy And Outcomes By

Part 1A study of efficacy and its correlation with plasma biomarkers for platinum-resistant recurrent ovarian cancer patients treated with PLD combined with Apatinib or PLD aloneObjective:The prognosis of patients with platinum-resistant recurrent ovarian cancer is poor,and the response rate of single drug chemotherapy is low.Anti-angiogenic therapy combined with chemotherapy could improve the prognosis of patients with platinum-resistant recurrent ovarian cancer.This study was conducted to evaluate the efficacy of apatinib an oral tyrosine kinase inhibitor that selectively inhibits VEGFR-2,in combination with PLD in patients with platinum-resistant recurrent OC,and to explore whether the levels of VEGF/ctDNA before treatment and changes of VEGF/ctDNA after treatment could be used as biomarkers of treatment response for patients with platinum-resistant recurrent ovarian cancer.Method:From Mar 22,2018 to January 28,2021,a total of 152 patients with at least 1 assessable lesion and histologically confirmed non-mucinous ovarian,primary peritoneal cancer,or fallopian-tube cancer were recruited.Patients were randomly assigned(1:1)to receive PLD alone(group B,40mg/m2 ? every 4 weeks for up to 6 or 8 cycles)or with apatinib 250mg orally once daily(group A)until disease progression,unacceptable toxicity,or consent withdrawal.Before treatment,paraffin and blood samples should be kept,and baseline disease evaluation should be done by abdominopelvic and chest CT.During the treatment,tumor response was evaluated according to RECIST standard every two cycles,and blood samples were collected again.A total of 73 patients were enrolled in Cancer Hospital,Chinese Academy of Medical Sciences.The concentration of VEGF in plasma was detected by ELISA,and ctDNA fraction in plasma was detected by NGS combined with targeted amplification and deep sequencing.Results:There were 78 patients in PLD combined with apatinib group and 74 patients in PLD monotherapy group.The median follow-up was 13.4 months.The median PFS was 5.8 months with aptinib-containing therapy versus 3.3 months with PLD alone(HR:0.44,95%Cl 0.28-0.69,P<0.001).And the median OS was 21.8 months,14.5 months respectively(P=0.038).The ORR and DCR were significantly improved in the apatinib plus PLD group(ORR:43.1%vs 10.9%,P<0.001;DCR:84.6%vs 57.8%)compared with in the PLD group.The results of single center suggested that the median PFS was also significantly improved in the aptinib-containing therapy group compared with in the PLD group(5.6 vs 2.8 months,P=0.005;HR=0.42,95%CI:0.23-0.78).The ORR was 40.0%(14/35)versus 7.4%(2/27)for combination and PLD monotherapy group,respectively(P=0.004),and DCR was 65.7%(23/35)and 51.8%(14/27),respectively(P=0.270).No significant difference was seen in OS between treatment groups,although the median OS of combination group was slightly longer than that of monotherapy group(21.7 vs 14.5 months,P=0.631).The median VEGF prior to treatment was 48.0pg/ml.In PLD combined with apatinib group,patients with more than 93.7pg/ml pre-treatment VEGF could have disease control with 41.2%sensitivity and 76.9%specificity(AUC 0.593,95%CI 0.385-0.801).And patients in PLD monotherapy group with more than 36.6pg/ml pre-treatment VEGF could have disease progression with 76.9%sensitivity and 50.0%specificity(AUC=0.519,95%CI:0.244-0.794).A VEGF increase of 30.8%was associated with progression disease in the combination group with 66.7%sensitivity and 56.2%specificity(AUC=0.569,95%CI:0.331-0.807).There was no correlation in PLD monotherapy group.The ctDNA was detected in 81.8%(30/37)patients,and the median ctDNA fraction was 1.3%(inter-quartile range IQR:0.07%-8.03%).In the combination group,PFS was significantly prolonged when ctDNA fraction was higher than the median value before treatment(P=0.028,HR:0.224,95%CI:0.059-0.848).patients with more than 1.1%pre-treatment ctDNA fraction could have disease control with 70.6%sensitivity and 83.3%specificity(AUC=0.716,95%CI:0.455-0.976).And patients with ctDNA fraction decreased by less than 8.8%or increased compared with the baseline value,could have disease progression,with sensitivity of 80%and specificity of 64.3%(AUC=0.700,95%CI:0.465-0.935).Conclusion:Compared with PLD alone,PLD combined with apatinib could prolong PFS,OS,and improve ORR,DCR in patients with platinum-resistant recurrent ovarian cancer.In platinum resistant patients with recurrent ovarian cancer,patients with high plasma VEGF concentration before treatment might benefit more from anti-angiogenic combination chemotherapy.Pre-treatment ctDNA fraction,ctDNA fraction changes during treatment might have any value in predicting the tumor response in patients treated with PLD and apatinib.Part 2An exploratory analysis about cycles of adjuvant chemotherapy and outcomes by substage for stage I ovarian clear cell carcinomaObjective:Ovarian clear cell cancer(OCCC)is the third most common epithelial ovarian cancer.The prognostic relevance of the different substages in early stage OCCC remains controversial,and the optimal duration of adjuvant chemotherapy for early stage ovarian cancer is unclear.This research sought to explore the prognostic impact of adjuvant chemotherapy and tumor substage on stage ? ovarian clear cell carcinoma(OCCC).Method:Data of 102 patients with stage ? OCCC who underwent surgery at the National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College from February 1999 to December 2018 was retrospectively analyzed.Prognostic factors were evaluated using the Cox Regression Model.The disease-free survival(DFS)and overall survival(OS)were assessed by the Kaplan-Meier method and compared between different groups with the log-rank test.P<0.05 was considered statistically significant.Results:The median follow-up duration was 40.5 months.Thirty-one(30.4%)patients were at stage ? A,and 17(16.7%),5(24.5%)and 17(16.7%)patients were at stage IC1,IC2 and IC3 respectively.The 5-year and 10-year DFS rates of the entire cohort were 82.8%and 78.8%respectively,and the 5-year OS was 97.9%.Patients at stages ICI(intraoperatively ruptured tumor)and IA had similar DFS(P=0.538,OR=0.024),and that of patients at stages IC2(tumor ruptured preoperatively or tumor on ovarian surface)or IC3(ascites or peritoneal washings with positive cytology)was significantly lower(72.6%vs 95.1%,P=0.039,OR=5.051).The 5-year DFS of patients receiving four(83.9%)and more than four(81.7%)cycles adjuvant chemotherapy were similar.Furthermore,univariate analysis showed that age,tumor size and CA199 levels were significantly correlated with DFS,although none of these variables were identified as independent prognostic factors in the multivariate analysis.Conclusion:Patients with stage ? OCCC have overall good prognosis.However,tumor surface involvement or positive cytology can worsen prognosis,and intraoperative tumor rupture may not affect the prognosis of OCCC.The prognosis may not be improved by more than four cycles chemotherapy following surgery.The remarkable increased CA199 may be an potential indicator of poor prognosis in stage ? OCCC.