The safety, efficacy, and treatment outcomes of a combination of low-dose decitabine treatment in patients with recurrent ovarian cancer

Abstract

Purpose: DNA demethylating agents have shown clinical effectiveness in hematological and solid tumors. This trial tested the safety, efficacy, and treatment outcomes of decitabine-based chemotherapy or combined with immunotherapy in recurrent ovarian cancer patients. Patients and methods: Fifty-five patients with recurrent ovarian cancer were enrolled and 52 were assessable for clinical response and survival. Patients either received 5-d decitabine treatment, followed by reduced-dose of paclitaxel/carboplatin administration (DTC cohort), or the aforementioned regimen combined with cytokine-induced killer cells therapy (DTC+CIK cohort). The primary end point was clinical response rate and progression-free survival (PFS). Secondary evaluation included safety assessment and overall survival (OS). Results: Disease control rate (DCR) and objective response rate (ORR) were 73.91% and 23.91% in disease measurable patients by RECIST criteria, totally 76.92% and 30.77%, including disease non-measurable patients, which were higher in platinum-resistant/refractory patients. Clinical benefits could be associated with the number of DAC treatment cycles and the inclusion of CIK immunotherapy. In DTC+CIK cohort, DCR and ORR reached 100% and 58.30%, respectively. Notably, DTC+CIK treatment in platinum-resistant/refractory patients had an ORR of 87.50%. Consistently, PFS was longer in platinum-resistant/refractory patients comparing with that of platinum-sensitive patients. PFS and OS were 8 and 19 mo in platinum-resistant/refractory patients with DTC+CIK therapy. The most common toxicities were nausea, anorexia, fatigue, neutropenia, and anemia; many of which were grade 1-2. Conclusion: Low-dose DAC/paclitaxel/carboplatin regimen demonstrates disease benefit, especially in patients with platinum-resistant/refractory ovarian cancer, and might show remarkable clinical response when combined with adoptive immunotherapy in platinum-resistant/refractory ovarian cancer patients.

Keywords: CIK therapy; decitabine; epigenetic therapy; platinum sensitivity; recurrent ovarian cancer.

Figure 1.

Trial profile DAC, 7 mg/m²/day for 5 d; T, paclitaxel 135 mg/m²; C, carboplatin AUC = 5.

Figure 2.

(A) Maximum change by RECIST (version 1.1) in ovarian cancer patients from baseline. Changes in target lesions from baseline in 46 patients with measurable disease who received DTC or DTC+CIK treatment. Each bar represents an individual patient in the clinical trial. The two horizontal dashed lines mark the thresholds for objective response (lower line, −30%) and PD (higher line, 20%), according to RECIST (version 1.1). (B) Partial response of platinum-resistant/refractory and recurrent high-grade serous ovarian cancer in a 56-y-old patient (UPN23), who received DTC+CIK treatment of 19 cycles. This patient had previously undergone primary surgery, and progressive disease had developed after treatment with systemic chemotherapies (i.e., cisplatin and docetaxel). The pelvic mesenteric lymph node metastases were observed on a baseline PET-CT image (left), these lesions were reduced at 6 mo (middle) and maintained for 19 mo (right) after the start of this treatment. The red circles show regression of recurrent lymph node metastases. (C) Tumor marker CA-125 decreased to normal range after five course of DAC-based therapy in patient UPN23. C0, baseline; C2, day 28 in cycle 2. The horizontal dashed line represents the cut-off level for CA-125 (35 U/mL). (D) Partial response of platinum-resistant and recurrent high-grade serous ovarian cancer in a 52-year-old patient (UPN33), who received DAC+TC+CIK treatment of five cycles, and PR maintained for 8 mo until disease progressed. The tumor lesions reduced after four cycles of treatment (right) as compared with the baseline (left) as analyzed by the MRI examination. (E) In UPN33, CA-125 level decreased to normal range after two cycles. C0, baseline; C1, day 28 in cycle 1. The horizontal dashed line represents the cut-off level for CA-125 (35 U/mL).

Figure 3.

Kaplan–Meier analysis of PFS and OS with different platinum sensitivity and treatments (A and B) Kaplan–Meier survival curves of progression-free survival (A) and overall survival (B) for the platinum-resistant/refractory patients and platinum-sensitive patients, using the log-rank test to evaluate significance. (C and D) Kaplan–Meier survival curves of progression-free survival (C) and overall survival (D) in platinum-resistant/refractory patients based on different treatments (DTC or DTC+CIK treatment), using the log-rank test to evaluate significance. (E and F) Kaplan–Meier survival curves of progression-free survival (E) and overall survival (F) in disease measurable platinum-resistant/refractory patients based on different treatments (DTC or DTC+CIK treatment), using the log-rank test to evaluate significance. (G and H) Kaplan–Meier survival curves of progression-free survival (G) and overall survival (H) in disease controlled patients based on the number of cycles of DAC treatment, using the log-rank test to evaluate significance. PFS, progression-free survival. OS, overall survival.