Chemotherapy For Recurrent Epithelial Ovarian Cancer Research Articles

Effectiveness of Platinum-Based Chemotherapy after Progression on Poly ADP Ribose Polymerase (PARP) Inhibitor in Epithelial Ovarian Cancer (042)

<b>Objectives:</b> PARP inhibitors have revolutionized ovarian cancer care with dramatic improvements in progression-free (PFS) and overall survival when used as maintenance therapy following platinum-based treatment. However, much remains unknown about the response to subsequent treatment after progression on PARP inhibitor (PARPi) therapy, including whether a 6-month platinum-free interval is an appropriate benchmark for using a platinum-based regimen. Therefore, we aimed to assess response to platinum-based chemotherapy in women with platinum-sensitive recurrent epithelial ovarian cancer (EOC) after progression on PARPi. <b>Methods:</b> We performed a retrospective chart review of all cases of EOC prescribed a PARPi at a tertiary care center from 2015 to 2020. We included patients who progressed on PARPi and were subsequently treated with platinum-based chemotherapy. Patients who received fewer than six months of PARPi treatment were excluded. The primary outcome was PFS on the platinum regimen (ptPFS), defined as the time from the start of platinum therapy to physician documented progression. Germline and somatic <i>BRCA</i> testing, number of prior lines of chemotherapy, duration of therapy with PARPi and subsequent platinum regimen, and demographic data were collected for each case. An accelerated failure time model was developed to assess the primary outcome with a multivariable model including <i>BRCA</i> status, prior lines of chemotherapy, and time on PARPi in 6-month intervals. <b>Results:</b> A total of 283 charts were reviewed, and 40 cases met the inclusion criteria. Of these, 60% (<i>n</i>=24) had a <i>BRCA</i> mutation (<i>BRCA</i>mut); 75% (<i>n</i>=18) were germline and 25% (<i>n</i>=6) were somatic mutations. Twenty percent (<i>n</i>=8) of patients received a PARPi after first-line treatment, 45% (<i>n</i>=18) after second, 28% (<i>n</i>=11) after third, and 7% (<i>n</i>=3) after fourth. Sixty percent (<i>n</i>=24) of patients were prescribed olaparib, 20% (<i>n</i>=8) niraparib, 10% (<i>n</i>=4) rucaparib, and 10% received two agents due to toxicity with their first. The median time on PARPi was 411 days, and the median ptPFS was 218 days. In the multivariable model (Table 1), <i>BRCA</i> mutations were associated with decreased ptPFS (<i>BRCA</i>wt 274 days vs <i>BRCA</i>mut 170 days, p=0.004). The median time on PARPi greater than 18 months was associated with improved ptPFS compared to 12-18 months and <12 months (262 vs 188 vs 163 days, respectively, p=0.007). The number of prior lines of therapy was not associated with ptPFS (p=0.13). <b>Conclusions:</b> This retrospective analysis supports the ongoing use of platinum-based chemotherapy in recurrent EOC after progression on PARPi therapy with outcomes comparable to those seen in OCEANS and GOG-213. These data suggest that resistance to PARPi does not necessarily imply platinum resistance. Poorer ptPFS in tumors with a <i>BRCA</i>mut compared to those without was unexpected. While the data surrounding post PARPi treatment response is limited, growing evidence from the recently reported OReO trial corroborates this finding. This raises the question of a difference in the underlying mechanism leading to platinum resistance and PARPi resistance in <i>BRCA</i>mut versus <i>BRCA</i>wt EOC. Molecular assessment of recurrent tumors with clinical correlation will be important to optimize treatment approaches.

Interval between secondary cytoreductive surgery and adjuvant chemotherapy is not associated with survivals in patients with recurrent ovarian cancer

BackgroundSecondary cytoreductive surgery (SCS) is possible in selected patients with recurrent epithelial ovarian cancer (EOC). The goal of SCS is complete resection, although chemotherapy is always followed. Delayed intervals between primary debulking surgery and adjuvant chemotherapy was reported to be associated with poorer survivals, however, the role of intervals in recurrent disease is still unknown.Materials and methodsThis retrospective cohort study reviewed data from electronic medical records of women with recurrent EOC treated at Samsung Medical Centre, Seoul, Korea, between January 1, 2002, and December 31, 2015. Patients who underwent SCS with adjuvant chemotherapy for recurrent EOC were eligible. We defined intervals as the period between the day of SCS and the first cycle of adjuvant chemotherapy.ResultsSeventy-nine patients were eligible for this study. Their median age was 48 (range, 18–69) years and median interval between the date of SCS and initiation of adjuvant chemotherapy was 10 (range, 4–115) days. The rate of complete resection was 72.2% (57/79). Division of the patients by interval (Group 1, interval ≤ 10 days; Group 2, interval > 10 days) revealed no difference in clinical parameters. No gross residual disease after SCS (no vs. any gross residual, p = 0.002) and longer platinum-free survival (over 12 vs. 6–12 months, p = 0.023) were independent favorable prognostic factors in Cox model; however, the intervals did not affect survival.ConclusionsDelayed intervals to adjuvant chemotherapy after secondary cytoreductive surgery is not associated with decreased survivals. It is important to identify recurrent EOC patients who might have no gross residual disease following SCS. Moreover, surgeons should strive for complete resection.

Intraperitoneal Chemotherapy for Recurrent Epithelial Ovarian Cancer Is Feasible With High Completion Rates, Low Complications, and Acceptable Patient Outcomes

Three large randomized clinical trials have shown a survival benefit for patients treated with intraperitoneal (IP) compared with intravenous chemotherapy for advanced stage epithelial ovarian cancer (EOC). However, the use of IP chemotherapy in recurrent EOC is controversial. The purpose of this study was to determine outcomes, completion rates, and frequency of complications in patients with platinum-sensitive recurrent EOC treated with IP chemotherapy. A retrospective, single-institution analysis of women who received IP chemotherapy for recurrent EOC from January 2003 to April 2010 was conducted. Study patients were identified from the Tumor Registry and office records. Demographic factors, stage, histology, surgical findings, cytoreduction status, and subsequent therapies were abstracted. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier methods. Fifty-six women who received IP chemotherapy for their first EOC recurrence were identified. The mean age of patients was 56.7 years (range, 40-79 y). Fifty-five patients (98.3%) had previously completed at least 6 cycles of intravenous chemotherapy. Of all patients, 87.5% were initially diagnosed with advanced stage disease (stage IIA-IV). All patients underwent secondary cytoreduction at the time of IP port placement. Moreover, 67.9% of patients were considered optimally cytoreduced (<1 cm residual disease) at the end of the secondary debulking surgery. Forty-two patients (75%) were able to successfully complete at least 6 cycles of IP chemotherapy. Reasons for noncompletion were disease progression, allergic reaction, renal failure, pain, severe nausea and vomiting, death, and patient refusal. Six patients (10.7%) developed port complications including pain around port site, port malfunction, and port erosion into small bowel. Median PFS since the initiation of IP chemotherapy was 10.5 months (95% confidence interval, 7.5-16.4 months) and median OS was 51 months (95% confidence interval, 40.8-61.1 months). Intraperitoneal chemotherapy is a feasible option for patients with recurrent EOC, with high completion rates, low frequency of complications, and acceptable PFS and OS.

Comparison of the efficacy between topotecan‐ and belotecan‐, a new camptothecin analog, based chemotherapies for recurrent epithelial ovarian cancer: A single institutional experience

To compare the efficacy and toxicity between topotecan- and belotecan-based chemotherapies in recurrent epithelial ovarian cancer (EOC). The clinical data of 80 patients treated with topotecan- (n = 45) or belotecan- (n = 35) based chemotherapy as at least a second-line chemotherapy were reviewed retrospectively between July 2001 and December 2007. Response was evaluated using the Response Evaluation Criteria in Solid Tumours (RECIST) and serum CA-125 levels. Hematological toxicity was examined according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. Time to progressive disease (TTPD), chemotherapy-specific survival (CSS) and overall survival (OS) according to the 2 chemotherapies were evaluated by the Kaplan-Meier analysis with the log-rank test. Overall response rate (ORR) was 24.4% in patients treated with topotecan-based chemotherapy, while it was 45.7% in those treated with belotecan-based chemotherapy (P = 0.046). Moreover, ORR was higher in platinum-sensitive patients treated with belotecan-based chemotherapy (58.8%) than those treated with topotecan-based chemotherapy (22.2%) (P = 0.041) although it was not significantly different in platinum-resistant patients (P = 0.471). Grade 3 or 4 anemia, neutropenia and thrombocytopenia developed in 14.8% vs 3.6%, 43.1% vs 55.6%, and 20.0% vs 12.8% of cycles in topotecan- and belotecan-based chemotherapies, respectively (P < 0.05). There were no significant difference in survival between the 2 chemotherapies. In our experience, belotecan-based chemotherapy seemed to be efficient with acceptable toxicity, compared to topotecan-based chemotherapy in recurrent EOC. However, randomized controlled trials are required for the comparison of the efficacy and toxicity between topotecan- and belotecan-based chemotherapies in recurrent EOC.

Randomized single-agents trials in recurrent epithelial ovarian cancer

The response to salvage treatment in recurrent epithelial ovarian cancer (REOC), is influenced by many biologic features which should be taken into account in the process of therapeutic decision. Until recently, single agents have been considered effective as combination chemotherapy in REOC and they still represent an option for well-defined categories of patients. In clinical practice, the selection of drugs for second-line treatment can be based on the knowledge that tumor size and response to prior platinum are predictors of response and that the efficacy of some commonly used single agents is supported by well designed clinical studies. Only two single-agent randomized studies with long-term survival analyses have been published; in the topotecan versus paclitaxel study, performed on a total of 235 patients, the long-term survival results did not confirm the initial report of a superiority of topotecan, with a median survival of 63 weeks and 53 weeks for patients treated with topotecan, and, respectively, paclitaxel. No comparative data were provided in the subgroup of potentially platinum-sensitive disease. In the phase III study of pegylated liposomal doxorubicin versus topotecan, into which 474 patients were treated between 1997 and 1999, the higher efficacy of pegylated liposomal doxorubicin was even more evident in the long-term survival analysis, with a 18% reduction in the risk of death, in the overall population which increased to 30% in the subset of platinum-sensitive patients. The survival after the two treatments, however, was not different in the group of patients with platinum-refractory disease. The toxicity profile of the two drugs was completely different, with palmar-plantar erythrodysestesia as most common adverse event after pegylated doxo (35% of patients) and severe neutropenia after topotecan (77% of patients). These data confirm the role of pegylated liposomal doxorubicin in the management of REOC and indicate that the identification of new active drugs in this disease is relevant but also feasible only in platinum-sensitive patients.

Chemotherapy in recurrent epithelial ovarian cancer (EOC): an analysis of prognostic factors.

Prognosis of patients with recurrent epithelial ovarian cancer (EOC) is generally poor. Cisplatin is the most effective drug. We used three cisplatin based chemotherapeutic (CT) regimens and retrospectively analyzed the data to determine the response rate, toxicity, survival and the impact of various prognostic factors on the outcome. Between August, 1989 and September, 1997, 102 patients were diagnosed to have recurrent EOC. Sixty-five of 102 patients received CT every 3 weeks using cisplatin 75 mg/m2 i.v. day 1 plus cyclophosphamide 750 mg/m2 i.v. day 1 (CP, Group A, n = 29), cisplatin 75 mg/m2 i.v. day 1, plus adriamycin 40 mg/m2 i.v. day 1 and cyclophosphamide (CAP, Group B, n = 22) and paclitaxel 135 mg/m2 i.v. day 1 plus cisplatin 75 mg/m2 i.v. day 1 (TP, Group C, n = 14). Twelve patients received single agent CT and were not analyzed. Remaining 25 patients refused CT treatment and were followed for survival. The overall response rate (complete and partial) was 59.2% for patients receiving CP (Group A), 45% for CAP (Group B) and 76.9% for those receiving TP (Group C), p = ns. Response rate was significantly higher for patients with platinum sensitive disease compared to those with platinum resistant disease; 55.76 vs 39%, p < 0.007. CT was generally tolerated well; 2 patients died of CT toxicity, one each in Group A (CP) and C (TP), respectively. The median survival from the date of relapse for patients receiving chemotherapy was 15 months compared to 4 months for those who did not receive chemotherapy, p < 0.001. Chemotherapy responders had a significantly higher median survival than chemotherapy non-responders, 24 months vs 10 months, p < 0.01. The median overall survival was not significantly different in the 3 groups; Group A--15 months, Group B--12 months and 15 months in Group C, p = 0.738. On univariate analysis--time since last CT (< 6 months vs > 6 months, p < 0.037, response to previous CT, p < 0.0183, cisplatinum sensitivity vs resistance, p < 0.032, number of sites (< 2 vs > 2) of recurrence, p < 0.004 and response to salvage CT, p < 0.01 were associated with survival benefit. On multivariate analysis, 2 factors--platinum sensitivity and response to salvage CT attained significance. Our study confirms the benefit of platinum based chemotherapy in recurrent EOC. Patients with platinum sensitive disease, and those responding to salvage chemotherapy benefit most.