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  Title	Efficacy and safety of nanoparticle albumin-bound paclitaxel plus carboplatin as neoadjuvant chemotherapy for stages III–IV, unresectable ovarian cancer: a single-arm, open-label, phase Ib/II study
  ID	4412469
  External ID	7255427812
  Author	Unknown
  Published Date	Oct. 28, 2024, 8:38 p.m.
  Summary	Sixty-two patients were enrolled and were given neoadjuvant therapy treated between October 2019 and December 2020, of whom 9 were in the phase Ib portion and 53 in the phase II portion. A total of 53
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  URL	https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-024-03697-1
  Sentiment	Negative: 0.14482    Neutral: 0.78034    Positive: 0.07484
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  Content ID	2629944
  Key	634c83a4-15f1-49a1-a740-7f3d69d0ed41
  Content	Sixty-two patients were enrolled and were given neoadjuvant therapy treated between October 2019 and December 2020, of whom 9 were in the phase Ib portion and 53 in the phase II portion. A total of 53 patients underwent surgery with an R0 resection rate of 73.6% (95% CI, 59.7–84.7%). With a median follow-up of 17.5 (range 0.7–36.7) months, for all patients, the best ORR was 83.9% (95% CI, 71.7–92.4%) with 47 partial responses, the median PFS was 18.6 (95% CI, 13.8–23.3%) months, and median OS was not reached. During the neoadjuvant chemotherapy, treatment-related adverse events (TRAEs) of any grade occurred in 91.9% (57/62) of all patients. The most common hematologic TRAEs were neutropenia (55/62, 88.7%), and non-hematologic toxicity was alopecia (36/62, 58.1%). Forty-nine patients (79.0%) experienced at least one grade 3–4 TRAEs, with the most common was neutropenia (44/62, 71.0%). Besides, delays in neoadjuvant chemotherapy and surgery due to AEs were observed in 9 (1 in phase Ib; 8 in phase II) and 7 (phase II) patients, respectively. Conclusions The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant chemotherapy nab-paclitaxel plus carboplatin in stage III-IV, unresectable OC. In addition, AEs resulting in chemotherapy and surgery delays should be cautiously considered in this clinical setting. Trial registration ClinicalTrials.gov, ChiCTR1900026893. Registered at 25 October 2019. Background Ovarian cancer (OC) is one of the leading causes of death from gynecological malignancies with almost 313,959 instances and 207,252 deaths per year worldwide [ ]. Due to its relatively asymptomatic nature, the majority of patients diagnosed with OC have advanced-stage cancer and have poor prognoses with a 5-year survival rate of 38.9% in China [ ]. Primary cytoreductive surgery followed by platinum-based chemotherapy remains the standard of care for patients with advanced-stage epithelial OC [ ]. All women with suspected stages IIIC–IV epithelial OC should be evaluated by a gynecologic oncologist prior to the initiation of therapy to determine whether they are candidates for primary cytoreductive surgery [ ]. For patients with advanced stages III–IV disease whose tumors are deemed unlikely to be completely cytoreduced to no gross residual disease (R0) or for patients who are poor surgical candidates, neoadjuvant chemotherapy has been evidenced with increased adoption in studies as a potential treatment option in this population [ ]. Among these, platinum-based drugs with paclitaxel are part of the standard neoadjuvant chemotherapy regimen [ ]. Two randomized trials supported that overall survival (OS) with neoadjuvant chemotherapy is not inferior to upfront surgery and is associated with reduced perioperative morbidity [ ]. However, there is still no evidence that neoadjuvant chemotherapy is superior to standard treatment [ ]. Furthermore, numerous questions remain unanswered, including the precise role of neoadjuvant chemotherapy in the management of advanced epithelial OC has not yet been established, and the optimal regimen of neoadjuvant chemotherapy continues to be controversial [ ]. There is an urgent need to further clarify the role of neoadjuvant chemotherapy and develop more effective therapeutic strategies in OC. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel clinical entity incorporating paclitaxel into an albumin nanoparticle [ ]. Compared with traditional solvent-based paclitaxel, it decomposes more readily in the body and effectively transports paclitaxel to tumor tissues via endocytosis; albumin as the carrier of paclitaxel can achieve higher drug concentration in physical strength, thereby bringing higher efficacy; it can be administered without hypersensitivity premedication and glucocorticoid pretreatment prior to clinical application is not required, resulting in a short infusion duration [ ]. Nab-paclitaxel has been approved for the treatment of metastatic breast cancer, locally advanced or metastatic non-small cell lung cancer, and metastatic pancreatic cancer . Meanwhile, nab-paclitaxel monotherapy also has a recommendation for the treatment of recurrent ovarian cancer based on a phase II trial [ ]. However, there is currently a lack of prospective clinical studies on the combination of nab-paclitaxel and carboplatin for patients with unresectable ovarian cancer in the neoadjuvant setting. Taken together, this phase Ib/II study aimed to explore the efficacy and safety of neoadjuvant nab-paclitaxel plus carboplatin in women with stages III–IV, unresectable OC. Methods Study design This study was a single-arm, open-label, phase Ib/II study conducted at Fudan University Shanghai Cancer Center (trial registration ID: ChiCTR1900026893). It was approved by the Ethics Committee of Ethics Committee of Tumor Hospital Affiliated to Fudan University (no. 1908205–18). The aim of phase Ib was to evaluate the tolerance and safety of neoadjuvant nab-paclitaxel plus carboplatin in patients with stage III-IV, unresectable OC; phase II aimed at determining the efficacy and safety of this combination in the overall population. The study was conducted in accordance with the International Conference on Harmonization of Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable local laws and regulations. The patients were informed of the investigational nature of the study and provided written informed consent before enrollment. Patient population For both the phase Ib and II portions of the study, eligible patients were women ≥ 18 years of age with International Federation of Gynecology and Obstetrics (FIGO) stages III–IV epithelial OC, peritoneal cancer or fallopian tube cancer confirmed by histopathology. Other key eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, estimated life expectancy of at least 12 weeks, and at least one measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria [ ]. In addition, patients were determined to meet neoadjuvant treatment for OC by one of the following criteria: patients with stages III–IV OC, as assessed by gynecologic oncologists, deemed ineligible for achieving R0 resection (Suidan score ≥ 3 or Fagotti score ≥ 8); patients were deemed intolerant to surgery (modified frailty index ≥ 0.36). Patients who experienced clinical major cardiovascular disease at screening were ineligible for this study. Patients with current or previous antitumor therapy (chemotherapy, radiotherapy, immunotherapy) or previous malignancies (except controlled cervical carcinoma in situ or non-melanoma skin cancer) within 5 years were excluded from the study. Patients who had central nervous system or brain metastases, or who had previous sensation or motor neuropathy of grade ≥ 2 were also excluded. Full details on eligibility and exclusion criteria are available in an Additional file 1. Procedures Neoadjuvant nab-paclitaxel (CSPC Ouyi Pharmaceutical Co., Ltd., Shijiazhuang, China) plus carboplatin was administered for 3 cycles before surgery for all eligible patients. Patients received 260 mg/m intravenous nab-paclitaxel on day 1 of every 3-week cycle; carboplatin, at a dosed to an area under the concentration–time curve (AUC) of 5 mg · min/mL, was given as intravenous infusion on day 1 of every 3-week cycle. The chemotherapy dose modification or delay, and treatment delay were allowed. Nab-paclitaxel was reduced by 40 mg/m for each dose level reduction, and each chemotherapy drug allowed a maximum of two levels of dose reduction. Dose escalation was not permitted in this study. Interval debulking surgery (IDS) was scheduled within 1 month after completion of neoadjuvant chemotherapy, per the investigators' assessment. Postoperative adjuvant chemotherapy was administered based on the assessment by the investigators of the patients' clinical conditions, regardless of whether the patient achieved R0 resection or not. The adjuvant chemotherapy regimen with the same drugs and dosages of neoadjuvant chemotherapy was recommended for 3–6 cycles. In addition, after adjuvant chemotherapy, maintenance treatment was also recommended at the discretion of investigators according to patients' circumstances. Assessments Laboratory parameters (including hematologic, biochemical, and urinalysis) and 12-lead electrocardiograms, complete history, physical examination, ECOG PS, and serum tumor markers including cancer-antigen-125 (CA-125) and BRCA mutations assessments were performed at baseline, at each treatment cycle, and at the end of treatment. CA-125 was evaluated by the modeled CA-125 elimination rate constant K (KELIM), with standardized (std) KELIM scores ≥ 1.0 being favorable and < 1.0 being unfavorable. Tumor responses by RECIST v1.1 with magnetic resonance imaging (MRI) or computed tomography (CT) were performed at the end of neoadjuvant chemotherapy. Meanwhile, efficacy evaluations were performed every 3 cycles of treatment. Pathologic response was assessed in surgical specimens by an expert gynecologic oncology pathologist in the participating institution, including pathologic complete response (pCR) and chemotherapy response score (CRS). The CRS of each of the omentum, adnexa, and diaphragm was determined to measure the response to therapy in post-treatment tissue; patients were classified into two distinct groups: one group with CRS1-2 versus those with CRS3. Before conducting CRS, the reviewing pathologist independently reviewed the original publication by Böhm et al. [ ] and completed the online training provided by the aforementioned publication's CRS system ( http://www.gpecimage.ubc.ca/aperio/images/crs ). The CRS scoring followed the description provided by Böhm et al. [ ]. Briefly, CRS1 indicated no or minimal tumor response; CRS2 indicated appreciable tumor response amidst viable tumor; CRS3 complete or near-complete response, with no residual tumor or minimal irregular scattered tumor foci, manifesting as individual cells, cell groups, or nodules not exceeding 2 mm. Safety was assessed by treatment-related adverse events (TRAEs), which were graded according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v5.0 [ ]. Perioperative morbidity and mortality were recorded. Postoperative surgical complications were graded according to the Clavien–Dindo classification [ ]. Endpoints The primary endpoint of phase Ib was severity and incidence rate of adverse events. The primary endpoint of phase II was the R0 resection rate; secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and safety. Exploratory endpoints included CA-125 KELIM, the BRCA mutation status, and CRS. Statistical analysis The phase Ib portion of the trial was intended to provide an initial look at safety outcomes in a small number of patients, and therefore, no formal sample size calculation was performed. The phase II planned sample size was 54 patients, which assumed a R0 reaction rate of 70% for the neoadjuvant nab-paclitaxel plus carboplatin based on a previous study of OC patients treated with carboplatin and paclitaxel (R0 response of approximately 60%) [ ], with a statistical power of 80%, a one-sided significance level of 0.025, and a 10% dropout rate. Analyses of the primary endpoint and secondary endpoints (including R0 resection rate, pCR, PFS, ORR, and OS) were performed in the full analysis set (FAS), which was defined as all patients who had received at least one dose of the study drug. Safety was evaluated based on the safety analysis set (SAS), which was defined as all patients who received at least one of the study drugs and had safety records. Demographics and baseline characteristics were summarized using descriptive statistics. Continuous variables with normal distribution were presented as median with range (minimum and maximum) and its respective 95% confidence interval (95% CI). Categorical variables were summarized as frequencies and percentages (%). The 95% CI of the R0 resection rate and ORR were calculated using the Clopper–Pearson method. PFS and OS were calculated using the Kaplan–Meier method with a 95% CI. The log-rank test determined survival differences across subgroups. Exploratory analysis was conducted to analyze the impact of tumor markers (CA-125 KELIM, BRCA) and different CRS profiles on the efficacy (R0 resection rate, PFS, ORR, and OS) and to plot survival curves; meanwhile, the maintenance treatment after the adjuvant chemotherapy was also analyzed. All statistical tests were two-sided, with significance set at p < 0.05. All analyses were conducted using IbM SPSS statistics v27.0. Results Patient characteristics Between October 2019 and December 2020, 10 patients were enrolled in the phase Ib portion of the study (of whom, 1 did not meet eligibility criteria and was excluded) and 54 patients were enrolled in the phase II portion (of whom, 1 did not meet eligibility criteria and was excluded). Nine patients received neoadjuvant chemotherapy in phase Ib and 53 received neoadjuvant chemotherapy in phase II, and thus 62 were included in the FAS and SAS. Of these, 53 (85.5%) patients subsequently underwent surgery (9 did not proceed with surgery due to investigator decision ( n = 4), withdraw ( n = 3), and AEs ( n = 2); Fig. Table summarizes the baseline characteristics of the included patients. In the phase Ib portion, the median age was 60 (range, 51–77) years and the majority of the patients (6/9, 66.7%) had a baseline ECOG performance status of 1. All patients had epithelial OC, with most of them histologically classified as high-grade serous carcinoma (8/9, 88.9%). Most patients (7/9, 77.8%) had FIGO stage III OC. Table 1 Baseline characteristics of included patients While in the phase II portion, patients had a median age of 57 (range, 37–70) years, with the majority (45/53, 84.9%) with a baseline ECOG performance status of 1. All patients also had epithelial OC, predominantly histologically classified as high-grade serous carcinoma (50/53, 94.3%). Moreover, most patients (37/53, 69.8%) were diagnosed with FIGO stage IV OC. Treatments In the phase Ib portion, 9 completed 3 cycles of neoadjuvant chemotherapy; in the phase II portion, 48 completed 3 cycles of neoadjuvant chemotherapy (5 discontinued due to 1 undergoing surgery ahead of schedule, 2 withdrew, and 2 AEs). Of these, the chemotherapy delay (phase Ib, n = 2; phase II, n = 21) and dose reductions of nab-paclitaxel (phase Ib, n = 1; phase II, n = 10) were observed both in phase Ib and phase II, mainly for toxicity. Fifty-three of 62 (85.5%) patients received surgery after neoadjuvant chemotherapy finally, including 7 in phase Ib and 46 in phase II, and the median interval from the completion of neoadjuvant chemotherapy to surgery was 26.0 (range, 13.0–42.0) days. Among surgical patients, 27 (50.9%) underwent pelvic and mid-abdomen resection; 26 (49.1%) underwent pelvic, mid-abdomen, and upper-abdomen resection; and 25 (47.2%) underwent retroperitoneal lymphadenectomy. The median operative time was 3.0 (range, 1.0–6.0) h. The median intraoperative blood loss was 600.0 (range, 50.0–2500.0) mL. The median length of postoperative hospital stay was 8.0 (range, 4.0–22.0) days. Postoperative adjuvant chemotherapy was initiated in 52 of 53 surgical patient population with 1 discontinuation due to AEs. The median cycles of adjuvant chemotherapy were 3.0 (range, 1.0–5.0) for all patients, and 50 (96.2%) received the adjuvant regimen of nab-paclitaxel plus carboplatin, while 2 (3.8%) received paclitaxel plus carboplatin. Of the 52 patients who received adjuvant chemotherapy, 33 (63.5%) were supported by subsequent maintenance treatment, with niraparib maintenance treatment (16/33, 48.5%) being the most frequent choice. Details of treatment information are provided in the Additional file 1: Table. S1. Efficacy In total, 56 out of 62 patients had at least tumor evaluation per RECIST v1.1 during the neoadjuvant chemotherapy period, with 9 in phase Ib and 47 in phase II (Table ). For all patients, the best ORR was 83.9% (95% CI, 71.7%-92.4%), including 47 PR; for patients in the phase II portion, the best ORR was 85.1% (95% CI, 71.7%-93.8%) with 40 PR. Table 2 Best overall response during the neoadjuvant treatment period For 53 patients undergoing IDS after neoadjuvant chemotherapy, the R0 resection rate was 73.6% (39/53; 95% CI, 59.7%–84.7%), and assessment of pathological response demonstrated that 3 patients had pCR with a pCR rate of 5.7% (95% CI, 1.2%–15.7%). As of the data cutoff date (December 2023), the median follow-up time was 17.5 (range 0.7–36.7) months. For all 62 patients, PFS events had occurred in 35 (56.5%) patients, of which 27 disease progression or recurrence and 8 died, with a median PFS of 18.6 (95% CI, 13.8–23.3%) months (Fig. A). Fifteen (24.2%) patients died. The median OS was not reached, with the 1-year OS of 89.8% (95% CI, 78.7–95.3%) and the 2-year OS of 65.7% (95% CI, 48.1–78.6%; Fig. B). Safety All patients were evaluated for safety (Table ), with 9 in phase Ib and 53 in phase II portions. During the neoadjuvant chemotherapy period, TRAEs of any grade occurred in 91.9% (57/62) of all patients. The most common hematologic TRAEs with nab-paclitaxel plus carboplatin was neutropenia (55/62, 88.7%), and non-hematologic toxicity was alopecia (36/62, 58.1%). Peripheral sensory neuropathy was observed in 13 patients (21%), with all cases being grade 1 or 2. Forty-nine patients (79.0%) experienced at least one grade 3–4 TRAEs. The most common grade 3–4 TRAEs were hematologic toxicities, including neutropenia (44/62, 71.0%), leucopenia (25/62, 40.3%), and thrombocytopenia (15/62, 24.2%). Meanwhile, only one patient (1.6%) experienced three to four non-hematologic toxicity TRAEs, which was aspartate aminotransferase increased; no hypersensitivity was observed in our study. TRAEs observed in the phase Ib and phase II portions were similar in nature and intensity, except urinary tract infection and aspartate aminotransferase increased. Urinary tract infection was not detected in phase Ib, whereas it was observed in four patients (7.5%) in phase II; grade 3–4 aspartate aminotransferase increases were observed in phase II, but not observed in phase Ib. Table 3. Summary of treatment-related adverse events that occurred in ≥5% of patients In the phase Ib portion, one patient (11.1%) had chemotherapy delay due to hematological AEs, including grade 2 neutropenia, grade 2 leucopenia, and grade 3 anemia; in the phase II portion, eight patients (15.1%) experienced chemotherapy delay due to AEs, including neutropenia, leucopenia, anemia, thrombocytopenia, and aspartate aminotransferase increased. In parallel, in the phase II portion, nab-paclitaxel dose reductions were observed in three patients (5.7%) due to AEs (neutropenia, leucopenia, platelet count decreased), and seven (15.2%) experienced surgery delays due to decreased platelet counts. In the phase Ib portion, there were no dose reductions of nab-paclitaxel or surgery delays associated with AEs. Of the 62 patients, 15 (24.2%) had died at the time of data cutoff, and the cause of death was not attributed to drug-related toxicity death. Among 53 patients undergoing IDS, 11 (20.8%) patients experienced surgical complications, including pulmonary embolism ( n = 4, 7.5%), postoperative anemia ( n = 4, 7.5%), pelvic infection ( n = 2, 3.8%), intestinal obstruction (1.9%), venous thrombosis ( n = 1, 1.9%), and intra-abdominal infection. No grade 3 or higher surgical complications and postoperative mortality were observed. No surgical complications leading to readmission within 30 days, emergency reoperation, or intensive care occurred. Exploratory analysis Of the 62 patients enrolled, 58 patients with CA-125 available values were assessable for KELIM during the treatment. Among them, the median CA-125 KELIM score was 0.8 (range 0.3–1.5), with 42 patients (72.4%) with a CA-125 KELIM score < 1.0 and 16 (27.6%) with a CA-125 KELIM score ≥ 1.0. To further assess CA-125 KELIM as an early indicator of the tumor intrinsic chemosensitivity in OC, we compared efficacy between two subgroups (CA-125 KELIM scores < 1.0 vs. ≥ 1.0) in all patients. However, the results indicated that there were no statistically significant differences in PFS, OS, or ORR between these two groups (all p > 0.05; Additional file 1: Fig. S1 and Table. S2). All patients underwent BRCA mutation status testing, and data were available for 52 patients (a total of 10 patients were excluded, including 6 without tumor assessments and 4 with unknown BRCA expression). We further investigated the efficacy between BRCA -positive and BRCA -negative patients. There were 18 patients with BRCA -positive and 34 BRCA -negative identified at the end of neoadjuvant chemotherapy. A similar ORR (83.3% vs. 88.2%; p = 0.682; Table S1) was found in these two groups. Notably, BRCA -positive patients (20.5 months; 95% CI 13.0–28.0%) exhibited significantly longer PFS compared to BRCA -negative patients (12.6 months; 95% CI 7.9–17.2%; p = 0.006; Fig. ). In addition, we also evaluated the subsequent maintenance treatment options for BRCA -positive and BRCA -negative patients. Of the 18 patients evaluated for BRCA -positive, 13 (72.2%) received maintenance therapy; of the 32 patients evaluated for BRCA -negative (2 patients with unknown BRCA gene expression during maintenance treatment), 20 (62.5%) received maintenance therapy. The results determined that olaparib (84.6%) was primarily utilized for maintenance treatment regimens for BRCA -positive patients, while niraparib (75.0%) was the main maintenance treatment regimen for BRCA -negative patients (Additional file 1: Table. S3). All patients were scored for histologic response to neoadjuvant chemotherapy and optimal CRS3 was achieved in 10, 3, and 2 patients by omental, adnexal, and diaphragmatic assessments, respectively. In addition, we conducted a subgroup analysis to observe the correlation between CRS scores and therapeutic outcomes. There were no significant differences CRS1-2 and CRS3 groups in terms of R0 resection rate, PFS, and OS. However, in the diaphragmatic assessment, 14 patients with CRS1-2 were evaluated for ORR, and all 14 patients achieved an ORR (ORR = 100%); whereas, 2 patients were assessed for CRS3, and neither achieved ORR (ORR = 0); this difference was statistically significant ( p = 0.008). The details of the efficacy outcome and histopathologic features corresponding to CRS1-3 are illustrated in the Additional file 1: Fig. S2 and Table. S4. Discussion To our knowledge, this was the first prospective trial to investigate the efficacy and safety of neoadjuvant nab-paclitaxel plus carboplatin in women with stages III–IV, unresectable OC. Meanwhile, this trial met its predefined, statistical, primary endpoint for R0 resection (73.6%) with a manageable safety profile. These data may provide potential evidence for the neoadjuvant nab-paclitaxel plus chemotherapy for this population. Recently, neoadjuvant chemotherapy has gradually become an accepted alternative treatment for certain women with advanced OC [ ]. The adoption of neoadjuvant chemotherapy for patients with stages IIIC–IV epithelial OC escalated from 8.6% to 45.1% between 2004 and 2016, with an annual increase of 10.3% from 2011 to 2016 [ ]. Accumulating clinical trials have demonstrated the clinical benefits of neoadjuvant chemotherapy before primary surgery compared to primary surgery followed by platinum-based adjuvant chemotherapy [ ]. Data from randomized controlled trials (CHORUS and EORTC-55971) showed that neoadjuvant chemotherapy followed by interval tumor reductive surgery has equivalent benefits on PFS (median PFS of 12 months) and OS (median OS of 24.1–30 months), better optimal cytoreduction rates (EORTC-55971) among women with advanced-stage OC compared with results observed with primary surgery followed by adjuvant chemotherapy [ ]. However, one of the criticisms of these studies was the low frequency of the R0 resections rate (51.2% in the EORTC-55971 trial and 39% in the CHORUS trial) [ ]. Comparing with these studies, in our study, neoadjuvant nab-paclitaxel plus carboplatin showed longer PFS (median PFS of 18.6 months), and it is particularly noteworthy that we achieved a promising R0 resection of 73.6%. Contemporary data and meta-analyses indicate a correlation between the volume of residual disease and patient outcomes, with patients undergoing complete gross resection (R0) having the best outcomes [ ]. Thus, irrespective of when surgery is performed—upfront or after neoadjuvant chemotherapy in the primary setting—the goal remains to achieve R0 resections [ ]. The explanation for the high R0 resection in our study compared with the aforementioned trials, the EORTC-55971 trial (median age 63 years) and CHORUS trial (median age 65 years) might be attributed to the younger median age of recruited patients (median age 58 years). Another possible explanation is that all primary tumors in our study originated from epithelial ovarian. Hao et al. found that the origin of advanced tumors tubal or ovarian showed different clinical and pathologic features, which could lead to different prognostic outcomes [ ]. Nevertheless, distinguishing between advanced tumors of tubal and ovarian origin remains a significant challenge, thus, the potential differences in prognosis based on tumor origin are not yet fully understood [ ] and require further research to clarify their impact on patient outcomes. In addition, a meta-analysis of 17 published studies to compare morbidity and mortality in patients treated with neoadjuvant chemotherapy compared to primary cytoreductive surgery in advanced OC revealed an R0 resections rate of 44.4% with neoadjuvant chemotherapy; meanwhile, patients in neoadjuvant chemotherapy setting had shorter surgery time (mean, 121–255 min) [ ]. Compared with this study, the R0 resection rate in the present study (73.6%) was also numerically higher. Meanwhile, the mean surgery time of 192 min was generally consistent with the above study. Taken together, this observation highlights the potential clinical benefit of neoadjuvant chemotherapy with nab-paclitaxel plus carboplatin for stages III–IV OC. However, this observation must be interpreted with caution as it was a single-arm study and urges the need for further large-scale multicenter randomized trials to validate the clinical efficacy of neoadjuvant chemotherapy nab-paclitaxel plus carboplatin. A study has reported the association between BRCA mutations and survival benefits in OC, indicating that BRCA mutation was significantly correlated with better PFS [ ]. In this study, we also found that BRCA -positive patients exhibited significantly longer PFS compared to those who were BRCA -negative (20.5 vs. 12 months; p = 0.006). Meanwhile, we also observed differences in maintenance treatment between BRCA -positive and BRCA -negative patients. BRCA -positive patients predominantly utilized olaparib (84.6%), whereas BRCA -negative patients primarily relied on niraparib (75.0%). This finding in medication selection based on BRCA mutation status is consistent with previous research reports [ ], suggesting the importance of personalized treatment strategies tailored to individual genetic profiles in optimizing patient outcomes. In addition, Steffen Böhm et al. introduced the CRS system, marking a significant milestone in the pathological assessment criteria following neoadjuvant chemotherapy for high-grade serous ovarian cancer [ ]. Böhm et al. found that tumor response in the omental site was significantly correlated with PFS but adnexal mass was not closely linked to outcome. In addition, a systematic review and meta-analysis by reviewing current evidence to determine whether the omental CRS is prognostic in women with tubo-ovarian cancer treated with neoadjuvant chemotherapy showed that CRS3 was significantly associated with improved PFS and OS compared to CRS1/2 [ ]. Another study that included adnexal CRS found that adnexal CRS was not associated with OS but was significantly associated with PFS [ ]. However, in our study, by analyzing the relationship between CRS and outcomes in OC patients receiving nab-paclitaxel plus carboplatin, we found no significant difference in PFS and OS based on the omentum and adnexa assessment. Besides, the experience with the use of CRS on the diaphragm is limited. In our pathological evaluations of the diaphragm, we found a significant difference in ORR between patients with CRS1-2 and CRS3 ( p = 0.008). However, given the small sample size (only two patients with CRS3 were included) and the potential bias in sampling from diaphragm specimens (the larger size of the diaphragmatic specimens might introduce sampling bias), our results should be interpreted with caution. Further research is warranted to elucidate the correlation between ORR and CRS. KELIM score as a reproducible indicator of the tumor-primary chemosensitivity was confirmed through the independent predictive value regarding the tumor response rate, PFS, and OS [ ]. However, in our study, we did not observe significant differences in PFS, OS, or ORR between the different KELIM scores. This may be due to potential limitations in the CA-125 KELIM score calculation in our study, which may be caused by the small sample size and the fact that CA-125 level measurements were conducted in local laboratories rather than being centralized. The safety profiles of neoadjuvant chemotherapy with nab-paclitaxel plus carboplatin were well tolerated and manageable. The most common hematological toxicity in this study included neutropenia, leucopenia, thrombocytopenia, and anemia. The hematologic safety profile reported here was similar to the findings from a retrospective study investigating the efficacy and safety of nab-paclitaxel combined with platinum as first-line chemotherapy for OC [ ]. No new safety signals were identified. In addition, hematological toxicities were the major reason for delays in chemotherapy and surgical delay, as well as nab-paclitaxel dose reductions in our study. This is consistent with the findings of Chen et al., who found that hematologic toxicity was the most common reason for surgical delay among patients with advanced OC receiving neoadjuvant chemotherapy [ ]. This observation highlights the clinical significance of vigilant hematologic monitoring and underscores the necessity for treatment strategies to mitigate toxicity-related disruptions in chemotherapy schedules. Meanwhile, TRAEs associated with nab-paclitaxel and carboplatin were similar to the known safety profile of each drug individually which has been observed in prior studies [ ]. Despite 49 patients (79.0%) experiencing at least one grade 3 or worse TRAE, these events were generally manageable, tolerable, and resolved soon with dose reductions. Peripheral sensory neuropathy is one principal toxicity induced by taxanes [ ]. In our study, 21.0% of patients experienced peripheral sensory neuropathy after this combination therapy, which was lower than that reported in a meta-analysis evaluating the incidence and severity of peripheral neuropathy in cancer patients treated with nab-paclitaxel-containing regimens (65%) [ ]. Meanwhile, no grade 3 or worse neurotoxicity occurred in our study. This compares favorably with previously reported rates of grade 3 to 4 neurotoxicity among patients treated with 3 weekly paclitaxel administered at lower doses (175–200 mg/m ), which have ranged from 11 to 29% [ ]. Besides, as reported in previous studies, the use of nab-paclitaxel reduces the incidence of hypersensitivity reactions, making it a suitable alternative to paclitaxel or docetaxel, especially when it is medically necessary to avoid hypersensitivity reactions [ ]. Our study findings also support this perspective, as no hypersensitivity reactions were observed. We must acknowledge several limitations inherent in our study. First, single-arm, single-center phase Ib/II design might lead to potential selection bias. Second, the sample size of this study was relatively small. The limited sample size may explain the lack of significant prognostic factors in exploratory analyses. Third, mature overall survival data were not available due to a short follow-up time. Finally, the biomarker correlative analyses were exploratory, limiting our ability to uncover biological processes associated with treatment response. However, these preliminary findings provide valuable insights that warrant further investigation in larger-size, control-group cohorts. Conclusions This study of neoadjuvant nab-paclitaxel plus carboplatin regimen met its predefined, statistical, primary endpoint for R0 resection, and showed an acceptable safety profile. The treatment modality of neoadjuvant nab-paclitaxel plus carboplatin followed by surgery may therefore be considered a feasible and promising treatment option for patients with stages III–IV, unresectable OC. Data availability The datasets supporting the results of the present study can be obtained from the corresponding author upon reasonable request. The datasets supporting the results of the present study can be obtained from the corresponding author upon reasonable request. Abbreviations OC: Ovarian cancer PFS: Progression-free survival OS: Overall survival ORR: Objective response rate TRAEs: Treatment-related adverse events FIGO: International Federation of Gynecology and Obstetrics ECOG: Eastern Cooperative Oncology Group RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1 IDS: Interval debulking surgery MRI: Magnetic resonance imaging CT: Computed tomography pCR: Pathologic complete response CRS: Chemotherapy response score TRAEs: Treatment-related adverse events FAS: Full analysis set SAS: Safety analysis set CI: Confidence interval References Guyot P, Ades AE, Ouwens MJ, Welton NJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12: 9. Konstantinopoulos PA, Matulonis UA. 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SHDC2020CR3059B) and Natural Science Foundation of Shanghai (no. 20ZR1413000). Author information Author notes Lina Yin and Wei Jiang contributed equally as first authors. Huijuan Yang and Boer Shan contributed equally as corresponding authors. Authors and Affiliations Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China Lina Yin, Wei Jiang, Lin Zhou, Xuan Pei, Shuang Ye, Wenbin Shen, Huijuan Yang & Boer Shan Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China Shuai Liu Department of Radiology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China Yi Fu Contributions LNY, WJ, HJY, and BES conceptualized and designed the study. LNY, WJ, SL, YF, LZ, XP, SY, and WBS provided materials and samples, as well as conducted data collection. LNY, WJ, SL, YF, LZ, HJY, and BES analyzed and interpreted the data. LNY, WJ, HJY, and BES wrote and edited the original draft, as well as reviewed and edited the draft. All authors read and approved the final manuscript. Corresponding authors Correspondence to Huijuan Yang or Boer Shan Ethics declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Tumor Hospital Affiliated to Fudan University (No. 1908205–18). Written informed consent was obtained from each patient. All procedures in the present study conformed to the ethical standards of the institutional and/or national research committee, Good Clinical Practice guidelines, and the Helsinki Declaration and its later amendments or comparable ethical standards. Consent for publication Not applicable. Competing interests The authors have no conflicts of interest to declare. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Additional file 1: Supplemental methods and supplementary results. Inclusion and exclusion criteria. Table S1. Treatment information. Table S2. ORR in subgroups based on CA-125 KELIM and BRCA mutations. Table S3. Maintenance therapy utilization by BRCA mutation status. Table S4. Efficacy in different CRS score subgroups. Fig. S1. Kaplan–Meier curves for progression-free survival (A) and overall survival (B) in subgroups with CA-125 KELIM scores < 1.0 and ≥ 1.0 Fig. S2. Histopathological features of tumor response after neoadjuvant chemotherapy corresponding to CRS1-3. A-C, CRS1-3 scores based on omental slides. 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