Randomized phase II trial of farletuzumab plus chemotherapy versus placebo plus chemotherapy in low CA-125 platinum-sensitive ovarian cancer.

OBJECTIVE: The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-α monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemotherapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels. METHODS: Eligibility included CA-125 ≤ 3 x upper limit of normal (ULN, 105 U/mL), high-grade serous, platinum-sensitive recurrent OC, previous treatment with debulking surgery, and first-line platinum-based chemotherapy with 1st recurrence between 6 and 36 months since frontline platinum-based treatment. Patients received investigator's choice of either carboplatin (CARBO)/paclitaxel (PTX) every 3 weeks or CARBO/pegylated liposomal doxorubicin (PLD) every 4 weeks x6 cycles in combination with either farletuzumab [5 mg/kg weekly] or placebo randomized in a 2:1 ratio. Maintenance treatment with farletuzumab (5 mg/kg weekly) or placebo was given until disease progression or intolerance. RESULTS: 214 patients were randomly assigned to farletuzumab+chemotherapy (142 patients) versus placebo+chemotherapy (72 patients). The primary efficacy endpoint, PFS, was not significantly different between treatment groups (1-sided α = 0.10; p-value = 0.25; hazard ratio [HR] = 0.89, 80% confidence interval [CI]: 0.71, 1.11), a median of 11.7 months (95% CI: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for farletuzumab+chemotherapy and placebo+chemotherapy, respectively. No new safety concerns were identified with the combination of farletuzumab+chemotherapy. CONCLUSIONS: Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950).

Trabectedin plus pegylated liposomal doxorubicin in patients with disease progression after PARP inhibitor maintenance: a real-life case-control study.

OBJECTIVE: Poly (ADP-ribose) polymerase (PARP) inhibitor resistance is problematic in epithelial ovarian cancer management and sequencing strategies may be performed to overcome this issue. In this context, our study evaluated the role of non-platinum doublet pegylated liposomal doxorubicin/trabectedin in ovarian cancer platinum-sensitive patients who experienced disease progression under PARP inhibitor maintenance. METHODS: This case-control study includes patients with recurrent epithelial ovarian cancer treated between March 2016 and April 2021 who progressed under PARP inhibitor maintenance. Data of patients treated with pegylated liposomal doxorubicin/trabectedin (experimental group) were matched 1:1 with a series of patients who received platinum-based treatment (control group). The study outcomes were overall clinical benefit (including complete, partial, and stable response), progression-free survival, and overall survival. The safety of both treatments was also evaluated. RESULTS: A total of 26 patients in both groups were analyzed. Clinical benefit was achieved in 15 (57%) patients in the study group and 17 (65%) patients in the control group (p=0.38). Patients receiving pegylated liposomal doxorubicin/trabectedin had 5 months of progression-free survival, compared with 5 months in patients treated with platinum-based treatment (p=0.62). Patients in the experimental group achieved a median overall survival of 16 months compared with 19 months in the control group (p=0.26) There was no difference concerning severe toxicities (G3-G4) between groups, except for hepatic toxicity, which was experienced in 30% of the patients receiving pegylated liposomal doxorubicin/trabectedin and none in the control group (p<0.009). CONCLUSIONS: Pegylated liposomal doxorubicin/trabectedin might be an alternative option to platinum-based treatment in patients experiencing disease progression during PARP inhibitor maintenance with an acceptable toxicity profile. This might be a therapeutic option in this setting, sparing platinum compounds for subsequent relapse.

Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial.

BACKGROUND: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. METHODS: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. FINDINGS: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. INTERPRETATION: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. FUNDING: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.

A European, Observational, Prospective Trial of Trabectedin Plus Pegylated Liposomal Doxorubicin in Patients with Platinum-Sensitive Ovarian Cancer.

PURPOSE: The noninterventional, prospective NIMES-ROC phase IV study (NCT02825420) evaluated trabectedin plus pegylated liposomal doxorubicin (PLD) in real-life clinical practice. PATIENTS AND METHODS: Eligible participants included adults with platinum-sensitive recurrent ovarian cancer (PS-ROC) who had received one or more cycles of trabectedin/PLD before inclusion according to the marketing authorization. The primary endpoint was progression-free survival (PFS) according to investigator criteria. RESULTS: Two hundred eighteen patients from five European countries were evaluated, 72.5% of whom were pretreated with at least two prior chemotherapy lines and received a median of six cycles of trabectedin/PLD (range: 1-24). Median PFS was 9.46 months (95% confidence interval [CI], 7.9-10.9), and median overall survival (OS) was 23.56 months (95% CI, 18.1-34.1). Patients not pretreated with an antiangiogenic drug obtained larger median PFS (p < .007) and OS (p < .048), largely owning to differences between the two populations. Twenty-four patients (11.0%) had a complete response, and 57 patients (26.1%) achieved a partial response for an objective response rate (ORR) of 37.2%. Fifty-nine patients (27.1%) had disease stabilization for a disease control rate of 64.2%. No statistically significant difference in PFS, OS, or ORR was observed by BRCA1/2 status and platinum sensitivity. Most common grade 3/4 adverse events (AEs) were neutropenia (30.3%), anemia (6.4%), thrombocytopenia (5.5%), and asthenia (5.0%). No deaths attributed to treatment-related AEs or unexpected AEs occurred. CONCLUSION: The combination of trabectedin/PLD represents a clinically meaningful and safe option for patients with PS-ROC regardless of prior treatment with an antiangiogenic drug, being comparable with previously observed outcomes in selected and less pretreated patients from clinical trials. IMPLICATIONS FOR PRACTICE: This noninterventional, prospective study, conducted in 57 reference sites across Europe, consistently confirmed that trabectedin plus pegylated liposomal doxorubicin (PLD) in routine clinical practice represents a clinically meaningful and safe option for women with platinum-sensitive recurrent ovarian cancer. Although the study population represented a heterogeneous, older, and more pretreated population than those in prospective clinical trials, the combination of trabectedin plus PLD induced comparable clinical benefits, with a similar and manageable safety profile. Overall, these findings show that trabectedin in combination with PLD maintains antitumor activity when administered to heavily pretreated patients in real-life clinical practice.

Lurbinectedin versus pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer: A multicenter, randomized, controlled, open-label phase 3 study (CORAIL).

OBJECTIVE: The randomized phase 3 CORAIL trial evaluated whether lurbinectedin improved progression-free survival (PFS) compared to pegylated liposomal doxorubicin (PLD) or topotecan in patients with platinum-resistant ovarian cancer. METHODS: Patients were randomly assigned (1:1) to lurbinectedin 3.2 mg/m2 1-h i.v. infusion q3wk (experimental arm), versus PLD 50 mg/m2 1-h i.v. infusion q4wk or topotecan 1.50 mg/m2 30-min i.v. infusion Days 1-5 q3wk (control arm). Stratification factors were PS (0 vs. ≥1), prior PFI (1-3 months vs. >3 months), and prior chemotherapy lines (1-2 vs. 3). The primary endpoint was PFS by Independent Review Committee in all randomized patients. This study was registered with ClinicalTrials.gov, NCT02421588. RESULTS: 442 patients were randomized: 221 in lurbinectedin arm and 221 in control arm (127 PLD and 94 topotecan). With a median follow-up of 25.6 months, median PFS was 3.5 months (95% CI, 2.1-3.7) in the lurbinectedin arm and 3.6 months (95% CI, 2.7-3.8) in the control arm (stratified log-rank p = 0.6294; HR = 1.057). Grade ≥ 3 treatment-related adverse events (AEs) were most frequent in the control arm: 64.8% vs. 47.9% (p = 0.0005), mainly due to hematological toxicities. The most common grade ≥ 3 AEs were: fatigue (7.3% of patients) and nausea (5.9%) with lurbinectedin; mucosal inflammation (8.5%) and fatigue (8.0%) in the control arm. CONCLUSIONS: The primary endpoint of improvement in PFS was not met. Lurbinectedin showed similar antitumor efficacy and was better tolerated than current standard of care in patients with platinum-resistant ovarian cancer.

Value of pre-existent bacterial colonization in patients with advanced/relapsed ovarian neoplasms undergoing cytoreductive surgery: a multicenter observational study (BONSAI).

OBJECTIVE: As an increasing number of patients with advanced/relapsed ovarian cancer need extensive cytoreductive procedures, there is an increasing number of complex cases collected in accredited tertiary cancer centers. With nosocomial infections and bacterial colonizations being a significant challenge in these patient cohorts, we aimed to evaluate the risk such infections pose to surgical outcome. METHODS: Prospective assessment of pathological bacterial colonization (vaginal, umbilical/groin, intraperitoneal, urine, oral/nose cavity) in patients who underwent open cytoreductive surgery for advanced/relapsed ovarian cancer in two large European tertiary referral centers for gynecologic malignancies. We recruited patients at initial diagnosis with International Federation of Gynecology and Obstetrics (FIGO) stage III and IV ovarian cancer and patients undergoing surgery for relapse. Swabs or cultures were taken from the following sites: vagina, groin and/or umbilicus, urine, intraperitoneal, mouth and/or nose. Only evidence of pathogenic bacteria was considered positive for bacterial colonization. RESULTS: A total of 172 primary advanced (70.9%) or relapsed (29.1%) ovarian cancer patients were included; 63.4% of them had received chemotherapy±additional targeted agents (16.3%) by the time of cytoreduction. 39.5% of the patients had a long-term vascular access line in situ. A bowel resection was performed in 44.8% and a splenectomy in 16.3% of the patients. Predefined surgical morbidity and mortality were 22.3% and 0%, respectively. Forty-one patients (23.8%) screened positive for pathogenic bacterial colonization with the presence of long-term intravenous access as the only independent risk factor identified (OR 2.34; 95% CI 1.05 to 5.34; p=0.04). Type of systemic treatments, previous bowel resections, previous hospitalizations, and patient demographics did not appear to significantly impact the risk of bacterial colonization. Furthermore, pathogenic bacterial colonization was shown to have no significant effect on peri-operative infection-related complications such as abscesses, wound infection, pneumonia, relaparotomy, or anastomotic leak. CONCLUSIONS: A total of 24% of patients undergoing cytoreductive surgery for ovarian cancer were confirmed positive for pathogenic bacterial colonization. The presence of long-term intravenous access was identified as the only significant risk factor for that, however the presence of pathogenic bacterial colonization per se did not seem to adversely affect outcome of cytoreductive effort or increase perioperative infection related complications.

Titanized polypropylene mesh in laparoscopic sacral colpopexy.

INTRODUCTION: This study investigated perioperative and mid-term clinical outcomes after laparoscopic sacrocolpopexy (LSCP) with light titanium-coated polypropylene (TCP) mesh in a large group of patients affected by International Continence Society stage II-IV pelvic organ prolapse (POP). METHODS: This multicenter retrospective study included 217 patients treated with LSCP using TCP mesh. We aimed to (1) analyze the intra- and postoperative complication rates according to the ICS/IUGA Complication Classification Code guidelines, (2) evaluate the anatomical results and (3) assess postoperative patient satisfaction with the Patient Global Impression Improvement questionnaire. Nonparametric Wilcoxon signed-rank tests, χ2 test and Fisher's exact test were used where appropriate. RESULTS: The intraoperative complications were two (0.9%) cases of hemorrhage, two (0.9%) cases of incidental cystotomy and four (1.8%) cases of incidental colpotomy. During the postoperative follow-up, we recorded mesh exposure in 3 (1.4%) out of 217 patients. These 3 patients were from a group of 22 women who underwent vaginal opening during surgery, while in the remaining 195 patients without incidental colpotomy, no mesh exposure was observed (13.6% vs. 0.0%, p < 0.001). No failure of the apical compartment was observed, while 3 (1.4%) out of 217 patients experienced isolated anterior recurrence, and 1 (0.4%) patient had isolated posterior recurrence. All patients reported PGI-I scores ≥ 3, and 209 patients (96.3%) had a PGI-I score ≥ 2. CONCLUSIONS: The use of light TCP mesh is safe and effective during LSCP for POP repair from both an anatomical and a functional point of view, posing a very low postoperative mesh-related complication risk.

Prognostic role of chemotherapy-induced neutropenia in first-line treatment of advanced ovarian cancer. A pooled analysis of MITO2 and MITO7 trials.

BACKGROUND: Chemotherapy-induced neutropenia (CIN) has been associated with improved prognosis in several cancer conditions. Contrasting data have been produced in ovarian cancer.

Real-World Management of Trabectedin/Pegylated Liposomal Doxorubicin in Platinum-Sensitive Recurrent Ovarian Cancer Patients: A National Survey.

BACKGROUND: Trabectedin (T) plus pegylated liposomal doxorubicin (PLD) is approved for treatment of platinum-sensitive recurrent ovarian cancer (ROC). Despite the recommendations and guidelines, variations in managing T/PLD administration in routine clinical practice cannot be excluded. We aimed at setting up an Italian survey collecting data about management of T/PLD administration in ROC patients. METHODS: We carried out the development of a questionnaire-based survey on routine clinical practice in the management of ROC patients administered T/PLD. The survey registered the physicians' approach to modification/discontinuation of treatment, type of modifications, reasons why, and so on. The survey was transmitted to medical oncologists and gynecologic oncologists practicing in national centers/institutions. RESULTS: Fifty-eight Italian centers/institutions returned the compiled questionnaire; participants practiced at community cancer centers or hospitals (56.9%), academic institutions (36.2%), and other settings (private clinics, etc) (6.9%). There was no statistically significant difference in the distribution of practice setting according to geographic areas. Most responders were medical oncologists (84.5%) and were members (82.8%) of at least 1 scientific society or cooperative group. Almost 31.5% of responders reported interruption of the whole treatment, mostly because of toxicity (41.2%), followed by patients' choice (29.4%), or achievement of clinical benefit (23.5%). Dose reduction was referred by 47.4% of responders. Reduction of dose for both drugs was referred by 88.5% of responders, and the extent of dose reduction ranged between 10% and 30%. CONCLUSIONS: This survey highlights the gaps in transposing evidence-based or consensus guidelines in the real-world management of T/PLD administration; these findings could be useful in order to focus the attention on specific knowledge and/or experience gaps and plan pertinent educational programs.

Endometriosis-associated clear cell carcinoma arising in caesarean section scar: a case report and review of the literature.

BACKGROUND: Malignant transformation has been reported in approximately 1% of the endometriosis cases; herein, we report a case of clear cell endometrial carcinoma arising from endometriosis foci located within a caesarean section scar. CASE PRESENTATION: In November 2014, a Caucasian, 44-year-old woman was transferred to our institution because of severe respiratory failure due to massive lung embolism and rapid enlargement of a subcutaneous suprapubic mass. Abdomino-pelvic magnetic resonance showed a 10.5 × 5.0 × 5.0 cm subcutaneous solid mass involving the rectus abdominis muscle. Pelvic organs appeared normal, while right external iliac lymph nodes appeared enlarged (maximum diameter = 16 mm). A whole-body positron emission tomography/computed tomography scan showed irregular uptake of the radiotracer in the 22 cm mass of the abdominal wall, and in enlarged external iliac and inguinal lymph nodes. In December 2014, the patient underwent exploratory laparoscopy showing normal adnexae and pelvic organs; peritoneal as well as cervical, endometrial and vesical biopsies were negative. The patient was administered neo-adjuvant chemotherapy with carboplatin and paclitaxel, weekly, without benefit and then underwent wide resection of the abdominal mass, partial removal of rectus abdominis muscle and fascia, radical hysterectomy, bilateral salpingo-oophorectomy, and inguinal and pelvic lymphadenectomy. The muscular gap was repaired employing a gore-tex mesh while the external covering was made by a pedicled perforator fasciocutaneous anterolateral thigh flap. Final diagnosis was clear cell endometrial adenocarcinoma arising from endometriosis foci within the caesarean section scar. Pelvic and inguinal lymph nodes were metastatic. Tumor cells were positive for CK7 EMA, CKAE1/AE3, CD15, CA-125, while immunoreaction for Calretinin, WT1, estrogen, and progesterone receptors, cytokeratin 20, CD10, alpha fetoprotein, CDX2, TTF1, and thyroglobulin were all negative. Liver relapse occurred after 2 months; despite 3 cycles of pegylated liposomal doxorubicin (20 mg/m2, biweekly administration), the death of the patient disease occurred 1 month later. CONCLUSIONS: Attention should be focused on careful evaluation of patient history in terms of pelvic surgery, and symptoms suggestive of endometriosis such as repeated occurrence of endometriosis nodules at CS scar, or cyclic pain, or volume changes of the nodules.

Impact of secondary cytoreductive surgery on survival in patients with platinum sensitive recurrent ovarian cancer: analysis of the CALYPSO trial.

OBJECTIVE: The role of secondary cytoreductive surgery (SCR) in platinum-sensitive recurrent ovarian cancer (ROC) remains controversial. The overall survival (OS) benefits for surgery reported in observational studies may be due to the selection of patients with better prognosis. METHODS: Using data from the CALYPSO trial, OS of patients who had SCR was compared to those treated with chemotherapy alone. Multivariate analyses were performed to adjust for prognostic factors. We also tested for an interaction between baseline prognostic groupings and the benefit of surgery. RESULTS: Of the 975 patients randomised in CALYPSO, 19% had SCR and 80% had chemotherapy alone. OS was longer for the SCR group than for chemotherapy alone (median, 49.9 vs. 29.7 months; adjusted hazard ratio (HR), 0.68; P = 0.004). For patients with SCR, the 3-year OS was 72% for those with no measurable disease, and 28% if residual tumour was larger than 5 cm. Patients with good prognostic features benefited the most from SCR (HR 0.43; P < 0.001). The benefit of SCR was less in patients with poorer prognostic features (test of trend P < 0.001). CONCLUSION: SCR was associated with improved OS in platinum-sensitive ROC, particularly in patients with favourable prognostic characteristics. However, these findings may be due to selection bias, and hence randomised trials are still essential.

Prognostic role and predictors of complete pathologic response to neoadjuvant chemotherapy in primary unresectable ovarian cancer.

OBJECTIVE: The objective of the study was to analyze in a large series of unresectable advanced ovarian cancer (AOC) patients the prognostic role of pathological response to neoadjuvant chemotherapy (NACT). STUDY DESIGN: We retrospectively evaluated 322 unresectable AOC patients treated with NACT followed by interval debulking surgery (IDS). Pathological response was classified as follows: complete (cPR) in the absence of residual disease, microscopic (microPR) in the presence of microscopic tumor foci (maximum diameter ≤3 mm), and macroscopic (macroPR) when macroscopic residual disease was detected. RESULTS: cPR was observed in 21 (6.5%), microPR in 104 (32.3%), and macroPR in 197 (61.2%) patients. No differences were observed in the distribution of baseline clinicopathological characteristics between the groups. Median progression-free survival was 36 months in cPR, 16 in microPR, and 13 in macroPR (P = .001). Median overall survival was 72 months in cPR, 38 in microPR, and 29 in macroPR (P = .018). The survival differences between microPR and macroPR patients were not confirmed when the analysis included only cases resected to no gross residual disease at IDS. cPR retained the independent prognostic role in the multivariate analysis. International Federation of Gynecology and Obstetrics stage IV was the only negative independent predictor of cPR (χ(2) = 5.362, P = .021). CONCLUSION: cPR is an uncommon event in AOC patients receiving NACT and is associated with a longer progression-free survival and overall survival compared with women showing no cPR, even in patients receiving IDS with no gross residual disease. The proposed classification of pathological response may serve in the next future as an easily assessable and highly valuable prognostic tool in this clinical setting.

Focus on Trabectedin in Ovarian Cancer: What Do We Still Need to Know?

In the era of single and combination maintenance therapies as well as platinum and Poly (ADP-ribose) polymerase inhibitors (PARPi) resistance, the choice of subsequent treatments following first-line platinum-based chemotherapy in recurrent ovarian cancer (ROC) patients has become increasingly complex. Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. This paper offers valuable insights into the multifaceted role and mechanism of action of trabectedin in ROC. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.

Timing and pattern of recurrence in ovarian cancer patients with high tumor dissemination treated with primary debulking surgery versus neoadjuvant chemotherapy.

PURPOSE: To compare the timing and pattern of recurrence in patients with advanced ovarian cancer (AOC) receiving primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). METHODS: We retrospectively evaluated a consecutive series of 175 stage IIIC-IV epithelial ovarian cancer patients, with diffuse peritoneal carcinomatosis documented at initial surgical exploration. Forty patients received complete PDS, and the remaining 135 were treated with NACT followed by IDS with absent residual tumor after surgery. RESULTS: No differences were observed in the distribution of clinical pathological characteristics at the time of diagnosis between the two groups. The median follow-up was 31 months (range 9-150 months). We observed 20 (50.0%) recurrences in the PDS group compared to 103 (76.3%) in the IDS group (p = 0.001). Duration of primary platinum-free interval (PFI) was shorter in IDS compared to PDS group (13 vs. 21 months, respectively; p = 0.014). A significantly higher percentage of patients in the IDS group experienced platinum-resistant recurrences (35.9 vs. 5.0%; p = 0.006) and carcinomatosis at the time of relapse (57.3 vs. 20.0%; p = 0.0021). Finally, in women with platinum-sensitive recurrence, we observed a shorter secondary PFI in the IDS compared to PDS group (p = 0.006). CONCLUSIONS: We documented a better behavior of recurrent disease in AOC patients with diffuse peritoneal carcinomatosis treated with complete PDS compared to women submitted to NACT followed by IDS with no residual tumor after surgery.

An open-label phase 2 study of twice-weekly bortezomib and intermittent pegylated liposomal doxorubicin in patients with ovarian cancer failing platinum-containing regimens.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is an established treatment for relapsed ovarian cancer. Preclinical and clinical evidences in other tumor types suggest that the proteasome inhibitor bortezomib can act synergistically with PLD. METHODS: Patients with relapsed ovarian cancer (N = 58), previously treated with platinum (100%) and taxane (95%), received bortezomib, 1.3 mg/m intravenous (days 1, 4, 8, and 11), and PLD, 30 mg/m intravenous (day 1), every 3 weeks. Tumor responses were assessed using Response Evaluation Criteria In Solid Tumors and Gynecologic Cancer Intergroup criteria. An optimal 2-stage design was implemented. Gene expression profiling in peripheral blood was characterized before and during treatment in 10 platinum-sensitive patients enrolled in stage 2 of the study. RESULTS: Median number of bortezomib-PLD cycles was 3.5. Of 38 patients in the platinum-sensitive group, 9 responses were observed (median duration, 4.8 months). The platinum-resistant group was closed at stage 1 owing to lack of response. Toxicity was moderate and mainly consisted of hematologic, gastrointestinal, and mucositis events. Of the total 58 patients, peripheral neuropathy was reported in 9 patients (none were grade 3). Transcription profiling identified the prevalence of genes associated with ribonucleoprotein complexes, RNA processing, and protein translation. The gene expression changes were more robust in patients who responded or had stable disease compared with patients who had progressive disease. CONCLUSIONS: The combination of bortezomib and PLD was well tolerated, but the antitumor activity is insufficient to warrant further investigation in ovarian cancer.

Prognostic role of Ca125 response criteria and RECIST criteria: analysis of results from the MITO-3 phase III trial of gemcitabine versus pegylated liposomal doxorubicin in recurrent ovarian cancer.

OBJECTIVES: The aim of the study was to investigate i) the association between the Ca125 based and the RECIST assessed response in recurrent ovarian cancer patients enrolled in a Phase III randomized trial (MITO-3) comparing salvage treatment with pegylated liposomal doxorubicin (PLD) versus gemcitabine (GEM); ii) the correlation between the early modifications of Ca125 levels during treatment and the RECIST assessed response; iii) the prognostic value of response based on Ca125 and the RECIST criteria. METHODS: Assessment of response was performed by the RECIST and the GCIG criteria. The prognostic impact of the response by the RECIST criteria and the GCIG criteria was analyzed by the landmark method. RESULTS: Overall, of 30 cases defined as responders on the basis of the GCIG criteria, 20 resulted as responders according to the RECIST criteria (NPV=66.7%); conversely, 93.7% of the cases considered not responders based on the GCIG criteria were defined as unresponsive at RECIST evaluation. Early modifications of Ca125 levels were not completely predictive of the ultimate RECIST defined response. Overall survival (OS) was longer in RECIST defined responders versus non responders, although the statistical significance was not reached (p value=0.092); conversely, median OS was significantly longer in GCIG defined responders than in non responding patients (p value=0.0059). In multivariate analysis, the GCIG assessed response maintained its independent association with OS. CONCLUSIONS: GCIG criteria for tumor response could replace the conventional assessment of response in the decision making process relative to the discontinuation or prolongation of the salvage treatment in ovarian cancer.

ENGOT-ov-6/TRINOVA-2: Randomised, double-blind, phase 3 study of pegylated liposomal doxorubicin plus trebananib or placebo in women with recurrent partially platinum-sensitive or resistant ovarian cancer.

AIMS: Trebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomised, double-blind, placebo-controlled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer. METHODS: Women with recurrent ovarian cancer (platinum-free interval ≤12 months) were randomised to intravenous PLD 50 mg/m2 once every 4 weeks plus weekly intravenous trebananib 15 mg/kg or placebo. PFS was the primary end-point; key secondary end-points were objective response rate (ORR) and duration of response (DOR). Owing to PLD shortages, enrolment was paused for 13 months; the study was subsequently truncated. RESULTS: Two hundred twenty-three patients were enrolled. Median PFS was 7.6 months (95% CI, 7.2-9.0) in the trebananib arm and 7.2 months (95% CI, 4.8-8.2) in the placebo arm, with a hazard ratio of 0.92 (95% CI, 0.68-1.24). However, because the proportional hazards assumption was not fulfilled, the standard Cox model did not provide a reliable estimate of the hazard ratio. ORR in the trebananib arm was 46% versus 21% in the placebo arm (odds ratio, 3.43; 95% CI, 1.78-6.64). Median DOR was improved (trebananib, 7.4 months [95% CI, 5.7-7.6]; placebo, 3.9 months [95% CI, 2.3-6.5]). Adverse events with a greater incidence in the trebananib arm included localised oedema (61% versus 32%), ascites (29% versus 9%) and vomiting (45% versus 33%). CONCLUSIONS: Trebananib demonstrated anticancer activity in this phase 3 study, indicated by improved ORR and DOR. Median PFS was not improved. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01281254.

Randomized Controlled Trial Testing the Efficacy of Platinum-Free Interval Prolongation in Advanced Ovarian Cancer: The MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG Study.

Purpose Platinum-based chemotherapy (PBC) for patients with progressing ovarian cancer (OC) is more effective with a longer time interval from previous platinum treatment (platinum-free interval [PFI]). In 1999, it was hypothesized that prolonging PFI with single-agent non-PBC (NPBC) may offer a strategy to improve overall outcome. MITO-8 aimed to verify this hypothesis commonly used in clinical practice although it has not been prospectively tested. Methods MITO-8 is an open-label, prospective, randomized, superiority trial. Patients with OC who experienced disease progression 6 to 12 months after their last platinum treatment were randomly assigned 1:1 to the experimental sequence of NPBC followed by PBC at subsequent relapse or the standard reverse treatment sequence. Overall survival (OS) was the primary end point. Results Two hundred fifteen patients were enrolled (standard arm [n = 108]; experimental arm [n = 107]). The trial ended before planned because of slow enrollment. PFI was prolonged in the experimental arm (median, 7.8 v 0.01 months). There was no OS benefit in the experimental arm (median, 21.8 v 24.5 months; hazard ratio, 1.38; 95% CI, 0.99 to 1.94; P = .06). Progression-free survival after the sequence was significantly shorter in the experimental arm (median, 12.8 v 16.4 months; hazard ratio, 1.41; 95% CI, 1.04 to 1.92; P = .025). Global quality-of-life change after three cycles was worse in the experimental arm. Slight differences were observed in the incidence of adverse effects. Conclusion MITO-8 supports the recommendation that PBC not be delayed in favor of an NPBC in patients with partially platinum-sensitive OC. PBC should be used as a control arm in future trials of new drugs in this setting.

Safety of a 3-weekly schedule of carboplatin plus pegylated liposomal doxorubicin as first line chemotherapy in patients with ovarian cancer: preliminary results of the MITO-2 randomized trial.

BACKGROUND: The MITO-2 (Multicentre Italian Trials in Ovarian cancer) study is a randomized phase III trial comparing carboplatin plus paclitaxel to carboplatin plus pegylated liposomal doxorubicin in first-line chemotherapy of patients with ovarian cancer. Due to the paucity of published phase I data on the 3-weekly experimental schedule used, an early safety analysis was planned. METHODS: Patients with ovarian cancer (stage Ic-IV), aged < 75 years, ECOG performance status

Cost-effectiveness of gemcitabine versus PEGylated liposomal doxorubicin for recurrent or progressive ovarian cancer: comparing chemotherapy with nanotherapy.

This article examines the cost-effectiveness of chemotherapy (gemcitabine) versus nanotherapy (PEGylated liposomal doxorubicin) in the treatment of ovarian cancer. Significant differences in costs were mainly due to the initial drug costs, which were €1285.28 in favor of chemotherapy. These costs were more than offset by hospitalization costs, which were €2670.21 in favor of the nanotherapy. The cost per quality-adjusted life week (QALW) for the nanotherapy was estimated to be €220.92/QALW for the base case and ranged from €170-318/QALW based on model assumptions. The clinical benefit associated with nanotherapy was achieved, yielding not only positive cost-effectiveness results, but also, surprisingly, financial savings. Although more studies are necessary, this first comprehensive analysis supports the further use of nanotherapy for ovarian cancer.