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.

Real world data of niraparib in platinum sensitive relapsed ovarian cancer: A multicenter experience of the MITO group.

OBJECTIVE: PARP (poly adenosine diphosphate [ADP]-ribose polymerase) inhibitors are approved as maintenance therapy in platinum sensitive ovarian cancer (OC), in first line and in the recurrent setting, regardless of BRCA mutational status. Real-world data after the introduction of these agents are needed to evaluate whether the benefit observed in phase III randomized clinical trials can be translated into clinical practice. The aim of our study was to provide real-life data on efficacy and safety of niraparib administered as maintenance in platinum sensitive relapsed OC patients (PSROC). METHODS: This retrospective/prospective observational study included relapsed OC patients that received niraparib as maintenance, at the time of platinum sensitive recurrence within the Italian expanded-access program. Clinical data at the time of diagnosis and at the time of recurrence were collected and analyzed. Median progression free survival (PFS) and overall survival (OS) were calculated as the time from start of niraparib treatment to subsequent radiologically confirmed relapse and death or last contact, respectively. RESULTS: Among 304 eligible patients, 260 (85%) had BRCA wild-type tumor and 36. (11.9%) were BRCA mutated. Median PFS was 9.1 months (95% CI: 6.9-11.2) and 10.3 months (95% CI: 7.0-13.5) in the BRCAwt and BRCAmut cohorts, respectively. Furthermore, median OS was 41.7 months (95% CI: 31.6-41.9) and 34.6 months (95% CI: N.E.) in the BRCAwt and BRCAmut cohorts, respectively. CONCLUSION: Data from this large real-life dataset suggested that maintenance with niraparib in the real-life setting of platinum sensitive OC recurrence is effective and well tolerated.

Management of oligometastatic ovarian cancer recurrence during PARP inhibitor maintenance.

OBJECTIVE: The benefit of surgery and maintenance treatment with PARP inhibitors (PARPi) has been clearly demonstrated in ovarian cancer. Also, the efficacy and safety of stereotactic body radiotherapy has been shown in patients with metastatic, persistent, and recurrent disease. The aim of this study is to evaluate the management of oligometastatic progression during PARPi maintenance treatment. METHODS: This is an observational, retrospective, single-arm study conducted from June 2017 to December 2020 in patients with recurrent ovarian cancer with oligometastatic progression under PARPi maintenance treatment and receiving surgery or stereotactic body radiotherapy for such recurrence. PARPi treatment was continued until further progression of the disease. The primary objective of the study was the median prolongation of the treatment-free interval-p (without platinum) after local treatment. RESULTS: A total of 186 patients with ovarian cancer were treated with PARPi at recurrence. Of these, 30 (16%) developed oligometastatic progression. The median age was 49.5 years (range 35-73). Olaparib, niraparib and rucaparib were administered to 33%, 60%, and 7% of patients, respectively. The median prolongation of the treatment-free interval-p of patients treated with surgery or stereotactic body radiotherapy was 6 and 10 months, respectively (p=0.53). The median treatment-free interval-p of patients treated with surgery or stereotactic body radiotherapy at the time of oligometastatic progression was 32 and 29 months, respectively (p=0.44). At the time of this publication, 50% of patients are still on treatment with PARPi following progression. CONCLUSIONS: Patients with recurrent ovarian cancer who have oligometastic progression during PARPi maintenance may continue to benefit from PARPi if combined with local treatment.

Medical treatment of patients with gynecologic cancer during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic, cancer care had to be reorganized; national and international recommendations were published to manage anticancer treatments safely and to reduce the risk of SARS-CoV-2 infection for patients and health workers. OBJECTIVE: To evaluate whether the adoption of recommendations for the management of patients with gynaecologic cancer receiving treatment during the pandemic resulted in containment of infections and continuing oncologic care. METHODS: Based on the published recommendations, and according to the local Health Direction guidelines, we developed and drafted a security protocol to modify access of patients with gynaecologic cancer to the "Fondazione Policlinico Agostino Gemelli-IRCCS, Rome" between February 1 and April 30, 2020 and compared results with the corresponding 3 months of 2019. RESULTS: Between February and April 2019, we registered 3254 admissions, including 2253 patients receiving intravenous chemotherapies, 298 receiving oral therapies, and 703 having hospital visits. Between February and April 2020, we registered 3213 admissions, including 2221 patients receiving intravenous chemotherapies, 401 receiving oral therapies, and 591 having hospital visits. Oral treatments and general visits were different in the two time periods (p<0.001). Despite the elevated patient flow, only one patient (0.1%) tested positive for COVID-19 and there were no cases among healthcare staff. CONCLUSIONS: Based on the adopted security protocol we provided continuity of care for all patients and limited the spread of the COVID-19 infection.

Multicenter, randomised, open-label, non-comparative phase 2 trial on the efficacy and safety of the combination of bevacizumab and trabectedin with or without carboplatin in women with partially platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Trabectedin, in addition to its antiproliferative effect, can modify the tumour microenvironment and this could be synergistic with bevacizumab. The efficacy and safety of trabectedin and bevacizumab ± carboplatin have never been investigated. METHODS: In this phase 2 study, women progressing between 6 and 12 months since their last platinum-based therapy were randomised to Arm BT: bevacizumab, trabectedin every 21 days, or Arm BT+C: bevacizumab, trabectedin and carboplatin every 28 days, from cycles 1 to 6, then trabectedin and bevacizumab as in Arm BT. Primary endpoints were progression-free survival rate (PFS-6) and severe toxicity rate (ST-6) at 6 months, assuming a PFS-6 ≤35% for BT and ≤40% for BT+C as not of therapeutic interest and, for both arms, a ST-6 ≥ 30% as unacceptable. RESULTS: BT+C (21 patients) did not meet the safety criteria for the second stage (ST-6 45%; 95%CI: 23%-69%) but PFS-6 was 85% (95%CI: 62%-97%). BT (50 patients) had 75% PFS-6 (95%CI: 60%-87%) and 16% ST-6 (95%CI 7%-30%). CONCLUSIONS: BT compared favourably with other platinum- and non-platinum-based regimens. The combination with carboplatin needs to be assessed further in a re-modulated safer schedule to confirm its apparent strong activity. CLINICAL TRIAL REGISTRATION: NCT01735071 (Clinicaltrials.gov).

Pathologic response to neoadjuvant chemotherapy in advanced ovarian cancer: utility of a scoring system to predict outcomes.

BACKGROUND: Growing evidence supports the role of neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer. Currently, there is no shared histopathologic scoring system to assess pathologic response in the specimens obtained at interval surgery after neoadjuvant chemotherapy This review aims to summarize the literature on pathologic response, focusing on proposed scoring systems. METHODS: The systematic review was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, focusing on the definition of pathologic response, its prognostic value, possible predictors, and future implications. Eighteen manuscripts focusing on pathologic response in epithelial ovarian cancer were selected for analysis. RESULTS: Overall, eight histopathologic scoring systems to evaluate pathologic response have been proposed. There are currently no available markers (serum, radiological, genomic) to select which patients could achieve the highest benefit from neoadjuvant chemotherapy experiencing a complete pathologic response. A three-tier scoring system (CRS) based on omental assessment and which classifies the response to neoadjuvant chemotherapy has been validated in external cohorts of epithelial ovarian cancer. This scoring system demonstrated adequate interobserver reproducibility. Data is limited on the pathologic complete response rate changes according to chemotherapy regimen. CONCLUSIONS: A histopathologic scoring system endowed with prognostic value could be helpful in personalizing the treatment decision in patients with epithelial ovarian cancer.

New medical approaches in advanced ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. Most women with advanced epithelial ovarian cancer will experience many episodes of recurrent disease with progressively shorter disease-free intervals. For women whose disease continues to respond to platinum-based drugs, the disease can often be controlled for 5 years or more. Enormous progress has been made in the management of this disease, and new targeted treatments such as antiangiogenic drugs, poly(adenosine diphosphate-ribose) polymerase inhibitors, and immune checkpoint inhibitors offer potential for improved survival. A variety of combination strategies are being evaluated to leverage these agents. The objective of this review is to summarize results from clinical trials that tested cytotoxic drugs and target strategies for the treatment of ovarian cancer with particular attention to Phase III and ongoing trials.

Dose-dense paclitaxel/carboplatin as neo-adjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer: a prospective phase II study.

PURPOSE: The role of dose-dense schedules in the neo-adjuvant treatment (NACT) of locally advanced cervical cancer (LACC) has been reported. This phase II study investigated activity of dose-dense paclitaxel/platinum before radical surgery (RS) in LACC patients. METHODS: The primary end-point was the rate of optimal pathological response (OPR: pathological complete/microscopic response). NACT (paclitaxel: 80 mg/m2) and carboplatin (AUC 2) were administered for 6 weeks. Overall response rate (ORR) to NACT was assessed by the RECIST criteria. Patients amenable to surgery were triaged to RS. The null hypothesis was that the OPR rate would improve from 30.0 to 45.0% (α error: 0.05, ß error: 0.2). The regimen would be considered active if > 25 OPRs were found. RESULTS: 36 patients were enrolled; 19 patients were stage IIB (52.8%) and 16 (44.4%) patients had pelvic lymph-node involvement at imaging. All patients completed neo-adjuvant chemotherapy; ORR was of 75.0%. RS was performed in 29 (93.5%) patients. Since the OPR was 16.1%, we evaluated the real chances to achieve the number of OPR required by the Simon design and decided to close the study. Grade 3/4 hematological toxicity occurred in 5 patients; surgical morbidity occurred in 14 patients. The 2-year PFS rate was 69.0%. CONCLUSION: Dose-dense neo-adjuvant paclitaxel/carboplatin is feasible and safe in LACC patients; however, failure to achieve the primary end-point has to be recognized. Given the heterogeneity of the available studies, robust data from an adequately sized prospective study focused on more homogeneous series are required.

Neo-adjuvant platinum-based chemotherapy followed by chemoradiation and radical surgery in locally advanced cervical cancer (Lacc) patients: A phase II study.

PURPOSE: The aim of this Phase II, non-randomized study was to assess activity and safety of neoadjuvant chemotherapy (NACT) before chemoradiation (CT/RT) followed by radical surgery (RS) in locally advanced cervical cancer (LACC) patients. METHODS AND MATERIALS: The primary end point was rate of pathologic complete response (pCR). FIGO Stage IB2-IVA patients were administered NACT chemotherapy (paclitaxel 80 mg/m2, carboplatin AUC 2), for 6 weeks, followed by Intensity Modulated Radiotherapy plus simultaneous boost (total dose of 50.4 Gy to CTV1, and 39.6 Gy to CTV2). Clinical response was assessed according to RECIST criteria. Responsive patients were triaged to RS. The regimen would be considered active if >20 pCRs were registered in 39 patients. RESULTS: 45 patients were enrolled into the study; 25 patients (55.5%) were FIGO stage IIB, 9 cases (20.0%) had stage III disease. At work up, pelvic lymph node involvement was documented in 38 (84.4%) patients; pCR was documented in 18 out of 40 patients (45.0%). Grade 3-4 hematological toxicity after NACT occurred in 4 patients; CT/RT associated grade 3 toxicity was found in 7 patients. Early and late postoperative complications were detected in 16, and 11 cases, respectively. Three-year PFS and OS were 66.0% and 86.0%, respectively. CONCLUSIONS: NACT followed by CT/RT by IMRT and RS, is feasible and safe; failure to achieve the primary endpoint has to be recognized; however, enrollment of a higher rate of poor prognosis patients compared to historical data used to calculate sample size, could have resulted in reduced activity.

Optimizing treatment in recurrent epithelial ovarian cancer.

INTRODUCTION: Optimal management of recurrent ovarian cancer (ROC) remains an area of uncertainty. An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease and median survival for these patients' ranges from 12 months to 24 months. Many patients receive several lines of treatment following recurrence and, although each subsequent line of therapy is characterized by shorter disease-free intervals, decisions about the most appropriate treatment is complex. Areas covered: This review focuses on chemotherapy, surgery and emerging biologic agents that present a therapeutic option for patients with ROC. Expert commentary: Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrence treated with a platinum-based agent. For patients whose cancer progresses after platinum retreatment and for those with platinum-resistant disease, numerous other non-platinum combination and targeted therapies have been shown to be effective in palliating cancer-related symptoms and extending life.

Early detection of recurrence or progression disease in patients with ovarian cancer after primary debulking surgery. Correlation between CT findings and CA 125 levels.

BACKGROUND: There are no standard approaches for follow up in advanced ovarian cancer (AOC) patients; the aim of this study is to evaluate correlation between computed tomography (CT) and CA 125 levels to assess early detection of recurrence or progression disease (PD). METHODS: We included 76 patients with AOC, who had prior debulking surgery, starting first or second line of chemotherapy and underwent follow-up CT examinations. Evaluation of tumor response to treatment by imaging was assessed using RECIST 1.1. Site of relapse was classified as: abdomen, chest and neck (observed in the upper chest scans). RESULTS: Change in CA 125 levels was calculated in respect previous evaluation at the end of treatment for each patient. The most suitable cut-offs could be identified in an increase in CA 125 levels >10.5% (sensitivity: 67.9%; specificity: 83.6%; LR+: 4.1; LR-: 0.4) in order to predict PD and in a change of -0.5% in order to exclude PD (sensitivity 83.0%; specificity: 69.6%; LR+: 2.7; LR-: 0.2). Site of relapse was abdomen (58.5%), abdomen and chest (33.9%), chest (3.8%), chest and neck (1.9%), and abdomen, chest and neck (1.9%). CONCLUSIONS: Increase in CA 125 levels >10.5% could be sufficiently predictive of PD requiring CT examination. Change of -0.5% is sufficiently predictive of absence of PD. Increase <10.5% and >0.5% needs clinical correlation to establish correct timing and extension of CT examination. Attention must be played in reducing number and extent of CT examinations to reduce exposure dose.

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.

Modulation of GemOx chemotherapy according to CIRS in elderly patients with advanced pancreatic cancer.

The present study evaluated activity and toxicity of modulated doses of gemcitabine associated to oxaliplatin in patients with secondary CIRS and with locally advanced pancreatic adenocarcinoma (LAPC) and metastatic pancreatic adenocarcinoma (MPC). Since January 2006, untreated LAPC and MPC patients have been assessed with ADL, IADL, CIRS to modulate chemotherapy dosages according to co-morbidity stage. Patiens aged<75 years, co-morbidity stage primary/intermediate, or ≥75 years and co-morbidity stage primary, received gemcitabine 1,000 mg/m² as a 10 mg/m²/min infusion on day 1 and oxaliplatin 70 mg/m² as a 2-h infusion on day 2 every 2 weeks. Patiens aged<75 years, co-morbidity stage secondary or ≥75 years and co-morbidity stage intermediate/secondary patients received gemcitabine 800 mg/m². Primary endpoint was the overall response rate (ORR). Secondary endpoints were disease control rate (DCR), PFS, OS and toxicity. Thirty-one patients were recruited: 26% (8/31) LAPC and 74% (23/31) MPC; median age 69 years. Co-morbidity stage primary/intermediate, 19; secondary, 12. Twenty-seven valuable patients: ORR 30% (CI±0.14); disease control rate 85% (CI±0.18). Median follow-up 13 months: median PFS and OS were 6 and 15 months, respectively. Valuable cycles 140. Grade 3/4 toxicity per patient: leukopenia, 18.5%; neutropenia, 55,5%; thrombocytopenia, 7.4%; SGOT/SGPT, 7.4%; gamma-GT, 7.4%; fever without neutropenia, 3.7%. Median received dose intensity: gemcitabine 400 mg/m2/w; oxaliplatin 35 mg/m2/w. Modulation of GemOx chemotherapy according, to CIRS stage in advanced pancreatic cancer confirms reported efficacy and tolerability.