Can integrative biomarker approaches improve prediction of platinum and PARP inhibitor response in ovarian cancer?

Epithelial ovarian carcinoma (EOC) encompasses distinct histological, molecular and genomic entities that determine intrinsic sensitivity to platinum-based chemotherapy. Current management of each subtype is determined by factors including tumour grade and stage, but only a small number of biomarkers can predict treatment response. The recent incorporation of PARP inhibitors into routine clinical practice has underscored the need to personalise ovarian cancer treatment based on tumour biology. In this article, we review the strengths and limitations of predictive biomarkers in current clinical practice and highlight integrative strategies that may inform the development of future personalised medicine programs and composite biomarkers.

Thromboembolic events and antithrombotic prophylaxis in advanced ovarian cancer patients treated with bevacizumab: secondary analysis of the phase IV MITO-16A/MaNGO-OV2A trial.

INTRODUCTION: The use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian cancer patients. We report on the incidence of thromboembolic events and the prevalence of antithrombotic therapy in patients enrolled in the single arm, phase IV, MITO-16A/MaNGO-OV2A trial. METHODS: In this trial, potential prognostic factors for patients with previously untreated ovarian cancer receiving a combination of platinum-based chemotherapy and bevacizumab were explored and the final analysis has already been reported. In this secondary analysis, the occurrence of thromboembolic events and the use of antithrombotic therapy were described according to the clinical characteristics of the patients. The prognostic role of thromboembolic events for progression-free and overall survival were also evaluated. RESULTS: From October 2012 to November 2014, 398 eligible patients were enrolled. 76 patients (19.1%) were receiving some type of anticoagulant or anti-aggregant treatment at baseline. Overall, 24 thromboembolic events were reported (cumulative incidence of 6.0%). The occurrence of thromboembolic events was not associated with baseline patient characteristics and was not modified by the use of antithrombotic prophylaxis (HR 0.60, 95% CI 0.18 to 2.0). Occurrence of thromboembolic events was not associated with progression-free survival (HR 1.34, 95% CI 0.83 to 2.15) or overall survival (HR 0.78, 95% CI 0.37 to 1.61). CONCLUSIONS: In our study, a 6.0% rate of thromboembolic events was reported during treatment with bevacizumab plus chemotherapy. Thromboembolic events were not associated with the clinical characteristics of the patients or with the use of antithrombotic prophylaxis, nor did they significantly affect the long-term prognosis. TRIAL REGISTRATION NUMBER: NCT01706120.

Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors as maintenance therapy in women with newly diagnosed ovarian cancer: a systematic review and meta-analysis.

PURPOSE: To investigate the efficacy and safety of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (including their different types) as maintenance therapy in women with newly diagnosed ovarian cancer, and to explore whether this therapy produces a survival benefit in a subgroup population with specific clinical characteristics. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library, Web of Science and relevant clinical research registry platforms on October 1, 2019, and included randomized controlled trials (RCTs) that compared PARP inhibitors with placebo in women (aged ≥ 18 years) with newly diagnosed epithelial ovarian cancer. RESULTS: We identified four RCTs with 3,070 participants. Compared with placebo, PARP inhibitor maintenance therapy showed a clinically significant benefit on progression free survival (PFS) in homologous recombination deficiency (HRD) positive population (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.29-0.53). In contrast, no clear differences were identified between the groups in the HRD negative population (HR, 0.83; 95% CI 0.67-1.03). Further, there was no clear difference between the groups in terms of other outcomes (overall survival, health-related quality of life, and adverse events). CONCLUSIONS: PARP inhibitor maintenance therapy significantly prolongs the PFS of patients with newly diagnosed ovarian cancer, especially in HRD positive patients. The diagnostic test used to determine HRD status plays an important role in guiding PARP inhibitor maintenance therapy. Compared with placebo, the effect of PARP inhibitors on ovarian cancer was probably not affected by the International Federation of Gynecology and Obstetrics stage status, response to first-line chemotherapy, and residual macroscopic disease after debulking surgery.

Management of nausea and vomiting from poly(ADP-ribose) polymerase inhibitor therapy for advanced ovarian cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors have rapidly emerged as a new class of daily oral chemotherapeutic agents that have the potential to dramatically alter the way in which primary peritoneal, fallopian tube and ovarian cancers are treated. However, the management of nausea and vomiting, the most common toxicities incurred by these agents, remains poorly understood. The purpose of this review is to provide an overview of current guidelines, antiemetic agents and management steps for patients experiencing nausea and vomiting associated with the use of PARP inhibitors.

A multimodality triage algorithm to improve cytoreductive outcomes in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center team ovary initiative.

OBJECTIVE: To describe outcomes using a multimodal algorithm to triage patients with advanced epithelial ovarian cancer (EOC) to primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT). METHODS: All patients with EOC treated at our institution from 04/2015-08/2018 were identified. We included patients without contraindication to PDS who underwent prospective calculation of a Resectability (R)-score. A low risk score for suboptimal cytoreduction was defined as ≤6, and a high risk score ≥7. Patients were triaged to laparotomy/PDS, laparoscopic evaluation of resectability (LSC), or NACT depending on R-score. RESULTS: Among 299 participants, 226 (76%) had a low risk score and 73 (24%) a high risk score. For patients with a low risk score, management included laparotomy/PDS, 181 (80%); LSC, 43 (19%) (with subsequent triage: PDS, 31; NACT, 12); and NACT, 2 (1%). For patients with a high risk score, management included laparotomy/PDS, 9 (12%); LSC, 51 (70%) (with subsequent triage: PDS, 28; NACT, 23); and NACT, 13 (18%). Overall, 83% underwent PDS, with a 75% CGR rate and 94% optimal cytoreduction rate. Use of the algorithm resulted in a 31% LSC rate and a 6% rate of suboptimal PDS. CONCLUSIONS: The multimodal algorithm led to excellent surgical results; 94% of patients achieved an optimal resection, with a very low rate of suboptimal cytoreduction.

Front-line chemo-immunotherapy with carboplatin-paclitaxel using oregovomab indirect immunization in advanced ovarian cancer: A randomized phase II study.

BACKGROUND: This randomized phase II study tested the hypothesis that schedule dependent chemo-immunotherapy with oregovomab improves progression free survival (PFS) and overall survival (OS) in optimally resected, Stage III/IV ovarian cancer. METHODS: Patients from both academic centers and private practice in the US and Italy with Stage III/IV optimally cytoreduced ovarian cancer were randomized to standard six cycle IV carboplatin-paclitaxel chemotherapy (CP) versus CP plus four immunizations with oregovomab (CPO). A translational assessment of a cellular immune response was the primary endpoint; PFS and OS were measured as secondary endpoints. FINDINGS: 97 patients at thirteen centers were accrued to the protocol, 47 to CPO and 50 to CP. Technical issues led to inconsistent performance of the primary CA125 ELISPOT leading to unevaluable results. At a median follow up of 42 months, PFS and OS outcomes revealed an unexpectedly large treatment effect for CPO relative to CP alone, with median PFS of 41.8 months (95% C.I.: 21.8 - N.E.) for CPO and 12.2 months (10.4-18.6) for CP (p = 0.0027, HR 0.46, CI 0.28-0.7). For OS, the median for CPO has not yet been reached (NE) (45.2-NE) and for CP was 43.2 months (31.8-NE) (p = 0.043, HR 0.35, CI 0.16-0.74). The oregovomab treatment resulted in no change in toxicity profile from CP. INTERPRETATION: The previously identified potential clinical benefit of IV CP when administered with oregovomab was further refined in this randomized phase II study. Increases of PFS and OS of statistically and clinically significant magnitude were evident in this study of a front line chemo-immunotherapy treatment of ovarian cancer.

Efficacy and safety results from GEICO 1205, a randomized phase II trial of neoadjuvant chemotherapy with or without bevacizumab for advanced epithelial ovarian cancer.

BACKGROUND: Bevacizumab is an approved treatment after primary debulking surgery for ovarian cancer. However, there is limited information on bevacizumab added to neoadjuvant chemotherapy before interval debulking surgery. OBJECTIVE: To evaluate neoadjuvant bevacizumab in a randomized phase II trial. METHODS: Patients with newly diagnosed stage III/IV high-grade serous/endometrioid ovarian cancer were randomized to receive four cycles of neoadjuvant chemotherapy with or without ≥3 cycles of bevacizumab 15 mg/kg every 3 weeks. After interval debulking surgery, all patients received post-operative chemotherapy (three cycles) and bevacizumab for 15 months. The primary end point was complete macroscopic response rate at interval debulking surgery. RESULTS: Of 68 patients randomized, 64 completed four neoadjuvant cycles; 22 of 33 (67%) in the chemotherapy-alone arm and 31 of 35 (89%) in the bevacizumab arm (p=0.029) underwent surgery. The complete macroscopic response rate did not differ between treatment arms in either the intention-to-treat population of 68 patients (6.1% vs 5.7%, respectively; p=0.25) or the 55 patients who underwent surgery (8.3% vs 6.5%; p=1.00). There was no difference in complete cytoreduction rate or progression-free survival between the treatment arms. During neoadjuvant therapy, grade ≥3 adverse events were more common with chemotherapy alone than with bevacizumab (61% vs 29%, respectively; p=0.008). Intestinal (sub)occlusion, fatigue/asthenia, abdominal infection, and thrombocytopenia were less frequent with bevacizumab. The incidence of grade ≥3 adverse events was 9% in the control arm versus 16% in the experimental arm in the month after surgery. CONCLUSIONS: Adding three to four pre-operative cycles of bevacizumab to neoadjuvant chemotherapy for unresectable disease did not improve the complete macroscopic response rate or surgical outcome, but improved surgical operability without increasing toxicity. These results support the early integration of bevacizumab in carefully selected high-risk patients requiring neoadjuvant chemotherapy for initially unresectable ovarian cancer.

Economic Analysis of Neoadjuvant Chemotherapy Versus Primary Debulking Surgery for Advanced Epithelial Ovarian Cancer Using an Aggressive Surgical Paradigm.

OBJECTIVES: Neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) for advanced epithelial ovarian cancer (AEOC) remains controversial in the United States. Generalizability of existing trial results has been criticized because of less aggressive debulking procedures than commonly used in the United States. As a result, economic evaluations using input data from these trials may not accurately reflect costs and outcomes associated with more aggressive primary surgery. Using data from an ongoing trial performing aggressive debulking, we investigated the cost-effectiveness and cost-utility of NACT versus PDS for AEOC. METHODS: A decision tree model was constructed to estimate differences in short-term outcomes and costs for a hypothetical cohort of 15,000 AEOC patients (US annual incidence of AEOC) treated with NACT versus PDS over a 1-year time horizon from a Medicare payer perspective. Outcomes included costs per cancer-related death averted, life-years and quality-adjusted life-years (QALYs) gained. Base-case probabilities, costs, and utilities were based on the Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasms trial. Base-case analyses assumed equivalent survival; threshold analysis estimated the maximum survival difference that would result in NACT being cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds. Probabilistic sensitivity analysis was used to characterize model uncertainty. RESULTS: Compared with PDS, NACT was associated with $142 million in cost savings, 1098 fewer cancer-related deaths, and 1355 life-years and 1715 QALYs gained, making it the dominant treatment strategy for all outcomes. In sensitivity analysis, NACT remained dominant in 99.3% of simulations. Neoadjuvant chemotherapy remained cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds if survival differences were less than 2.7 and 1.4 months, respectively. CONCLUSIONS: In the short term, NACT is cost-saving with improved outcomes. However, if PDS provides a longer-term survival advantage, it may be cost-effective. Research is needed on the role of patient preferences in tradeoffs between survival and quality of life.

Maveropepimut-S, a DPX-Based Immune-Educating Therapy, Shows Promising and Durable Clinical Benefit in Patients with Recurrent Ovarian Cancer, a Phase II Trial.

PURPOSE: Patients with platinum-resistant ovarian cancer respond poorly to existing therapies. Hence there is a need for more effective treatments. PATIENTS AND METHODS: The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase II study to evaluate the safety and effectiveness of maveropepimut-S with cyclophosphamide in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL maveropepimut-S 3 weeks apart, followed by one 0.1-mL doses, every 8 weeks up to progression. Oral cyclophosphamide, 50 mg twice daily, was administered in repeating weekly on and off cycles. RESULTS: Twenty-two patients were enrolled. Median age was 58 years (38-78 years). Among the evaluable population, the objective response rate (ORR) was 21% [90% confidence interval (CI), 7.5%-41.9%], with a disease control rate (DCR) of 63% (90% CI, 41.8%-81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four SD patients maintained clinical benefit up to 25 months. Most treatment-related adverse events (TRAE) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T-cell responses were observed in treated patients with clinical benefit. CONCLUSIONS: Maveropepimut-S with intermittent low-dose cyclophosphamide is well-tolerated, with clinical benefit for patients with recurrent ovarian cancer. Observed responses are irrespective of the platinum status.

Weakly supervised deep learning for prediction of treatment effectiveness on ovarian cancer from histopathology images.

Despite the progress made during the last two decades in the surgery and chemotherapy of ovarian cancer, more than 70 % of advanced patients are with recurrent cancer and decease. Surgical debulking of tumors following chemotherapy is the conventional treatment for advanced carcinoma, but patients with such treatment remain at great risk for recurrence and developing drug resistance, and only about 30 % of the women affected will be cured. Bevacizumab is a humanized monoclonal antibody, which blocks VEGF signaling in cancer, inhibits angiogenesis and causes tumor shrinkage, and has been recently approved by FDA as a monotherapy for advanced ovarian cancer in combination with chemotherapy. Considering the cost, potential toxicity, and finding that only a portion of patients will benefit from these drugs, the identification of new predictive method for the treatment of ovarian cancer remains an urgent unmet medical need. In this study, we develop weakly supervised deep learning approaches to accurately predict therapeutic effect for bevacizumab of ovarian cancer patients from histopathological hematoxylin and eosin stained whole slide images, without any pathologist-provided locally annotated regions. To the authors' best knowledge, this is the first model demonstrated to be effective for prediction of the therapeutic effect of patients with epithelial ovarian cancer to bevacizumab. Quantitative evaluation of a whole section dataset shows that the proposed method achieves high accuracy, 0.882 ± 0.06; precision, 0.921 ± 0.04, recall, 0.912 ± 0.03; F-measure, 0.917 ± 0.07 using 5-fold cross validation and outperforms two state-of-the art deep learning approaches Coudray et al. (2018), Campanella et al. (2019). For an independent TMA testing set, the three proposed methods obtain promising results with high recall (sensitivity) 0.946, 0.893 and 0.964, respectively. The results suggest that the proposed method could be useful for guiding treatment by assisting in filtering out patients without positive therapeutic response to suffer from further treatments while keeping patients with positive response in the treatment process. Furthermore, according to the statistical analysis of the Cox Proportional Hazards Model, patients who were predicted to be invalid by the proposed model had a very high risk of cancer recurrence (hazard ratio = 13.727) than patients predicted to be effective with statistical signifcance (p < 0.05).

The role of the tumor primary chemosensitivity relative to the success of the medical-surgical management in patients with advanced ovarian carcinomas.

In patients with advanced ovarian carcinomas, the first-line treatment has historically relied on debulking surgery and platinum-based chemotherapy. If the major therapeutic/prognostic role of the surgery part is well understood, and integrated in disease-management algorithms, the impact of chemotherapy efficacy has been insufficiently addressed. This review describes the main indicators of the chemosensitivity reported in the literature (pathological response score & biomarkers; genomic alterations; DNA scars; imaging; and circulating tumor markers), and investigates the respective roles of the debulking surgery and tumor primary chemosensitivity relative to the success of the comprehensive medical-surgical treatment. The tumor primary chemosensitivity exhibits a major independent prognostic impact on the feasibility of complete interval debulking surgery after neoadjuvant chemotherapy, risk of subsequent platinum-resistant relapse, efficacy of subsequent maintenance therapies with bevacizumab or PARP inhibitors, progression-free survival, overall and long-term survival. While both the completeness of the surgery and the tumor primary chemosensitivity are undoubtedly major prognostic factors, the impact of the surgery may differ according to the primary chemosensitivity. This assumption raises a potential new concept: in patients with advanced ovarian carcinomas, the maximum tumor debulking should ideally be both biological (induced by systemic treatments) and physical (induced by surgery) for maximizing patient survival. Besides BRCA and HRD biomarkers, future trials and algorithms may integrate indicator(s) of the tumor primary chemosensitivity for guiding more subtly the surgical and medical management in first-line setting. Moreover, such a parameter would help in the development of novel approaches meant to reverse the resistance to chemotherapy and PARP inhibitors.

The prophylactic effects of long-acting granulocyte colony-stimulating factor for febrile neutropenia in newly diagnosed patients with epithelial ovarian cancer: a randomised controlled study.

OBJECTIVE: This study explored the prophylactic effects of long-acting granulocyte colony-stimulating factor (G-CSF) for febrile neutropenia (FN) in newly diagnosed patients with epithelial ovarian cancer (EOC). METHODS: Patients were randomised into a study group (long-acting G-CSF for all chemotherapy cycles) and a control group (short-acting G-CSF for first cycle and treatment per physician discretion for subsequent cycles) at a ratio of 1:2. The incidences of FN and myelosuppression and the number of clinical visits, medication doses, complete blood count (CBC) tests and adverse events were compared between the two groups. A regression model was used to determine the risk factors for FN. RESULTS: From 30 November 2018 to 1 April 2019, 84 cases were included in the final analysis; there were 24 (28.6%) and 60 (71.4%) patients in the study and control groups, respectively, and 605 chemotherapy cycles. The study group or chemotherapy cycles utilising long-acting G-CSF had significantly fewer utilisations and doses of short-acting G-CSF; clinical visits; CBC tests; and incidences of FN and myelosuppression; and less G-CSF-associated pain. The utilisation of G-CSF was the only independent factor for FN in a binary regression model. CONCLUSION: Long-acting G-CSF could effectively reduce the incidences of FN and myelosuppression and had mild adverse effects in newly diagnosed patients with EOC receiving chemotherapy. TRIAL REGISTRATION NUMBER: NCT03740464.

Long-term multidisciplinary integrative therapy management resulted in favorable outcomes for ovarian cancer during pregnancy: a case report and literature review.

BACKGROUND: Ovarian cancer during pregnancy is relatively rare and treatment strategies are inexperienced in surgery and chemotherapy. Multidisciplinary management of advanced epithelial ovarian cancer in pregnant patients with strong desire of fertility including sufficient mental and medical understanding, perioperative consideration, intraoperative decision, chemotherapy sensitivity and follow-up after treatment can gain successful outcomes for both maternal disease and fetus's development. CASE PRESENTATION: A 34-year-old primigravidae was diagnosed with advanced epithelial ovarian tumor and then first cytoreductive surgery to resect macroscopical lesions and protect the uterus for fetus was performed following with four chemotherapy courses (docetaxel and carboplatin) before delivery and four other chemotherapy courses after delivery. Chemotherapy drugs were decided by sensitivity test and the patient's anaphylaxis. Second surgery involved cesarean section with a healthy offspring and secondary cytoreductive surgery. Operative strategies were considered to gain a balance of disease and risk for fetus. Psychosocial support was provided during the course of diagnosis and treatment for a healthy coping situation. This patient relapsed 19 months after the last chemotherapy course and was treated by additional adjuvant therapy to a clinical remission. The 33-month baby boy has no evidence with disease until now. The follow-up of both mother and baby is still continuing. CONCLUSIONS: Ovarian cancer during pregnancy has low incidence which must increase in future as women delay reproduction age. Ovarian cancer cytoreductive surgery and chemotherapy have limitation to handle conditions under a desire of fetus protection. Multidisciplinary treatment model is a therapeutic solution and a challenge for gynecological surgeons, medical oncologists, pathologists, obstetricians, neonatologists, pharmacists, anesthetist, and psychologists.

Clinical Value of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Response Evaluation after Primary Treatment of Advanced Epithelial Ovarian Cancer.

AIMS: To prospectively evaluate the use of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in the definition of the treatment response after primary treatment of advanced epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Forty-nine patients with advanced EOC had an 18F-FDG PET/CT scan before and after primary treatment. The treatment response was defined with the currently used radiological and serological Response Criteria in Solid Tumors (RECIST1.1/GCIC) criteria and the modified PET Response Criteria in Solid Tumors (PERCIST). The concordance of the two methods was analysed. If the patient had a complete response to primary treatment by conventional criteria, the end of treatment 18F-FDG PET/CT scan (etPET/CT) was not opened until retrospectively at the time of disease progression. The ability of etPET/CT to predict the time to disease recurrence was analysed. The recurrence patterns were observed with an 18F-FDG PET/CT at the first relapse. RESULTS: The agreement of the RECIST1.1/GCIC and modified PERCIST criteria in defining the primary treatment response in the whole patient cohort was good (weighted kappa coefficient = 0.78). Of the complete responders (n = 28), 34% had metabolically active lesions present in the etPET/CT, most typically in the lymph nodes. The same anatomical sites tended to activate at disease relapse, but were seldom the only site of relapse. In patients with widespread intra-abdominal carsinosis at diagnosis, the definition of metabolic response was challenging due to problems in distinguishing the physiological FDG accumulation in the bowel loops from the residual tumour in the same area. The presence of metabolically active lesions in the etPET/CT did not predict earlier disease relapse in the complete responders. CONCLUSIONS: In the present study, etPET/CT revealed metabolically active lesions in complete responders after EOC primary therapy, but they were insignificant for the patient's prognosis. The current study does not favour routine use of 18F-FDG PET/CT after EOC primary treatment for complete responders.

Guía de práctica de clínica de cáncer de ovario epitelial / Epithelial Ovarian Cancer Clinic Practice Guide

Generar recomendaciones basadas en la mejor evidencia disponible acerca del manejo de personas con cáncer de ovario.