Article

Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials

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Abstract

Background: Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations. Methods: We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic. Findings: Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0-9·6; EORTC, 9·2 years [IQR 7·3-10·4]; CHORUS, 5·9 years [IQR 4·3-7·4]). Median age was 63 years (IQR 56-71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8-13·0). 55 (5%) women had FIGO stage II-IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1-51·3] and 26·9 months [12·7-50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86-1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7-53·7) and 23·6 months (10·5-46·9), respectively (HR 1·20, 95% CI 1·06-1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1-47·6] and 21·2 months [10·0-36·4], respectively; HR 0·76, 95% CI 0·58-1·00; p=0·048; median progression-free survival 10·6 months [7·9-15·0] and 9·7 months [5·2-13·2], respectively; HR 0·77, 95% CI 0·59-1·00; p=0·049). Interpretation: Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC-IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status. Funding: National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer).

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... Population-based evidence 2 clearly shows survival benefit from the combination of surgery and chemotherapy; however, there remains a significant proportion of women that endure the enormous burden of radical surgery and chemotherapy only to relapse or die within 12 months. 3,4 Surgery and platinum-based chemotherapy are the standard of care in the UK, 5 but substantial variation in practice exists in the use of both. 6,7 Between 2013 and 2015 the proportions of women receiving surgery for stage III and IV EOC were 66.3% and 36.4%, ...
... Debate remains on the relative benefits. 4,[15][16][17] However, it has been established that intraoperative and postoperative complications are lower in patients undergoing DDS. 15 Two randomised controlled trials 15,18 have demonstrated non-inferiority of DDS after neoadjuvant chemotherapy; hence, neither approach is superior with regard to prognosis. Research is ongoing to determine if survival differs between PDS and DDS when strictly limited to centres that offer radical surgery. ...
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Plain language summary Biomarkers may offer unforeseen insights into clinical diagnosis, as well as the likely course and outcome of a condition. In this paper, the focus is on the use of biological molecules found in body fluids or tissues for diagnosis and prediction of outcome in ovarian cancer patients. In cancer care, biomarkers are being used to develop personalised treatment plans for patients based on the unique characteristics of their tumour. This tailoring of care can be used to pursue specific targets identified by biomarkers, or treat the patient according to specific tumour characteristics. Surgery is one of the core treatments for ovarian cancer, whether it is offered in primary surgery or following chemotherapy in delayed surgery. Biomarkers already exist to guide the treatment of tumours with chemotherapy, but very little research has determined the value of biomarkers in tailoring surgical care for ovarian cancer. Such research is required to identify new biomarkers and assess their effectiveness in a clinical setting as well as to help identify specific tumour types to guide surgery. Biomarkers could help to determine the success of removing the disease surgically, or help to identify tumour deposits that persist after chemotherapy. All of these aspects would improve current practice. This Scientific Impact Paper highlights research that may pave the way towards bespoke surgery according to the biological characteristics of a tumour and aid gynaecological oncologists to provide surgical treatment according to individual need, rather than a blanket approach for all.
... EORTC 55971 and CHORUS were then combined and analyzed together in a metaanalysis. The aim of this analysis was to show non-inferiority in OS with NACT compared with PDS [97]. Data for 1220 women were included, the majority of which had stage IIIC (86%) or IV (19%) disease. ...
... This analysis concluded that NACT is non-inferior to PDS in stage IIIC-IV ovarian, fallopian tube, or primary peritoneal cancer with long term follow up and there may be a survival benefit of NACT over PDS in patients with stage IV disease. NACT was concluded to be a reasonable alternative for patients with advanced stage ovarian cancer, especially those with high tumor burden or poor preoperative performance status [97]. ...
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Primary debulking surgery (PDS) has remained the only treatment of ovarian cancer with survival advantage since its development in the 1970s. However, survival advantage is only observed in patients who are optimally resected. Neoadjuvant chemotherapy (NACT) has emerged as an alternative for patients in whom optimal resection is unlikely and/or patients with comorbidities at high risk for perioperative complications. The purpose of this review is to summarize the evidence to date for PDS and NACT in the treatment of stage III/IV ovarian carcinoma. We systematically searched the PubMed database for relevant articles. Prior to 2010, NACT was reserved for non-surgical candidates. After publication of EORTC 55971, the first randomized trial demonstrating non-inferiority of NACT followed by interval debulking surgery, NACT was considered in a wider breadth of patients. Since EORTC 55971, 3 randomized trials—CHORUS, JCOG0602, and SCORPION—have studied NACT versus PDS. While CHORUS supported EORTC 55971, JCOG0602 failed to demonstrate non-inferiority and SCORPION failed to demonstrate superiority of NACT. Despite conflicting data, a subset of patients would benefit from NACT while preserving survival including poor surgical candidates and inoperable disease. Further randomized trials are needed to assess the role of NACT.
... 9 A treatment strategy of neoadjuvant chemotherapy with interval debulking surgery may be applied to patients with an advanced-stage ovarian tumour. 11 The present patient, with an ECOG/WHO performance status of 2, underwent colonfibroscopy and panendoscopy that revealed a normal mucosa layer, and abdominal CT showed only an adnexal mass without an enlarged gastrointestinal tract tumour. Pleural effusion and ascites cytology resulted in a diagnosis of malignant adenocarcinoma. ...
... Therefore, the therapeutic strategy for the present case was neoadjuvant therapy followed by interval debulking surgery. 11,12 According to case findings, a preoperative evaluation is vital. Fine-needle aspiration cytologic cells combined with immunochemistry with cytokeratin 7 and Pax-8 has been suggested as a tool that may be used to distinguish the primary site. ...
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Metastatic tumours to the ovary comprise 10–25% of ovarian malignancies and may originate from various primary sites. Here, the case of a 49-year-old female patient who presented with periumbilical nodules and abdominal bloating is reported. She was found to have bilateral ovarian tumours with peritoneal carcinomatosis and ascites. Primary ovarian cancer was suspected while no contributory gastrointestinal lesion was detected by imaging studies and endoscopic examinations. Three cycles of neoadjuvant chemotherapy were administered, followed by interval debulking surgery. Appendiceal cancer was highly suspected based on analysis of a frozen section obtained during surgical debulking. Following the pathology investigation, the patient was finally diagnosed with primary appendiceal adenocarcinoma. She underwent chemotherapy comprising irinotecan and fluorouracil. Due to disease progression despite several chemotherapy regimens, the patient declined further treatment and was lost to follow-up 1 year after the debulking surgery. Metastatic tumours to the ovary may mimic primary ovarian cancers and often present with nonspecific manifestations. Therefore, meticulous exploration of the primary site is warranted if the diagnosis is clinically suspicious.
... Two studies, CHORUS [8] and EORTC 55971 [9], compared 'upfront' debulking surgery followed by chemotherapy with NACT/IDS. Outcomes in terms of median survival differed between the two studies with median survival in CHORUS at 23.6 months, versus 30.2 months for EORTC 55971 (p = 0.004), but overall, no survival difference was noted between patients who underwent neoadjuvant chemotherapy compared with upfront debulking surgery (27.6 months and 26.9 months p = 0.586). ...
... It was noted that women with stage IV ovarian cancer had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery with a median progression-free survival of 10.6 months compared with 9.7 months (p = 0.049) and a median overall survival of 24.3 months compared with 21.2 months (p = 0.048) [9]. ...
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Unlike many other malignancies, overall survival for women with epithelial ovarian cancer has improved only modestly over the last half-century. The perspectives presented here detail the views of a gynecologic oncologist looking back and the view of the academic editor looking forward. Surgical beginnings in 1809 are merged with genomics, surgical advances, and precision therapy at present and for the future. Presentations in this special issue focus on factors related to the diagnosis of ovarian cancer: (1) markers for the preoperative assessment of primary and metastatic ovarian tumors, (2) demonstrations of the presence of pelvic fluid in ultrasound studies of ovarian malignancies, (3) the effects of age, menopausal status, and body habitus on ovarian visualization, (4) the ability of OVA1 to detect ovarian cancers when Ca125 was not informative, (5) the detection of tumor-specific changes in cell adhesion molecules by tissue-based staining, (6) presentation of a high discrimination model for ovarian cancer using IOTA Simple Rules and CA125, (7) review of low-grade serous carcinoma of the ovary, and (8) a comprehensive case report on ovarian carcinosarcoma.
... Epithelial ovarian cancer, the sixth most common cancer in women in the UK, is usually diagnosed late: 60% of 7400 annual diagnoses have advanced stage disease. 1 Consequently, most patients require extensive cytoreductive abdominopelvic surgery involving total hysterectomy, bilateral salpingo-oophorectomy, tumor debulking, and omentectomy, in addition to platinum-based chemotherapy (usually multiple courses for disease recurrences until chemoresistance limits further treatment). 2 Thanks to recent advances in treatment options including poly ADP ribose polymerase (PARP) inhibitors, 3 the number of women living with their disease as women with epithelial ovarian cancer is growing, with over 40% of patients alive at 5 years. 1 In view of the increasing number of people surviving or 'Living With And Beyond Cancer', Macmillan and National Health Service (NHS) England have emphasized the importance of holistic and person-centered care to maximize quality of life. 4 Women with epithelial ovarian cancer are ideal patients in whom to target efforts to improve quality of life, given their relatively young age at diagnosis (63 years median age at diagnosis) when most women are still living a full and active life, their extensive and sometimes debilitating disease and treatment, and the growing length of time with which they are living with their cancer. ...
... A retrospective study of data from the National Cancer Database, consisting of up to 9,800 advanced EOC patients treated with NACT-IDS versus up to 27,000 patients who underwent PDS suggested worse OS in the NACT-IDS group [29]. However, data from 2 RCTs of women with biopsy-proven stage IIIC and IV invasive EOC comparing PDS and chemotherapy with NACT-IDS and adjuvant chemotherapy showed that survival in the NACT-IDS group was similar or better than the PDS group [30], suggesting cautious use of retrospective studies as evidence in favour of upfront PDS. ...
Article
Epithelial ovarian cancer (EOC) is among the top ten causes of cancer deaths worldwide, and is one of the most lethal gynecological malignancies in high income countries, with incidence and death rates expected to rise particularly in Asian countries where ovarian cancer is among the 5 most common cancers. Despite the plethora of randomised clinical trials investigating various systemic treatment options in EOC over the last few decades, both progression-free and overall survival have remained at approximately 16 and 40 months respectively. To date the greatest impact on treatment has been made by the use of poly (ADP-ribose) polymerase (PARP) inhibitors in women with advanced EOC and a BRCA1/2 mutation. Inhibition of PARP, the key enzyme in base excision repair, is based on synthetic lethality whereby alternative DNA repair pathways in tumor cells that are deficient in homologous recombination is blocked, rendering them unviable and leading to cell death. The Australia New Zealand Gynaecological Oncology Group (ANZGOG) is the national gynecological cancer clinical trials organization for Australia and New Zealand. ANZGOG's purpose is to improve outcomes and quality of life for women with gynecological cancer through cooperative clinical trials and undertaking multidisciplinary research into the causes, prevention and treatments of gynecological cancer. This review summarizes current ovarian cancer research and treatment approaches presented by Australian and New Zealand experts in the field at the 2020 ANZGOG webinar series entitled "Ovarian Cancer systems of Care".
... Removal of all visible tumor cells offers the best survival outcomes, whereas suboptimal cytoreduction, defined as residual disease at the conclusion of surgery of greater than 1 cm 3 , offers no improvement in overall survival [5,6]. Thus, those patients who have presumed unresectable disease or who are judged to be poor surgical candidates are best offered neoadjuvant chemotherapy (NACT) followed by interval cytoreduction and post-operative adjuvant consolidation chemotherapy [7,8]. ...
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Background Investigate the impact of interval cytoreductive surgery (ICS) on progression in an orthotopic mouse model of ovarian cancer and the impact of chemotherapy delivered at various timelines following surgery. Methods Luciferase-expressing ID8 murine ovarian cancer cells were implanted intra-bursally and IP to C57BL/7 mice. Once disease was established by bioluminescence, 2 cycles of neoadjuvant cisplatin were administered, and animals received either ICS (removal of the injected bursa/primary tumor) or anesthesia alone. Postsurgical chemotherapy was administered on the same day as the intervention (ICS/anesthesia), or on day 7 or day 28 following the intervention. Progression was quantified serially with in vivo bioluminescence imaging. Volume of ascitic fluid volume collected at necropsy was measured. Results Animals were matched for tumor burden at stratification. There was no accelerated growth of residual tumor after interval cytoreduction compared to controls. Animals who received chemotherapy on postoperative day (POD) 7 had better disease control compared to standard-of-care POD 28. Animals who underwent surgery had less ascites at necropsy compared to those who had anesthesia alone. Conclusions In this animal model, surgical wounding with suboptimal cytoreduction after neoadjuvant chemotherapy did not cause accelerated expansion of residual disease. Surgical wounding appears to impair cisplatin activity when given at time of surgery.
... (27.6 vs. 26.9 months, respectively) (Vergote et al., 2010(Vergote et al., , 2018. The SCORPION and JCOG0602 trials further demonstrated decreased perioperative morbidity, operative times, and length of hospital stay with NACT + ICS (Fagotti et al., 2016;Onda et al., 2016). ...
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Objective: While primary cytoreductive surgery (PCS) is considered the standard of care for women who present with stage IV endometrial cancer, neoadjuvant chemotherapy (NACT) followed by interval cytoreductive surgery (ICS) has emerged as an alternative treatment strategy. We summarized the literature and compared outcomes of PCS compared to NACT and ICS. Methods: We conducted a systematic search on PubMed, Embase, Web of Science, and Scopus for articles published from January 1, 1990 to December 31, 2020. Key search terms included multiple descriptors of advanced disease status in combination with "endometrial cancer" and "neoadjuvant chemotherapy". Our review included studies that examined survival and surgical outcomes of patients with stage III or IV endometrial cancer treated with neoadjuvant chemotherapy followed by interval cytoreductive surgery versus those who received primary cytoreductive surgery. We excluded studies examining only patients with leiomyosarcomas, carcinosarcomas, and stromal sarcomas due to the biologic heterogeneity of these malignancies. Results: The nine included studies encompassed 5,844 patients, of which 1,317 (22.5%) received NACT and 4,527 received PCS (77.5%). With the exception of a single study, all were retrospective observational studies or case series. Use of NACT in patients with stage IV EC increased from 16.0% in 2010 to 23.9% in 2015. Five studies analyzed median overall survival and all but one reported no significant difference between NACT + ICS vs. PCS. Optimal cytoreduction (<1 cm of residual disease) rates were similar across both treatment groups in three separate analyses, however pooled data suggest improved rates of optimal cytoreduction for NACT + ICS vs. PCS patients (81.9% vs. 51.5% respectively). Patients receiving NACT experienced significantly shorter hospital admissions and lower operative times compared to PCS counterparts. Conclusions: NACT followed by ICS reduces perioperative morbidity while offering similar overall survival.
... Ovarian cancer (OC) is a common gynecological malignancy, The 5-year survival rate of OC patients remains low because of the high heterogeneity of the tumor and high incidence of drug resistance during chemotherapy [1][2][3][4][5]. The standard treatment for OC is maximal cytoreductive surgery and postoperative paclitaxel-platinum combined chemotherapy, with a higher survival rate than other regimens, including cyclophosphamide-platinum/ gemcitabine and so on [6]. Most patients develop treatment resistance after prolonged treatment, and almost all patients with recurrent ovarian cancer (ROC) eventually develop platinum resistance [7,8]. ...
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Background The prognosis of high grade serous ovarian cancer (HGSOC) patients is closely related to the immune microenvironment and immune response. Based on this, the purpose of this study was to construct a model to predict chemosensitivity and prognosis, and provide novel biomarkers for immunotherapy and prognosis evaluation of HGSOC. Methods GSE40595 (38 samples), GSE18520 (63 samples), GSE26712 (195 samples), TCGA (321 samples) and GTEx (88 samples) were integrated to screen differential expressed genes (DEGs) of HGSOC. The prognosis related DEGs (DEPGs) were screened through overall survival analysis. The DEGs-encoded protein–protein interaction network was constructed and hub genes of DEPGs (DEPHGs) were generated by STRING. Immune characteristics of the samples were judged by ssGSEA, ESTIMATE and CYBERSORT. TIMER was used to analyze the relationship between DEPHGs and tumor-infiltrating immunocytes, as well as the immune checkpoint genes, finally immune-related DEPHGs (IDEPHGs) were determined, and whose expression in 12 pairs of HGSOC tissues and tumor-adjacent tissues were analyzed by histological verification. Furthermore, the chemosensitivity genes in IDEPHGs were screened according to GSE15622 (n = 65). Finally, two prediction models of paclitaxel sensitivity score (PTX score) and carboplatin sensitivity score (CBP score) were constructed by lasso algorithm. The area under curve was calculated to estimate the accuracy of candidate gene models in evaluating chemotherapy sensitivity. Results 491 DEGs were screened and 37 DEGs were identified as DEPGs, and 11 DEPHGs were further identified. Among them, CXCL13, IDO1, PI3, SPP1 and TRIM22 were screened as IDEPHGs and verified in the human tissues. Further analysis showed that IDO1, PI3 and TRIM22 could independently affect the chemotherapy sensitivity of HGSOC patients. The PTX score was significantly better than TRIM22, PI3, SPP1, IDO1 and CXCL13 in predicting paclitaxel sensitivity, so was CBP score in predicting carboplatin sensitivity. What’s more, both of the HGSOC patients with high PTX score or high CBP score had longer survival time. Conclusions Five IDEPHGs identified through comprehensive bioinformatics analysis were closely related with the prognosis, immune microenvironment and chemotherapy sensitivity of HGSOC. Two prediction models based on IDEPHGs might have potential application of chemotherapy sensitivity and prognosis for patients with HGSOC.
... In our cohort, the prolonged median overall survival of up to 38 months was comparable with that reported in the SCORPION trial 45 and substantially better than the 27 months from the individual patient meta-analysis of the EORTC and CHORUS trials. 46 Complete surgical resection, to 'reset the clock', may partly overcome the negative effect of tumour load, in line with a recent study. 47 Standard chemotherapy does not reduce the eventual likelihood of death from ovarian cancer per se. ...
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Introduction: Accurate prediction of patient prognosis can be especially useful for the selection of best treatment protocols. Machine Learning can serve this purpose by making predictions based upon generalizable clinical patterns embedded within learning datasets. We designed a study to support the feature selection for the 2-year prognostic period and compared the performance of several Machine Learning prediction algorithms for accurate 2-year prognosis estimation in advanced-stage high grade serous ovarian cancer (HGSOC) patients. Methods: The prognosis estimation was formulated as a binary classification problem. Dataset was split into training and test cohorts with repeated random sampling until there was no significant difference (p = 0.20) between the two cohorts. A ten-fold cross-validation was applied. Various state-of-the-art supervised classifiers were used. For feature selection, in addition to the exhaustive search for the best combination of features, we used the-chi square test of independence and the MRMR method. Results: Two hundred nine patients were identified. The model's mean prediction accuracy reached 73%. We demonstrated that Support-Vector-Machine and Ensemble Subspace Discriminant algorithms outperformed Logistic Regression in accuracy indices. The probability of achieving a cancer-free state was maximised with a combination of primary cytoreduction, good performance status and maximal surgical effort (AUC 0.63). Standard chemotherapy, performance status, tumour load and residual disease were consistently predictive of the mid-term overall survival (AUC 0.63-0.66). The model recall and precision were greater than 80%. Conclusion: Machine Learning appears to be promising for accurate prognosis estimation. Appropriate feature selection is required when building an HGSOC model for 2-year prognosis prediction. We provide evidence as to what combination of prognosticators leads to the largest impact on the HGSOC 2-year prognosis.
... The findings of this trial raise questions about the place of single-agent carboplatin, but it should be noted that it was a small trial and the findings need to be confirmed.6.3 | Neoadjuvant chemotherapyAn increasing proportion of patients with advanced stage ovarian cancer are being treated with upfront neoadjuvant chemotherapy (NACT) for 3-4 cycles prior to interval debulking and further chemotherapy. This is based on the results of four trials that have reported equivalent outcomes for progression-free survival and overall survival, but less morbidity and lower mortality compared with primary debulking surgery (PDS).57 Vergote et al.55 reported the results in 2010 of the first randomized EORTC-NCIC (National Cancer Institute of Canada) study of PDS versus three cycles of NACT followed by interval debulking. ...
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In 2014, FIGO's Committee for Gynecologic Oncology revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same system. Most of these malignancies are high-grade serous carcinomas (HGSC). Stage IC is now divided into three categories: IC1 (surgical spill); IC2 (capsule ruptured before surgery or tumor on ovarian or fallopian tube surface); and IC3 (malignant cells in the ascites or peritoneal washings). The updated staging includes a revision of Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination. This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2 is now "microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph node" metastasis. This review summarizes the genetics, surgical management, chemotherapy, and targeted therapies for epithelial cancers, and the treatment of ovarian germ cell and stromal malignancies.
... However, randomised controlled trials [18][19][20] and a recent analysis by COCHRANE suggested that there was little or no difference in primary survival outcomes between PDS and NACT [21]. Meta-analysis of two randomised trials (EORTC 55971 and CHORUS) indicated that patients in the NACT group achieved higher CC0 rates and lower perioperative complication rates when compared with patients in the PDS group [22]. However, the CC0 rates in the PDS groups were below 20%, which were lower compared with the rates reported in other studies [23,24]. ...
Article
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Background: The aim of this study was to assess current French practices in the management of patients with advanced epithelial ovarian cancer. Method: a 58-question electronic survey was distributed anonymously to the members of the SFOG (French Society of Gynaecological Oncology), GINECO-ARCAGY (National Investigators Group for Ovarian and Breast Cancer Studies in France) and FRANCOGYN (French research group in oncological and gynaecological surgery). Initial diagnostic workup and staging, pathological data, surgical data, treatments and follow-up strategies were assessed. Results: a total of 107 participants responded to emailed surveys. Most of the respondents were obstetrician-gynaecologists (37.4%), surgical oncologists (34.6%) and medical oncologists (17.8%). According to most (76.8%) participants, less than 50% of patients were eligible for primary debulking surgery (PDS). The LION study criteria were applied in 69.5% of cases during PDS and 39% after chemotherapy. The timing of BRCA testing was very heterogeneous and ranged from 1 to 6 months. The use of bevacizumab as an adjuvant schedule was lower in cases of no residual disease (for 54.5% of respondents) compared to cases of residual disease (for 63.6% of respondents). In cases of BRCA1-2 mutations, olaparib was given by 75.8-84.8% of respondents, whereas niraparib was given in cases of BRCA wild-type diseases. Conclusion: this survey provides an extensive and a unique review of current French practices in the management of patients with advanced epithelial ovarian cancer in 2021.
... While initially effective, the majority of patients develop recurrence at the rate of 60-85% [7]. Grossly visible residual disease following debulking surgery is a negative predictor for survival, among other factors, such as patient's age, tumor grade, and pre-surgical tumor burden [3,8,9]. ...
Article
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High-grade serous carcinoma of the ovary is a deadly gynecological cancer with poor long-term survival. Dysregulation of microRNAs has been shown to contribute to the formation of cancer stem cells (CSCs), an important part of oncogenesis and tumor progression. The let-7 family of microRNAs has previously been shown to regulate stemness and has tumor suppressive actions in a variety of cancers, including ovarian. Here, we demonstrate tumor suppressor actions of let-7i: repression of cancer cell stemness, inhibition of migration and invasion, and promotion of apoptosis, features important for cancer progression, relapse, and metastasis. Let-7i over-expression results in increased sensitivity to the PARP inhibitor olaparib in samples without BRCA mutations, consistent with induction of BRCAness phenotype. We also show that let-7i inhibits the expression of several factors involved in the homologous recombination repair (HRR) pathway, providing potential mechanisms by which the BRCAness phenotype could be induced. These actions of let-7i add to the rationale for use of this miRNA as a treatment for ovarian cancer patients, including those without mutations in the HRR pathway.
... NACT combined with cytoreductive surgery is a new therapeutic strategy for the treatment of patients with AOC. Studies have confirmed that NACT can reduce tumor burden, improve the quality of surgery, reduce complications, and raise the quality of life of OC patients [11][12][13]. At present, the impact of NACT on the survival status of patients with AOC remains controversial. ...
Article
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Purpose: To explore the clinical efficacy and safety of neoadjuvant chemotherapy (NACT) combined with minimally invasive laparoscopic cytoreductive surgery in the treatment of patients with advanced ovarian cancer (AOC). Methods: The clinical data of 116 patients with AOC were divided into NACT group (NACT combined with laparoscopic cytoreductive surgery, n=58) and control group (cytoreductive surgery alone, n=58). The short-term efficacy, surgery-related indexes, incidence of adverse reactions, and changes in levels of serum human epididymis protein 4 (HE4), vascular endothelial growth factor (VEGF) and carbohydrate antigen 125 (CA125) before and after treatment were compared between the two groups. The survival status of patients after treatment was recorded. Results: The operation time, intraoperative blood loss, ascites volume, postoperative ventilation time, and average postoperative length of hospitalization in NACT group were all significantly shorter and less than those in the control group. The optimal cytoreduction rate in NACT group was far higher than that in the control group. The overall response rate in NACT group was obviously higher than that in the control group. After treatment, the levels of serum HE4, VEGF and CA125 greatly declined in the two groups compared with those before treatment, while they were obviously lower in the NACT group than those in the control group. The follow-up results revealed that the median overall survival (OS) was 31.1 months and 28.9 months, and the 3-year OS rate was 43.1% (25/58) and 31.0% (18/58), respectively, in the NACT group and control group. Conclusion: NACT can significantly shorten the duration of cytoreductive surgery of AOC, reduce intraoperative blood loss, accelerate postoperative recovery, raise the optimal cytoreduction rate, and enhance the clinical efficacy, without greatly improving the survival of patients.
... The EORTC 55791 trial [42] and the CHORUS trial [43] showed a similar survival in the neo-adjuvant therapy group followed by IDS compared to primary debulking followed by ACT. A meta-analysis [44] of these studies demonstrated a significantly improved OS for stage IV ovarian cancer patients in the NACT group (24.3 versus 21.1 months, HR 0.76 (95% CI 0.58-1.00), p = 0.048). ...
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In monotherapy, immunotherapy has a poor success rate in ovarian cancer. Upgrading to a successful combinatorial immunotherapy treatment implies knowledge of the immune changes that are induced by chemotherapy and surgery. Methodology: Patients with a new d ovarian cancer diagnosis underwent longitudinal blood samples at different time points during primary treatment. Results: Ninety patients were included in the study (33% primary debulking surgery (PDS) with adjuvant chemotherapy (ACT), 61% neo-adjuvant chemotherapy (NACT) with interval debulking surgery (IDS), and 6% debulking surgery only). Reductions in immunosuppression were observed after NACT, but surgery reverted this effect. The immune-related proteins showed a pronounced decrease in immune stimulation and immunosuppression when primary treatment was completed. NACT with IDS leads to a transient amelioration of the immune microenvironment compared to PDS with ACT. Conclusion: The implementation of immunotherapy in the primary treatment schedule of ovarian cancer cannot be induced blindly. Carboplatin-paclitaxel seems to ameliorate the hostile immune microenvironment in ovarian cancer, which is less pronounced at the end of primary treatment. This prospective study during primary therapy for ovarian cancer that also looks at the evolution of immune-related proteins provides us with an insight into the temporary windows of opportunity in which to introduce immunotherapy during primary treatment.
... The five trials included two large, welldocumented RCTs (CHORUS (Kehoe 2015) and EORTC 55971 (Vergote 2010)) which reported no significant di erence in survival between IDS compared with UDS. It was suggested that IDS may have better overall survival in stage IV disease, whereas women with FIGO stage IIIC disease with extrapelvic metastases smaller than 5 cm may have better progression-free survival a er upfront debulking (Vergote 2018). The selection of women with advanced ovarian cancer for UDS or IDS remains controversial (Vergote 2013). ...
... In patients with completely resectable disease and good performance status, primary debulking surgery (PDS) is the first option to consider, as it has been consistently associated with improved survival outcomes in retrospective studies [4][5][6]. Neoadjuvant chemotherapy (NACT) is associated with lower morbidity and postoperative mortality [7,8], and it is preferred in medically non-operable patients or in the low likelihood of achieving complete cytoreduction, with non-inferior survival benefit [7,9,10]. Classically, interval debulking surgery (IDS) is performed after three or four cycles of NACT, and 2 or 3 cycles of adjuvant chemotherapy are delivered after CRS to complete a total of 6 cycles of chemotherapy. ...
Article
Objective: We sought to evaluate the impact on survival of tumor burden and surgical complexity in relation to the number of cycles of neoadjuvant chemotherapy (NACT) in patients with advanced ovarian cancer (OC) with minimal (CC-1) or no residual disease (CC-0). Methods: This retrospective study included patients with International Federation of Gynaecology and Obstetrics IIIC-IV stage OC who underwent debulking surgery at 4 high-volume institutions between January 2008 and December 2015. We assessed the overall survival (OS) of primary debulking surgery (PDS group), early interval debulking surgery after 3-4 cycles of NACT (early IDS group) and delayed debulking surgery after 6 cycles (DDS group) with CC-0 or CC-1 according to peritoneal cancer index (PCI) and Aletti score. Results: Five hundred forty-nine women were included: 175 (31.9%) had PDS, 224 (40.8%) early IDS and 150 (27.3%) DDS. Regardless of Aletti score, median OS after PDS was significantly higher than after early IDS or DDS, but the survival difference was higher in women with an Aletti score <8. Among patients with PCI ≤10, median OS after PDS was significantly higher than after early IDS or DDS. In women with PCI >10, there were no differences between PDS and early IDS, but DDS was associated with decreased OS. Conclusion: The benefit of complete PDS compared with NACT was maximal in patients with a low complexity score. In patients with low tumor burden, there was a survival benefit of PDS over early IDS or DDS. In women with high tumor load, DDS impaired the oncological outcome.
... Patients with high-volume metastatic disease first receive three cycles of carboplatin and paclitaxel prior to surgery, with three additional cycles after surgery ("neoadjuvant chemotherapy"). A debulking surgery that leaves behind no visible disease confers the most survival benefit to the patient, and the choice of treatment sequence is weighted to maximize the benefit and minimize the morbidity of surgery [10,11]. Unfortunately, recurrence rates are high, being greater than 70%, and long-term survival is infrequent, with only 15% of women with advanced stage cancer surviving 7-10 years [12]. ...
Article
Full-text available
High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor–stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.
... This highlights the difficulties encountered by the physician in trying to find the balance in terms of complications and survival when deciding the best treatment appliable to high risk patients. The reduction of morbidity and mortality associated with NACT, makes it a valid therapeutic option in women with poor performance status or high tumor load (FIGO stages IIIC-IV) (13,54). ...
... P ¼ 0.048) than those who underwent upfront CRS. 30 Another phase III RCT, the SCORPION trial, included 171 patients with stage IIIC-IV EOC who had high tumour load assessed by laparoscopy. In this trial, similar PFS and OS were observed between the NACT followed by interval CRS and upfront CRS arms. ...
Article
Full-text available
Ovarian cancer is one of the deadliest gynaecological malignancies and tends to be diagnosed at an advanced stage. Similar to many malignancies, surgery plays a critical role in many aspects of ovarian cancer management. Hyperthermic intraperitoneal chemotherapy (HIPEC) involves the induction of hyperthermia and delivery of intraperitoneal chemotherapy directly into the peritoneal cavity. Combined with cytoreductive surgery, HIPEC is an emerging treatment modality for ovarian cancer. Ovarian cancer survival outcomes can be improved by treatment with surgery and HIPEC in selected patients. Thus, this study aimed to review the current role of surgery and HIPEC in epithelial ovarian cancer. Evidence from the monumental and recent literature will be introduced.
... Neoadjuvant chemotherapy (NACT), followed by surgery is a therapeutic approach for extensive disease when complete surgical resection is not initially possible either due to bulky or diffusely unresectable disease or because of patients' medical comorbidities. NACT significantly reduces the tumor burden before surgery and allows an easier and optimal cytoreduction [8] [9]. It also decreases the morbidity, blood loss, and intensive care unit (ICU) and hospital stays [10]. ...
... Until recently, the standard of care for newly diagnosed advanced EOC was surgery with carboplatin and paclitaxel chemotherapy ± bevacizumab followed by maintenance bevacizumab (Figure 1). Surgery should be performed prior to chemotherapy with the goal of macroscopic complete resection [2] or after neoadjuvant chemotherapy [3]. The antivascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab was the first approved biological treatment for EOC. ...
Article
Full-text available
Recent data have demonstrated substantial efficacy with poly (ADP-ribose) polymerase (PARP) inhibitors as treatment and/or maintenance therapy in patients with newly diagnosed advanced epithelial ovarian cancer (EOC). Here, we review efficacy and safety results from four recent Phase III trials in newly diagnosed EOC: SOLO1 (olaparib), PAOLA-1 (olaparib in combination with bevacizumab), PRIMA (niraparib), and VELIA (veliparib). The implications of these data for current clinical practice and areas for future research are discussed, including ongoing studies of targeted agents in the newly diagnosed setting. Data from SOLO1, PAOLA-1, PRIMA, and VELIA confirm the benefit of PARP inhibitors (olaparib, niraparib, veliparib) for women with newly diagnosed EOC. The greatest benefit was seen in patients with a BRCA1 and/or BRCA2 mutation or in the homologous recombination deficiency (HRD)-test positive subgroup. These four well-conducted studies have generated practice-changing data. However, deciding how to apply these results in clinical practice is challenging, and substantial differences in trial design impede cross-trial comparisons. Recent PARP inhibitor approvals (olaparib, niraparib) in the newly diagnosed EOC setting have provided new maintenance treatment options for a broader patient population. The results of these studies call for personalized medicine based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. Important areas for future research include appropriate use of both BRCA mutation and HRD testing to inform magnitude of PARP inhibitor benefit as well as exploring further options for patients who are HRD-test negative and for those who become PARP inhibitor resistant.
... 3 This strategy has been validated in a recent pooled analysis of the long-term follow-ups of two randomised trials in patients with high tumour burden at presentation or poor performance status. 12 In the case of recurrent ovarian cancer, the benefit of secondary cytoreductive surgery is dependent on the patient population. 13 While the intervention did not significantly improve overall survival (OS) of patients with platinumsensitive recurrent ovarian cancer receiving chemotherapy in the GOG-0213 trial, 14 recently reported results from the DESKTOP-III trial indicate that complete resection resulted in a significant increase of OS in patients with a first relapse (after a 6+ months platinum-free interval) and a positive German Gynaecological Oncology Group (AGO) score. ...
Article
Ovarian cancer is often diagnosed at an advanced stage, which is associated with worse survival outcomes and more limited therapeutic options. Over the last years, knowledge regarding the molecular features of ovarian cancer has advanced considerably, enabling the development of several options for diagnosis and treatment in a patient-tailored approach. Identification of homologous recombination deficiency (such as mutations of the BRCA1 and BRCA2 genes, or genomic instability) affecting DNA repair, has become essential in guiding treatment decisions, especially after the development of targeted agents. Therapeutic decisions take into consideration the cancer subtype, its molecular features and disease stage. Fundamental principles of good treatment for women with ovarian cancer include debulking surgery (to reduce the tumour to no residual disease whenever possible), along with appropriate systemic treatment (chemotherapy and targeted agents). To aid Belgian physicians in developing the best individual medical strategies for patients with primary and recurrent ovarian cancer, we present here standard of care applicable in Belgium, that also includes recently developed targeted agents and currently applicable reimbursement criteria.
... To the best of our knowledge, there are no reliable prognostic markers for the surgical outcome of IDS after NACT. Even though a lot of research has been done to identify patients that benefit from upfront surgery in a primary setting [11,15,16], there are very little data on predictive markers for surgical outcome in a neoadjuvant setting. Radiologic imaging and CA-125 levels are widely used to monitor the disease under chemotherapy [5,17], but so far no safe and practical method has been identified to predict the surgical outcome [18][19][20][21][22]. ...
Article
Full-text available
Purpose Achieving complete cytoreduction (CCR) is crucial for a patient’s prognosis with advanced epithelial ovarian cancer (EOC). So far, prognostic predictors have failed to predict surgical outcome after neoadjuvant chemotherapy (NACT). In clinical trials, scores were used to predict operability in recurrent ovarian cancer (Harter et al. in N Engl J Med 385(23):2123–2131, 2021) but there is no known prediction score for CCR after NACT. The Peritoneal Cancer Index (PCI) is an established tool to predict surgical outcome in primary setting (Lampe et al. in 25:135–144, 2015). We now examined the predictive power of the PCI to achieve CCR after NACT. Methods In this single-center study, the data of patients with advanced stage EOC (FIGO > IIIb) treated between 01/2015 and 12/2020 were analyzed retrospectively. Inclusion criteria were a mandatory staging laparoscopy, a PCI score > 25, and NACT. CT scans were analyzed in blinded fashion according to RECIST criteria (Borgani et al. in 237; 93–99, 2019) Reaction of PCI after NACT was compared with the analysis of radiologic imaging and CA-125 levels. Results Three hundred and sixteen patients were screened, 62 were treated with NACT, and 23 were included in our analysis. 87% of cases presented with an FIGO IIIc stadium. The reduction of PCI itself after NACT showed to be the most powerful predictor for achieving CCR. The reduction of the initial PCI score by minimum of 8.5 points was a better predictor for CCR than reaching a PCI < 25. In contrast to data deriving from patients undergoing primary debulking surgery (PDS), we found a PCI of 17, rather than 25, to be a more valuable cut-off for CCR in neoadjuvant-treated patients. Conclusion The extend of PCI reduction after NACT is a better predictor for achieving CCR compared with CA125 levels and radiologic imaging. The PCI must be assessed differently in neoadjuvant setting than in a primary situation. CCR was most likely for a post-NACT PCI < 17.
... Initial treatment for AOC includes debulking surgery and systemic treatment, with PDS followed by platinum-based chemotherapy being the preferred option. Nevertheless, a recent pooled analysis of two randomized trials shows that NACT could be a valuable treatment option for patients with stage IIIC-IV, particularly in those with a high tumor burden at diagnosis or poor performance status, for whom PDS is not advisable [11]. However, these two trials have been criticized due to a low rate of optimal cytoreduction; moreover, another randomized trial failed to demonstrate non-inferiority of NACT vs PDS [12]. ...
... Ces deux essais ont conclu à la noninfériorité du traitement par CNA comparativement à la CCMp avec des résultats de survie globale équivalents. On retrouve une survie globale de [30]. Un troisième essai randomisé de non-infériorité comparant la CNA à la CCMp sur une cohorte de patientes japonaise (JCOG) a également été mené avec pour critère de jugement principal (CJP) la survie globale [31]. ...
Article
Full-text available
Résumé L’objectif de cette revue est d’évaluer le positionnement optimal de la chirurgie de cytoréduction et des traitements médicaux périopératoires lors de la prise en charge initiale et lors de la rechute des carcinomes épithéliaux ovariens de stades avancés. Lors de la prise en charge initiale, une chirurgie première doit être proposée si l’absence de résidu tumoral est envisageable au prix d’une chirurgie raisonnable (gestes de résection à envisager et leurs complications mais également en fonction de l’état général de la patiente). Dans les recommandations actuelles, trois à quatre cycles de chimiothérapie néoadjuvante sont proposés avant une chirurgie d’intervalle aux patientes non éligibles à une chirurgie première. La réalisation d’une chirurgie d’intervalle tardive (par exemple après ≥ cinq à six cycles de chimiothérapie) ne constitue pas un standard thérapeutique et doit être proposée uniquement en cas de mauvaise réponse tumorale après trois à quatre cycles et lorsqu’une chirurgie complète semble faisable. Lors de la première récidive tumorale chez des patientes platino-sensibles, une chirurgie de cytoréduction première peut être envisagée si l’absence de résidu tumoral est envisageable. On peut s’appuyer sur des scores prédictifs (score AGO ; score i-model) permettant de sélectionner les patientes. En absence de données robustes, il ne peut être préconisé de réaliser une chirurgie de cytoréduction lors de la première récidive chez les patientes platino-résistantes ou bien en situation de récidive ultérieure. Néanmoins, l’obtention d’une chirurgie complète dans ces situations cliniques semble apporter un bénéfice en survie globale et sa réalisation doit reposer au cas par cas sur un avis d’équipes spécialisées.
... This approach is supported by three randomised trials that each found that overall survival with neoadjuvant chemotherapy and delayed primary surgery is not inferior to upfront surgery and is associated with reduced perioperative morbidity. [5][6][7][8] There has been substantial interest in the assessment of weekly dose-dense paclitaxel schedules. Preclinical studies suggest that administration of metronomic taxane improves drug delivery, increases tumour cell apoptosis, and reduces angiogenesis. ...
Article
Full-text available
Background: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8. Methods: In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and group 3 and group 1, in the intention-to-treat population. Safety was assessed in all patients who started at least one chemotherapy cycle. The trial is registered on ClinicalTrials.gov, NCT01654146, and ISRCTN registry, ISRCTN10356387, and is closed to accrual. Findings: Between June 6, 2011, and Nov 28, 2014, 1566 patients were randomly assigned to group 1 (n=522), group 2 (n=523), or group 3 (n=521). The median age was 62 years (IQR 54-68), 1073 (69%) of 1566 patients had high-grade serous carcinoma, 1119 (71%) had stage IIIC-IV disease, and 745 (48%) had IPS. As of data cutoff (March 31, 2020), with a median follow-up of 69 months (IQR 61-75), no significant difference in overall survival was observed in either comparison: median overall survival of 47·4 months (95% CI 43·1-54·8) in group 1, 54·8 months (46·6-61·6) in group 2, and 53·4 months (49·2-59·6) in group 3 (group 2 vs group 1: hazard ratio 0·87 [97·5% CI 0·73-1·05]; group 3 vs group 1: 0·91 [0·76-1·09]). No significant difference was observed for progression-free survival in either comparison and evidence of non-proportional hazards was seen (p=0·037), with restricted mean survival time of 23·9 months (97·5% CI 22·1-25·6) in group 1, 25·3 months (23·6-27·1) in group 2, and 24·8 months (23·0-26·5) in group 3. The most common grade 3-4 adverse events were reduced neutrophil count (78 [15%] of 511 patients in group 1, 183 [36%] of 514 in group 2, and 154 [30%] of 513 in group 3), reduced white blood cell count (22 [4%] in group 1, 80 [16%] in group 2, and 71 [14%] in group 3), and anaemia (26 [5%] in group 1, 66 [13%] in group 2, and 24 [5%] in group 3). No new serious adverse events were reported. Seven treatment-related deaths were reported (two in group 1, four in group 2, and one in group 3). Interpretation: In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group. Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.
... [9][10][11] However, few studies have investigated OS exclusively among women with stage IV comparing PDS with IDS. 12 [16][17][18] because IDS is associated with a reduction in surgical invasiveness and postoperative complication rates. 10,11,19 However, selecting the right Stage IV patients for IDS is a great challenge because studies report that approximately 10% of women selected for NACT never receive surgery. ...
Article
Full-text available
Introduction: It is debated whether women with FIGO (International Federation of Gynecology and Obstetrics) Stage IV epithelial ovarian cancer should be offered primary debulking surgery (PDS) or interval debulking surgery (IDS). Furthermore, the impact of complete resection of intra-abdominal disease (R0) despite their extra-abdominal metastases is questioned. The objective of this study was to investigate the impact of intra-abdominal residual tumor, Stage IVA vs IVB, the localization and number of metastases defining Stage IV disease on overall survival (OS) comparing PDS and IDS in FIGO Stage IV epithelial ovarian cancer. Material and methods: We included 2091 women registered with Stage IIIC-IV ovarian cancer in the Danish Gynecological Cancer Database during 2009-2016. The impact of residual tumor was evaluated using univariate and multivariate analyses. Results: In total, 681 patients had stage IV disease, of whom 26% underwent PDS, 38% IDS, and 36% chemotherapy only. Overall survival for PDS and IDS were similar. Patients achieving R0 at PDS showed a tendency towards a higher OS than patients achieving R0 at IDS, though the difference was non-significant. In women with Stage IVA and IVB disease there was a survival benefit in achieving R0 both when treated with PDS and IDS. Women with Stage IVB disease treated with chemotherapy only had a significantly lower OS than patients achieving R0 at both PDS and IDS. Malignant pleural effusion and having five metastatic sites compared with having one was associated with a poorer OS. Conclusions: Our study shows similar OS in patients with Stage IV disease treated with IDS compared with PDS. Complete intra-abdominal tumor resection improves the prognosis in both PDS and IDS in Stage IV ovarian cancer. Malignant pleural effusion seems to be a negative prognostic factor and should have more focus in future studies.
... Therefore, cytoreductive surgery after NACT is often undertaken in patients who are physically, nutritionally, and/or psychologically affected. The aim of NACT is to achieve radiological and clinical improvement to increase the likelihood of optimal cytoreduction at interval cytoreductive surgery [4,5]. ...
Article
Full-text available
Background Cytoreductive surgery followed by systemic chemotherapy is the standard of treatment in advanced ovarian cancer where feasible. Neoadjuvant chemotherapy (NACT) followed by surgery is applicable where upfront cytoreductive surgery is not feasible because of few certain reasons. Nevertheless, surgical interventions and the chemotherapy itself may be associated with postoperative complications usually entailing slow postoperative recovery. Prehabilitation programs consist of the patient’s preparation before surgery to improve the patient’s functional capacity. The aim of this study was to evaluate the impact of a prehabilitation program during neoadjuvant treatment and interval cytoreductive surgery for ovarian cancer patients. Methods A retrospective observational pilot study of patients with advanced ovarian cancer treated with NACT and interval cytoreductive surgery was conducted. The prehabilitation group received a structured intervention based on physical exercise, nutritional counseling, and psychological support. Nutritional parameters were assessed preoperatively and postoperatively, and functional parameters and perioperative and postoperative complications were also recorded. Results A total of 29 patients were included in the study: 14 in the prehabilitation group and 15 in the control group. The patients in the prehabilitation program showed higher mean total protein levels in both preoperative (7.4 vs. 6.8, p = 0.004) and postoperative (4.9 vs. 4.3, p = 0.005) assessments. Up to 40% of controls showed intraoperative complications vs. 14.3% of patients in the prehabilitation group, and the requirement of intraoperative blood transfusion was significantly lower in the prehabilitation group (14.3% vs. 53.3%, p = 0.027). The day of the first ambulation, rate of postoperative complications, and length of hospital stay were similar between the groups. Finally, trends towards shorter time between diagnosis and interval cytoreductive surgery ( p = 0.097) and earlier postoperative diet restart ( p = 0.169) were observed in the prehabilitation group. Conclusion Prehabilitation during NACT in women with ovarian cancer candidates to interval cytoreductive surgery may improve nutritional parameters and thereby increase postoperative recovery. Nevertheless, the results of this pilot study are preliminary, and further studies are needed to determine the clinical impact of prehabilitation programs.
... Furthermore, AL in these studies was often reported as a secondary outcome or just as corollary data amongst other postoperative complications. For example, the AL's rate has not been reported in the randomised OC clinical trials assessing the role of primary versus interval cytoreduction after NACT [58][59][60]. Another significant limitation is the impossibility of separately assessing risk factors simultaneously present in the same patient and/or in the same group of patients. Also, due to the quality of the reported data, known pre-operative (high BMI, diabetes, chronic obstructive pulmonary disease) or intraoperative risk factors for AL (site of the bowel resection, distance of the anastomosis from the anal verge, surgeon's experience, and the degree of centralisation of the treatment) could not be analysed. ...
Article
Objective This systematic review and meta-analysis aimed to summarise the available evidence on the pre- and intra-operative risk factors for anastomotic leakage (AL) after bowel resection and anastomosis for ovarian cancer (OC). Study design We searched online databases from Pubmed, Scopus, ScienceDirect, and Cochrane Library from inception to October 2020. Pre- and intra-operative risk factors for AL were considered as the primary outcomes. Research heterogeneity and bias were evaluated by I² and by the Newcastle Ottawa scale, respectively. The study was registered with PROSPERO, CRD42018095225. Results The overall AL rate after OC surgery (median ± SD) was 5.3 ± 12% (277 AL on 5178 anastomoses). Thirteen non-randomised studies were included in the meta-analysis enrolling a total of 3274 patients. Pre albumin level ≤3 gr/dl, multiple bowel resections and primary cytoreductive surgery were associated with a significantly high risk of AL with a pooled OR of 5.29 (95% CI: 1.51–18.59), OR=4.4 (95% CI: 1.19–16.66) and OR=1.71 (95% CI: 1.05–2.77), respectively. Optimal cytoreduction, ASA score, ascites, and protective stoma were not associated with an increased risk of AL. Conclusion Based on the best available evidence, preoperative albumin level < 3 gr./ dl, multiple bowel resections and primary cytoreductive surgery were associated with an increased risk for AL after bowel surgery for OC.
Article
The incidence and mortality rates of ovarian cancer are increasing globally. Ovarian cancer is diagnosed at an advanced stage in 80% of women. After standard, platinum-based, front-line chemotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors and antiangiogenic agents are successfully employed as maintenance strategies for newly diagnosed, advanced ovarian cancer patients. Landmark clinical studies, including SOLO-1, PAOLA-1, PRIMA, and VELIA, have provided crucial insights on optimizing first-line maintenance treatment using PARP inhibitors. A group of ovarian cancer experts, primarily from low- and middle-income countries, met in September 2019 to discuss new developments for the first-line treatment of ovarian cancer and its implications. Key implications of the evolving clinical data included: (1) olaparib or niraparib maintenance therapy appears to be the preferred choice for patients with BRCA1/2 mutations; hence, BRCA testing is beneficial in identifying these patients; (2) niraparib monotherapy and olaparib in combination with bevacizumab have demonstrated significant benefit in progression-free survival (PFS) in homologous recombination deficiency (HRD)-positive patients; (3) bevacizumab, niraparib alone, or observation can be an alternative for HRD-negative patients; (4) further data is warranted to explore the role of PARP inhibitors in treating HRD-negative, ovarian cancer patients to confirm findings of the exploratory analysis of PRIMA; (5) PARP inhibitors may be beneficial for stage IV ovarian cancer patients with inoperable disease and patients with prior neoadjuvant chemotherapy; and (6) there is an urgent need to increase awareness in both clinicians and patients on BRCA and HRD testing for optimizing treatment decision-making and improving clinical outcomes in newly diagnosed, advanced ovarian cancer patients. In clinical medicine, the limited availability of family history (FH) information and the complexity of FH criteria has hampered the implementation of BRCA testing. Moreover, many cancer patients with BRCA mutations are not tested because they do not meet the criteria for FH. Consequently, BRCA testing in many high income countries, including the US and Australia, is underused and used inappropriately, which has resulted in the loss of valuable opportunities for better cancer management and cancer prevention.
Article
High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Treatment is not uniform, with some patients undergoing primary debulking surgery followed by chemotherapy (PDS) and others being treated directly with chemotherapy and only having surgery after three to four cycles (NACT). Which strategy is optimal remains controversial. We developed a mathematical framework that simulates hierarchical or stochastic models of tumor initiation and reproduces the clinical course of HGSC. After estimating parameter values, we infer that most patients harbor chemoresistant HGSC cells at diagnosis and that, if the tumor burden is not too large and complete debulking can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. These predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management.
Article
Background: Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require a combination of surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. Objectives: To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). Search methods: We searched the following databases up to 9 October 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. Selection criteria: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. Data collection and analysis: Two review authors independently extracted data and assessed risk of bias in each included trial. We extracted data of overall (OS) and progression-free survival (PFS), adverse events, surgically-related mortality and morbidity and quality of life outcomes. We used GRADE methods to determine the certainty of evidence. Main results: We identified 2227 titles and abstracts through our searches, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1774 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the four studies where data were available and found little or no difference with regard to overall survival (OS) (Hazard Ratio (HR) 0.96, 95% CI 0.86 to 1.08; participants = 1692; studies = 4; high-certainty evidence) or progression-free survival in four trials where we were able to pool data (Hazard Ratio 0.98, 95% CI 0.88 to 1.08; participants = 1692; studies = 4; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were variably and incompletely reported across studies. There are probably clinically meaningful differences in favour of NACT compared to PDS with regard to overall postoperative serious adverse effects (SAE grade 3+): 6% in NACT group, versus 29% in PDS group, (risk ratio (RR) 0.22, 95% CI 0.13 to 0.38; participants = 435; studies = 2; heterogeneity index (I2) = 0%; moderate-certainty evidence). NACT probably results in a large reduction in the need for stoma formation: 5.9% in NACT group, versus 20.4% in PDS group, (RR 0.29, 95% CI 0.12 to 0.74; participants = 632; studies = 2; I2 = 70%; moderate-certainty evidence), and probably reduces the risk of needing bowel resection at the time of surgery: 13.0% in NACT group versus 26.6% in PDS group (RR 0.49, 95% CI 0.30 to 0.79; participants = 1565; studies = 4; I2 = 79%; moderate-certainty evidence). NACT reduces postoperative mortality: 0.6% in NACT group, versus 3.6% in PDS group, (RR 0.16, 95% CI 0.06 to 0.46; participants = 1623; studies = 5; I2 = 0%; high-certainty evidence). QoL on the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scale produced inconsistent and imprecise results in three studies (MD -0.29, 95% CI -2.77 to 2.20; participants = 524; studies = 3; I2 = 81%; very low-certainty evidence) but the evidence is very uncertain and should be interpreted with caution. Authors' conclusions: The available high to moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT probably reduces the risk of serious adverse events, especially those around the time of surgery, and reduces the risk of postoperative mortality and the need for stoma formation. These data will inform women and clinicians (involving specialist gynaecological multidisciplinary teams) and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.
Article
Background: CA125 level normalization at different chemotherapy cycles has been reported to be a prognosticator in advanced epithelial ovarian cancer. Objective: In the present study, we investigated whether the time (in days) to CA125 normalization or nadir during treatment could be used as markers to predict survival. Methods: Patients with FIGO stage III-IV epithelial ovarian cancer treated with cytoreductive surgery followed by adjuvant chemotherapy between 2008 and 2016 were enrolled in this retrospective study. Clinicopathological characteristics, changes in CA125 level during treatment, and survival outcomes were analyzed. Time-dependent receiver operating characteristic curve analysis was used to determine the optimal cut-off values of the time to normalization and time to nadir of CA125 levels to predict survival. Univariate and multivariate Cox regression analysis were used to examine the impact of each variable on survival. Results: A total of 106 patients were included in the analysis. The optimal cut-off values for the time to normalization and nadir for predicting survival were 60 and 194 days, respectively. In Kaplan-Meier survival analysis, CA125 level normalization ⩽ 60 days and CA125 ⩽ 35 u/mL after the third cycle, and CA125 level ⩽ 10 u/mL after the sixth cycle of chemotherapy were associated with significantly better 5-year progression-free survival (PFS) and overall survival (OS). In multivariate analysis, only CA125 level normalization > 60 days was significantly associated with poor survival outcomes (PFS, HR 2.62 [95% CI: 1.54, 4.45], p= 0.004; OS, HR 2.40 [95% CI: 1.19, 4.81], p= 0.014). Conclusions: Normalization of CA125 level within 60 days after cytoreductive surgery followed by adjuvant chemotherapy in patients with advanced ovarian epithelial cancer could be used as a marker to predict survival.
Article
Introduction: Surgical complications after primary or interval debulking surgery in advanced ovarian cancer were investigated and associations with patient characteristics and surgical outcomes were explored. Material and methods: A population-based cohort study including all women with ovarian cancer, FIGO III-IV, treated with primary or interval debulking surgery, 2013-2017. Patient characteristics, surgical outcomes and complications according to the Clavien-Dindo (CD) classification system ≤30 days postoperatively, were registered. Uni- and multivariable regression analyses were performed with severe complications (CD ≥ III) as endpoint. PFS in relation was analyzed using the Kaplan-Meier method. Results: The cohort included 384 women, where 304 (79%) were treated with primary and 80 (21%) with interval debulking surgery. Complications CD I-V were registered in 112 (29%) patients and CD ≥ III in 42 (11%). Preoperative albumin was significantly lower in the CD ≥ III cohort compared with CD 0-II (P = 0.018). For every increase per unit in albumin, the risk of complications decreased by a factor of 0.93. There was no significant difference in completed chemotherapy between the cohorts CD 0-II 90.1% and CD ≥ III 83.3% (P = 0.236). In the univariable analysis; albumin <30 g/L, primary debulking surgery, complete cytoreduction and intermediate/high surgical complexity score (SCS) were associated with CD ≥ III. In the following multivariable analysis, only intermediate/high SCS was found to be an independent significant prognostic factor. Low (n = 180) vs intermediate/high SCS (n = 204) showed a median PFS of 17.2 months (95% confidence interval [CI] 15.2-20.7) vs 21.5 months (95% CI 18.2-25.7), respectively, with a significant log-rank; P = 0.038. Conclusions: Advanced ovarian cancer surgery is associated with complications but no significant difference was seen in completion of adjuvant chemotherapy when severe complications occur. Importantly, our study shows that intermediate/high SCS is an independent prognostic risk factor for complications. Low albumin, residual disease and primary debulking surgery were found to be associated with severe complications. These results may facilitate forming algorithms in the decision-making procedure of surgical treatment protocols.
Article
Objective The aims of the present study were to assess the oncological outcomes of platinum-sensitive recurrent ovarian cancer patients undergoing secondary cytoreduction (SCS) after treatment with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) at diagnosis and to compare the performance of different selection models in these patients. Methods Retrospective, observational, single-center cohort study including patients with platinum-sensitive recurrent epithelial ovarian cancer with abdominal/inguinal/cardiophrenic disease between November 2012 and November 2020. Patients were selected as surgical candidates with PET/CT-scan and with diagnostic laparoscopy. Results 272 patients were included in the study. Of these, 165 (60.7%) patients were treated with PDS at diagnosis and 107 (39.3%) with IDS. SCS was performed in 178 (65.4%) cases, with complete gross resection achieved in 155/178 (87.1%). No progression-free survival (PFS) difference was demonstrated when patients treated with PDS were compared with those treated with NACT+IDS at first diagnosis (median 21 versus 21 months; p = 0.684); no post-recurrence survival (PRS) difference was evident between the two groups (median 81 versus 77 months, respectively; p = 0.574). Current selection models to candidate patients to SCS adequately performed in patients treated with IDS at diagnosis, as well as in the PDS group, with combination of PET/CT-scan and laparoscopy being an accurate tool in prediction of no gross residual disease at SCS in this pre-selected population. Conclusions Patients with platinum-sensitive recurrent epithelial ovarian cancer treated with NACT/IDS as primary treatment have similar post-recurrence survival outcomes of those treated with PDS. Current models to select patients for SCS can be safely applied to IDS patients.
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Ovarian cancer (OC) is a leading cause of premature mortality worldwide, mainly because of its advanced stage at diagnosis and poor outcomes in metastatic phase. Quality and timely surgery is the key intervention for both the curative and the palliative setting, providing one of the largest benefits on the survival outcomes. However, patients with OC, at all stages, benefit of a number of pharmacological treatments, both chemotherapy and targeted agents. Therapeutic advances in OC reflect a better knowledge of the biology and the critical pathogenetic mechanisms of tumorigenesis. For instance, the discovery of homologous recombination deficiency, particularly BRCA gene mutations, and the implementation of anti-(Poly ADP-ribose polymerase) PARP treatments have been largely considered to be milestones in cancer treatment. PARP inhibitors are now approved as maintenance therapy in platinum-sensitive OC. Antiangiogenic agents can play an important role in the advanced disease. Immunotherapy has been tested in OC with less impactful results, suggesting the need of more efforts to identify predictive factors to refine the patient selection. Despite the progresses in treatment discovery, the prognosis of patients with more advanced diseases or exhibiting treatment resistance still remains dismal. The personalization of treatment, together with the developing of new drugs, will improve the prognosis of this disease, addressing an unmet area of the cancer treatment.
Article
Importance Randomized clinical trials have found that, in patients with advanced-stage epithelial ovarian cancer, neoadjuvant chemotherapy has similar long-term survival and improved perioperative outcomes compared with primary cytoreductive surgery. Despite this, considerable controversy remains about the appropriate use of neoadjuvant chemotherapy, and the proportion of patients who receive this treatment varies considerably among cancer programs in the US. Objective To evaluate the association between high levels of neoadjuvant chemotherapy administration and overall survival in patients with advanced ovarian cancer. Design, Setting, and Participants This difference-in-differences comparative effectiveness analysis leveraged differential adoption of neoadjuvant chemotherapy in Commission on Cancer–accredited cancer programs in the US and included women with a diagnosis of stage IIIC and IV epithelial ovarian cancer between January 2004 and December 2015 who were followed up through the end of 2018. The data were analyzed between September 2020 and January 2021. Exposures Treatment in a cancer program with high levels of neoadjuvant chemotherapy administration (more often than expected based on case mix) or in a program that continued to restrict its use after the 2010 publication of a clinical trial demonstrating the noninferiority of neoadjuvant chemotherapy compared with primary surgery for the treatment of patients with advanced ovarian cancer. Main Outcomes and Measures Case mix–standardized median overall survival time and 1-year all-cause mortality assessed with a flexible parametric survival model. Results We identified 19 562 patients (mean [SD] age, 63.9 [12.6] years; 3.2% Asian, 8.0% Black, 4.8% Hispanic, 82.5% White individuals) who were treated in 332 cancer programs that increased use of neoadjuvant chemotherapy from 21.7% in 2004 to 2009 to 42.2% in 2010 to 2015 and 19 737 patients (mean [SD] age, 63.5 [12.6] years; 3.1% Asian, 7.7% Black, 6.5% Hispanic, 81.8% White individuals) who were treated in 332 programs that marginally increased use of neoadjuvant chemotherapy (20.1% to 22.5%) over these periods. The standardized median overall survival times improved by similar magnitudes in programs with high (from 31.6 [IQR, 12.3-70.1] to 37.9 [IQR, 17.0-84.9] months; 6.3-month difference; 95% CI, 4.2-8.3) and low (from 31.4 [IQR, 12.1-67.2] to 36.8 [IQR, 15.0-80.3] months; 5.4-month difference, 95% CI, 3.5-7.3) use of neoadjuvant chemotherapy after 2010 (difference-in-differences, 0.9 months; 95% CI, −1.9 to 3.7). One-year mortality declined more in programs with high (from 25.6% to 19.3%; risk difference, −5.2%; 95% CI, −6.4 to −4.1) than with low (from 24.9% to 21.8%; risk difference, −3.2%, 95% CI, −4.3 to −2.0) use of neoadjuvant chemotherapy (difference-in-differences, −2.1%; 95% CI, −3.7 to −0.5). Conclusions and Relevance In this comparative effectiveness research study, compared with cancer programs with low use of neoadjuvant chemotherapy, those with high use had similar improvements in median overall survival and larger declines in short-term mortality.
Article
Background This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting.Methods Ovarian, fallopian tube or primary peritoneal cancer patients with stage III–IV disease received neoadjuvant chemotherapy (NAC) every 3 weeks consisting of paclitaxel (80 mg/m2) on days 1, 8, and 15; carboplatin (AUC 6.0 mg/mL × min.) on day 1; and bevacizumab (15 mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications.ResultsTwenty-four patients were included in this study. The median age was 55.5 years (37–80 years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7–92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred.Conclusions Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved.
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From past to present, silver has existed available in many treatments in the field of health including dentistry. In the 1800s, antimicrobial and antirheumatic properties were discovered. Silver components were used in medicine for tetanus and rheumatic drugs as well as for the treatment of cold and gonorrhea. In the following years, with the discovery of antibiotics, studies on the use of silver in medicine were suspended. However, with the emergence of antibiotic resistance and the inability to prevent it, the interest in silver and its compunds has increased and studies on combined use have become the focus of attention. Silver compounds including silver nitrate (AgNO3) and silver sulfadiazine have been utilized as topical antibacterial agents with the aim of controlling skin infections which are confronted in incidents such as burns and chronic ulcers. Using silver compounds in the field of dentistry dates back to previous times owing to their antibacterial and antimicrobial properties. Silver amalgam and dental casting alloys are utilized in dentistry for a long time. In this respect, silver nitrate, being a silver compound, was used as an anti- caries, cavity sterilizing and dentin desensitizing agent. In the 1960s, combined agent studies were carried out, which put forward that compounds with fluoride would be more effective. AgNO3, AgF and Ag (NH3)2F as well as other silver particulate additives were investigated and utilized for management of caries. Various clinical studies have been conducted upon silver in caries management. Applying silver fluoride (AgF) compounds clinically, however, is limited as a result of the associated black staining. In order to eliminate this disadvantage, studies are carried out on silver nanoparticles (NPs) and silver diamine fluoride (Ag (NH3)2F ) compound, which are new compounds and used as anti-caries and dentin desensitizing agents today. Moreover, silver compounds and NPs are focused on for different types of dental applications which involve restorative material, endodontic retrograde cement, dental implants and caries preventive solution.
Article
Objective To evaluate a relation between BRCA1/2 status and the Chemotherapy Response Score in patients with epithelial ovarian cancer undergoing neoadjuvant chemotherapy and interval debulking surgery. Methods Data were retrospectively collected on patients with unresectable disease undergoing three or four cycles of neoadjuvant chemotherapy and interval debulking surgery at the Gynecologic Oncology Unit of the Catholic University of the Sacred Heart from January 2016 to December 2020. All patients were assessed for BRCA1/2 somatic mutation at diagnosis. The omental specimens obtained at the interval surgery were evaluated according to Bohm’s Chemotherapy Response Score System. Results A total of 172 patients were included in the analysis, 69 (40%) patients were BRCA1/2 mutation carriers and 103 (60%) patients were wild type. In the wild-type group ( BRCAwt ), 73 (70.9%) patients had a Chemotherapy Response Score of 1 or 2 and 30 (29.1%) patients had a score of 3. In the BRCA1/2 carriers group ( BRCAmut ), 39 (56.5%) patients had a score of 1 or 2 and 30 (43.5%) patients had a score of 3. Among the BRCAwt group, those with a Chemotherapy Response Score of 3 had a prolonged median progression-free survival (22 vs 15 months, p=0.003). Among the BRCAmut carriers group, no differences were found (30 vs 27 months, p=0.55). No difference in overall survival was observed in either the BRCAmut carriers population (p=0.23) or the BRCAwt population (60 vs 44 months, p=0.06). Conclusions Patients with BRCA1/2mut seem to achieve a score of 1, 2 or 3 with the same frequency. In contrast, patients with BRCAwt seem to have a score of 1 or 2 more frequently than a score of 3. In patients with BRCA1/2mut , this score may not be an indicator of chemosensitivity.
Article
Treatment of low- and high-grade ovarian cancer has changed dramatically in the past decades. The two main pillars of treatment are multivisceral surgery with the aim of macroscopic complete resection and, from Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage IC, platinum-based adjuvant chemotherapy. In advanced disease as well as low- and high-grade serous ovarian cancer, the primary chemotherapy combination of carboplatin and paclitaxel has become the international standard. The question of the importance of neoadjuvant chemotherapy in primary ovarian cancer has not yet been answered, but will hopefully be clarified by the completed Trial of Radical Upfront Surgical Therapy (TRUST). Although the impact of maintenance therapy in the quantitively much rarer low-grade ovarian cancer has not been conclusively evaluated, maintenance therapy in advanced high-grade ovarian cancer is standard. Depending on homologous recombination deficiency (HRD) status and the possibility of bevacizumab therapy, the three treatment options are 1. bevacizumab mono-maintenance; 2. niraparib (poly adenosine diphosphate-ribose polymerase [PARP] inhibitor) mono-maintenance, or 3. a combination of olaparib (PARP inhibitor) and bevacizumab. In the coming years, further combination strategies including PARP and immune checkpoint inhibitors, bevacizumab, and endocrine therapy will be investigated in large trials.
Article
Introduction The role of a molecular pattern predictive of hyperthermic intraperitoneal chemotherapy (HIPEC) efficacy in advanced ovarian cancer (AOC) patients has been poorly investigated. We aimed to assess the effect of HIPEC after primary debulking surgery (PDS) in AOC according to patient's Breast Cancer Gene (BRCA) mutational status. Methods This is a retrospective, single center, case-control study. Data on AOC patients receiving HIPEC at the end of PDS as previously enrolled in a phase II monocentric trial (HIPEC group), were retrieved and matched for clinical and surgical characteristics with a group of cases who underwent PDS without receiving HIPEC between 01/2010 and 01/2015 (No HIPEC group). Patients with International Federation of Gynecology and Obstetrics (FIGO) stage ≥IIIB disease, aged between 18-70 years, with a laparoscopic Predictive Index value (PIV) ≤8 and residual disease ≤2.5 mm were included. Results 70 patients were included. With the except of age (p=0.012), the populations were balanced for the main characteristics. At a median follow-up of 48 months, no differences in Progression Free Survival (PFS) (p=0.968) and Overall Survival (OS) (p=0.789) were recorded. Survival analysis according to HIPEC administration and BRCA mutational status showed an improved PFS (p=0.011) and OS (p=0.003) in BRCA mutated compared to wild-type patients when HIPEC was not administered, whilst they were superimposable in case of HIPEC administration (p=0.857 vs p=0.372; respectively). No differences in terms of neither intra-operative (p=1.0) nor early post-operative complications (p=0.920) were detected. Conclusions Our results show that HIPEC in AOC may be a promising treatment in BRCA wild-type patients, as it seems to balance their decreased chemosensitivity compared to mutation carriers.
Article
The growing use of neoadjuvant chemotherapy to treat advanced-stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA-sequencing and panel DNA-sequencing of 596 cancer-related genes was performed on paired FFPE specimens collected before and after chemotherapy, and differentially expressed genes (DEGs) and CNVs in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy resistant specimens. AP-1 transcription factor family genes (FOS, FOSB, FRA-1) were particularly upregulated in chemotherapy resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses SIK2. In vitro, combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and SIK2 copy number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance.
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Ovarian cancer is the third most frequent gynaecological malignancy worldwide and in Mexico, with a high mortality rate, due to that in many cases its diagnosis is made in advanced stages. Prognosis is important for determining the subtype and the degree of evolution. During lasts years, the management of ovarian cancer has undergone an important evolution with the incorporation of new therapeutic options, which in turn represent an increase in the survival of these patients. We present recommendations for the management of ovarian cancer developed by an expert panel Mexican based on available evidence so far and the characteristics of health care in the country.
Article
Ovarian cancer continues to be the leading cause of gynaecological cancer death in the UK. It has previously been described as the ‘silent killer’, as symptoms are typically absent or non-specific early in the disease leading to a later stage at diagnosis where fewer treatment options are available. Stage at presentation influences patient survival, and therefore, early detection within primary care is vital. Currently, there is no screening programme for ovarian cancer, and so diagnosis relies on investigation of symptomatic women presenting to healthcare professionals and an awareness of vague symptoms that could indicate ovarian cancer pathology. This article aims to provide an overview of ovarian cancer, including epidemiology, risk factors, signs and symptoms, and diagnosis within primary care. We will also briefly discuss current treatment strategies for ovarian cancer.
Article
Introduction: The survival benefits of surgical cytoreduction in ovarian cancer are well-established. However, the surgical outcome has never been assessed while controlling for the efficacy of chemotherapy. This leaves the possibility that cytoreduction may not be beneficial for patients whose cancer does not respond well to adjuvant treatment. We sought to answer whether surgical cytoreduction independently improves overall survival when controlling for chemotherapy outcome. Material and methods: We performed a retrospective case-control study using our institution's ovarian cancer database to evaluate the effect of optimal cytoreduction on advanced stage, high-grade serous ovarian cancer. Patients' characteristics were compared using both univariate and multivariate regression modeling to assess for independent predictors of overall survival. Results: A total of 470 patients were assessed for inclusion; 234 responders to chemotherapy and 98 nonresponders. Significant survival characteristics were identified and included in the multivariate analysis. Independent predictors of survival in the multivariate analysis were age, responder status, optimal cytoreduction, neoadjuvant chemotherapy, and number of chemotherapy cycles. Kaplan-Meier survival curves showed improved survival for both patients who responded to chemotherapy and for those undergoing optimal cytoreduction (p < 0.001). We also demonstrated improved survival for patients receiving optimal cytoreduction among both nonresponders and responders (p < 0.001). Conclusions: Our analysis shows that patients who undergo optimal cytoreduction have an overall survival benefit regardless of their response to chemotherapy. Therefore, cytoreduction should be considered in all patients, even in those with advanced disease, if an optimal result can be achieved. This study was underpowered to assess patients who received neoadjuvant chemotherapy as a separate subgroup, but the order of treatment was controlled for in the overall analysis.
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Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.
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Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
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Cancer incidence and mortality estimates for 25 cancers are presented for the 40 countries in the four United Nations-defined areas of Europe and for the European Union (EU-27) for 2012. We used statistical models to estimate national incidence and mortality rates in 2012 from recently-published data, predicting incidence and mortality rates for the year 2012 from recent trends, wherever possible. The estimated rates in 2012 were applied to the corresponding population estimates to obtain the estimated numbers of new cancer cases and deaths in Europe in 2012. There were an estimated 3.45 million new cases of cancer (excluding non-melanoma skin cancer) and 1.75 million deaths from cancer in Europe in 2012. The most common cancer sites were cancers of the female breast (464,000 cases), followed by colorectal (447,000), prostate (417,000) and lung (410,000). These four cancers represent half of the overall burden of cancer in Europe. The most common causes of death from cancer were cancers of the lung (353,000 deaths), colorectal (215,000), breast (131,000) and stomach (107,000). In the European Union, the estimated numbers of new cases of cancer were approximately 1.4 million in males and 1.2 million in females, and around 707,000 men and 555,000 women died from cancer in the same year. These up-to-date estimates of the cancer burden in Europe alongside the description of the varying distribution of common cancers at both the regional and country level provide a basis for establishing priorities to cancer control actions in Europe. The important role of cancer registries in disease surveillance and in planning and evaluating national cancer plans is becoming increasingly recognised, but needs to be further advocated. The estimates and software tools for further analysis (EUCAN 2012) are available online as part of the European Cancer Observatory (ECO) (http://eco.iarc.fr). Copyright © 2013 Elsevier Ltd. All rights reserved.
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Primary debulking surgery before initiation of chemotherapy has been the standard of care for patients with advanced ovarian cancer. We randomly assigned patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (so-called interval debulking surgery). Of the 670 patients randomly assigned to a study treatment, 632 (94.3%) were eligible and started the treatment. The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking. The hazard ratio for death (intention-to-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P=0.01 for noninferiority), and the hazard ratio for progressive disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival. Neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resection of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003636.)
Article
Objective: To compare outcomes of women with advanced-stage low-grade serous ovarian cancer and high-grade serous ovarian cancer and identify factors associated with survival among patients with advanced-stage low-grade serous ovarian cancer. Methods: A retrospective study of patients diagnosed with grade 1 or 3, advanced-stage (stage IIIC and IV) serous ovarian cancer between 2003 and 2011 was undertaken using the National Cancer Database, a large administrative database. The effect of grade on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. Among women with low-grade serous ovarian cancer, propensity score matching was used to compare all-cause mortality among similar women who underwent chemotherapy and lymph node dissection and those who did not. Results: A total of 16,854 (95.7%) patients with high-grade serous ovarian cancer and 755 (4.3%) patients with low-grade serous ovarian cancer were identified. Median overall survival was 40.7 months among high-grade patients and 90.8 months among women with low-grade tumors (P<.001). Among patients with low-grade serous ovarian cancer in the propensity score-matched cohort, the median overall survival was 88.2 months among the 140 patients who received chemotherapy and 95.9 months among the 140 who did not receive chemotherapy (P=.7). Conversely, in the lymph node dissection propensity-matched cohort, median overall survival was 106.5 months among the 202 patients who underwent lymph node dissection and 58 months among the 202 who did not (P<.001). Conclusion: When compared with high-grade serous ovarian cancer, low-grade serous ovarian cancer is associated with improved survival. In patients with advanced-stage low-grade serous ovarian cancer, lymphadenectomy but not adjuvant chemotherapy was associated with improved survival.
Article
Purpose: To provide guidance to clinicians regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer. Methods: The Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an Expert Panel and conducted a systematic review of the literature. Results: Four phase III clinical trials form the primary evidence base for the recommendations. The published studies suggest that for selected women with stage IIIC or IV epithelial ovarian cancer, neoadjuvant chemotherapy and interval cytoreduction are noninferior to primary cytoreduction and adjuvant chemotherapy with respect to overall and progression-free survival and are associated with less perioperative morbidity and mortality. Recommendations: All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy. The primary clinical evaluation should include a CT of the abdomen and pelvis, and chest imaging (CT preferred). Women with a high perioperative risk profile or a low likelihood of achieving cytoreduction to < 1 cm of residual disease (ideally to no visible disease) should receive neoadjuvant chemotherapy. Women who are fit for primary cytoreductive surgery, and with potentially resectable disease, may receive either neoadjuvant chemotherapy or primary cytoreductive surgery. However, primary cytoreductive surgery is preferred if there is a high likelihood of achieving cytoreduction to < 1 cm (ideally to no visible disease) with acceptable morbidity. Before neoadjuvant chemotherapy is delivered, all patients should have confirmation of an invasive ovarian, fallopian tube, or peritoneal cancer. Additional information is available at www.asco.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki.
Article
We conducted a phase III, non-inferiority trial comparing upfront primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) for stage III/IV ovarian, tubal, and peritoneal cancers (JCOG0602). Two earlier studies, EORTC55971 and CHORUS, demonstrated non-inferior survival of patients treated with NAC. However, they could not evaluate true treatment invasiveness because of adding diagnostic laparotomy or laparoscopy before treatment in over 30% of both arms of EORTC55971 and in 16% of NAC arm of CHORUS. Patients were randomised into the standard arm (PDS followed by eight cycles of paclitaxel and carboplatin [TC]) and NAC arm (four cycles of TC, IDS, and four cycles of TC). In the standard arm, IDS was optional for patients who had undergone suboptimal or incomplete PDS. Treatment invasiveness was compared between arms (UMIN000000523). Between November 2006 and October 2011, 301 patients were randomised. In the standard arm, 147/149 underwent PDS and 49 underwent IDS. In the NAC arm, 130/152 underwent IDS. The NAC arm required fewer surgeries (mean 0.86 versus 1.32, p < 0.001) and shorter total operation time (median 273 min versus 341 min, p < 0.001) than the standard arm and required a lower frequency of abdominal organ resection (23.7% versus 37.6%, p = 0.012) or distant metastases resection (3.9% versus 10.7%, p = 0.027). In the NAC arm IDS, blood/ascites loss was smaller (median 787 ml versus 3235 ml, p < 0.001) and albumin transfusion and G3/4 adverse events after surgery in total were less frequent (26.2% versus 58.5%, p < 0.001; 4.6% versus 15.0%, p = 0.005, respectively). Our findings demonstrated that NAC treatment is less invasive than standard treatment. NAC treatment may become the new standard treatment for advanced ovarian cancer when non-inferior survival is confirmed in the planned primary analysis in 2017.
Article
Objective: To establishing whether neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is superior primary debulking surgery (PDS) in terms of clinical outcome as well as peri-operative morbidity in advanced epithelial ovarian cancer (AEOC) endowed with high tumour load (HTL). Material and methods: This is a single-Institution, superiority, randomised phase III trial enrolling supposed AEOC women. Patients considered pre-operatively eligible were triaged to staging laparoscopy to assess the predictive index (PI) of tumour load. All AEOC women with PI≥8 or≤12 (considered as HTL) were included. They were randomly assigned (1:1 ratio) to undergo either PDS followed by systemic adjuvant chemotherapy (arm A, standard), or NACT followed by IDS (NACT/IDS) (arm B, experimental). Co-primary outcome measures were postoperative complications (graded according to the Memorial Sloan Kettering Cancer Center surgical secondary events grading system) and progression free survival (PFS); secondary outcomes were overall survival, and quality of life (QoL). QoL was assessed using the EORTC QoL questionnaires. A sample size of 110 patients was required for the analysis of the first co-primary end-point (major peri-operative morbidity) whereas recruitment is still on-going to achieve the statistical power on PFS. Results: Between October 2011 and November 2014, we registered 280 AEOC. Of the 110 eligible women, 55 were assigned to arm A and 55 to arm B. Despite different extension of surgery, rates of complete residual disease (residual tumour=0 cm) were superimposable between the groups (45.5% versus 57.7%; p=0.206). Twenty-nine patients (52.7%) in arm A experienced early grade III-IV complications versus three patients (5.7%) in IDS (p=0.0001). The most common complication was grade III and consisted of symptomatic pleural effusion requiring thoracic drainage (17/55 women (30.9%) in arm A versus 1/52 (1.9%) in arm B, p=0.0001). Three grade IV (5.4%) (i.e., two re-operations for postoperative haemorrhage and one septic multi-organ failure), and two grade V (3.6%) (two deaths for acute cardiopulmonary failure) early complications were observed in arm A only. Mean QoL scores of several scales/items were shown to ameliorate over time in both arms. Emotional functioning, cognitive functioning, nausea/vomiting, dyspnoea, insomnia and hair loss were statistically and clinically better in NACT/IDS compared to PDS arm. Conclusions: Perioperative moderate/severe morbidity as well as QoL scores were shown to be more favourable in NACT/IDS arm than PDS in AEOC patients with very HTL. Completion of patient enrolment and analysis of survival data will clarify whether PDS with such a high rate of severe complications is an acceptable treatment in AEOC women with HTL.
Article
Objective: Since almost two decades standard 1st-line chemotherapy for advanced ovarian cancer (AOC) has been a platinum/taxane combination. More recently, this general strategy has been challenged because different types of AOC may not benefit homogenously. Low-grade serous ovarian cancer (LGSOC) is one of the candidates in whom efficacy of standard chemotherapy should be revised. Methods: This study is an exploratory case control study of the AGO-metadatabase of 4 randomized phase III trials with first-line platinum combination chemotherapy without any targeted therapy. Patients with advanced FIGO IIIBIV low-grade serous ovarian cancer were included and compared with control cases having high-grade serous AOC. Results: Out of 5114 patients in this AGO database 145 (2.8%) had LGSOC and of those thirty-nine (24.1%) had suboptimal debulking with post-operative residual tumor >1cm, thus being eligible for response evaluation. An objective response was observed in only 10 patients and this 23.1% response rate (RR) was significantly lower compared to 90.1% RR in the control cohort of high-grade serous ovarian cancer (HGSOC) (p<0.001). Both, LGSOC and HGSOC patients who underwent complete cytoreduction had significantly better progression free survival (PFS) and overall survival (OS) in comparison to those with residuals after primary surgery, accordingly (p<0.001). Conclusions: Our observation indicates that low-grade serous cancer is not as responsive to platinum-taxane-based chemotherapy as high-grade serous AOC. In contrast, surgical debulking showed a similar impact on outcome in both types of AOC thus indicating different roles for both standard treatment modalities. Systemic treatment of low grade serous AOC urgently warrants further investigations.
Article
The international standard of care for women with suspected advanced ovarian cancer is surgical debulking followed by platinum-based chemotherapy. We aimed to establish whether use of platinum-based primary chemotherapy followed by delayed surgery was an effective and safe alternative treatment regimen. In this phase 3, non-inferiority, randomised, controlled trial (CHORUS) undertaken in 87 hospitals in the UK and New Zealand, we enrolled women with suspected stage III or IV ovarian cancer. We randomly assigned women (1:1) either to undergo primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy. Each 3-week cycle consisted of carboplatin AUC5 or AUC6 plus paclitaxel 175 mg/m(2), or an alternative carboplatin combination regimen, or carboplatin monotherapy. We did the random assignment by use of a minimisation method with a random element, and stratified participants according to the randomising centre, largest radiological tumour size, clinical stage, and prespecified chemotherapy regimen. Patients and investigators were not masked to group assignment. The primary outcome measure was overall survival. Primary analyses were done in the intention-to-treat population. To establish non-inferiority, the upper bound of a one-sided 90% CI for the hazard ratio (HR) had to be less than 1·18. This trial is registered, number ISRCTN74802813, and is closed to new participants. Between March 1, 2004, and Aug 30, 2010, we randomly assigned 552 women to treatment. Of the 550 women who were eligible, 276 were assigned to primary surgery and 274 to primary chemotherapy. All were included in the intention-to-treat analysis; 251 assigned to primary surgery and 253 to primary chemotherapy were included in the per-protocol analysis. As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22·6 months in the primary-surgery group versus 24·1 months in primary chemotherapy. The HR for death was 0·87 in favour of primary chemotherapy, with the upper bound of the one-sided 90% CI 0·98 (95% CI 0·72-1·05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 [24%] of 252 women vs 30 [14%] of 209, p=0·0007, and 14 women [6%] vs 1 woman [<1%], p=0·001). The most common grade 3 or 4 postoperative adverse event was haemorrhage in both groups (8 women [3%] in the primary-surgery group vs 14 [6%] in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p=0·0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group. In women with stage III or IV ovarian cancer, survival with primary chemotherapy is non-inferior to primary surgery. In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer. Cancer Research UK and the Royal College of Obstetricians and Gynaecologists. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
To investigate whether biomarkers consisting of baseline characteristics of advanced stage ovarian cancer patients can help in identifying subgroups of patients who would benefit more from primary surgery or neoadjuvant chemotherapy. We used data of the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial in which 670 patients were randomly assigned to primary surgery or neoadjuvant chemotherapy. The primary outcome was overall survival. Ten baseline clinical and pathological characteristics were selected as potential biomarkers. Using Subpopulation Treatment Effect Pattern Plots (STEPP), biomarkers with a statistically significant qualitative additive interaction with treatment were considered as potentially informative for treatment selection. We also combined selected biomarkers to form a multimarker treatment selection rule. The size of the largest metastatic tumour and clinical stage were significantly associated with the magnitude of the benefit from treatment, in terms of five-year survival (p for interaction: 0.008 and 0.016, respectively). Stage IIIC patients with metastatic tumours ⩽45mm benefited more from primary surgery while stage IV patients with metastatic tumours >45mm benefited more from neoadjuvant chemotherapy. In stage IIIC patients with larger metastatic tumours and in stage IV patients with less extensive metastatic tumours both treatments were equally effective. We estimated that by selecting treatments for patients based on largest metastatic tumour and clinical stage, the potential five-year survival rate in the population of treated patients would be 27.3% (95% confidence interval (CI) 21.9-33.0), 7.8% higher than if all were treated with primary surgery, and 5.6% higher if all were treated with neoadjuvant chemotherapy. Although survival was comparable after primary surgery and neoadjuvant chemotherapy in the overall group of patients with ovarian cancer in the EORTC 55971 trial, we found in this exploratory analysis that patients with stage IIIC and less extensive metastatic tumours had higher survival with primary surgery, while patients with stage IV disease and large metastatic tumours had higher survival with neoadjuvant chemotherapy. For patients who did not meet these criteria, both treatment options led to comparable survival rates.
Article
In most randomized clinical trials (RCTs) with a right-censored time-to-event outcome, the hazard ratio is taken as an appropriate measure of the effectiveness of a new treatment compared with a standard-of-care or control treatment. However, it has long been known that the hazard ratio is valid only under the proportional hazards (PH) assumption. This assumption is formally checked only rarely. Some recent trials, particularly the IPASS trial in lung cancer and the ICON7 trial in ovarian cancer, have alerted researchers to the possibility of gross non-PH, raising the critical question of how such data should be analyzed. Here, we propose the use of the restricted mean survival time at a prespecified, fixed time point as a useful general measure to report the difference between two survival curves. We describe different methods of estimating it and we illustrate its application to three RCTs in cancer. The examples are graded from a trial in kidney cancer in which there is no evidence of non-PH, to IPASS, where the opposite is clearly the case. We propose a simple, general scheme for the analysis of data from such RCTs. Key elements of our approach are Andersen's method of 'pseudo-observations,' which is based on the Kaplan-Meier estimate of the survival function, and Royston and Parmar's class of flexible parametric survival models, which may be used for analyzing data in the presence or in the absence of PH of the treatment effect.
Article
The effect of tumor bulk resection on survival was studied in 102 patients with stages II and III ovarian cancer. A multiple linear regression equation provuded both simultenaous control of multiple confounding variables and an assessment of these variables as independent predictors of survival. The most important factors were the histologic grade of the tumor and the size of the largest residual tumor mass after operation. Survival time was uniformly poor if the diameter of the largest residual tumor mass exceeded 1.5 cm irrespective of total tumor volume (mean=12.7 months, SE=1.6 mo). Survival time was inversely proportional to residual mass size under 1.6 cm, and surgery improved survival relative to reduction in mass size below this limit. Extensive resections of tumor bulk with failure to remove all masses greater than 1.5 cm in diameter did not influence survival. Surgery provides optimum benefit when all gross tumor can be excised safely.
Article
During chemotherapy and after relapse several types of operations are used in ovarian cancer: secondary cytoreductive surgery, interval cytoreductive surgery, second-look surgery, and palliative secondary surgery. The role of these operations has been difficult to define because there is considerable variation in the patterns of behaviour of tumours among those with persistent or recurrent disease. The definitions, indications and impact of these procedures are reviewed.
Article
The CONSORT (Consolidated Standards of Reporting Trials) Statement, including a checklist and a flow diagram, was developed to help authors improve their reporting of randomized controlled trials. Its primary focus was on individually randomized trials with 2 parallel groups that assess the possible superiority of one treatment compared with another but is now being extended to other trial designs. Noninferiority and equivalence trials have methodological features that differ from superiority trials and present particular difficulties in design, conduct, analysis, and interpretation. Although the rationale for such trials occurs frequently, those designed and described specifically as noninferiority or equivalence trials appear less commonly in the medical literature. The quality of reporting of those that are published is often inadequate. In this article, we present an adapted CONSORT checklist for reporting noninferiority and equivalence trials and provide illustrative examples and explanations for those items amended from the original CONSORT checklist. The intent is to improve reporting of noninferiority and equivalence trials, enabling readers to assess the validity of their results and conclusions.
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