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GINECO, Paris, FranceUniversité Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon-Sud, EMR UCBL/HCL 3738, Lyon, FranceMedical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL, Lyon, France
GINECO, Paris, FranceUniversité Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon-Sud, EMR UCBL/HCL 3738, Lyon, FranceMedical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL, Lyon, France
In ovarian cancer patients, the 1st-line treatment relies on surgery and chemotherapy.
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The prognostic role of the chemotherapy efficacy has been insufficiently addressed.
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Indicators of the chemosensitivity include pathological, genomic or circulating markers.
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Both the surgery completeness and chemosensitivity impact the treatment success.
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The debulking surgery utility may differ according to the primary chemosensitivity.
Abstract
In patients with advanced ovarian carcinomas, the first-line treatment has historically relied on debulking surgery and platinum-based chemotherapy. If the major therapeutic/prognostic role of the surgery part is well understood, and integrated in disease-management algorithms, the impact of chemotherapy efficacy has been insufficiently addressed.
This review describes the main indicators of the chemosensitivity reported in the literature (pathological response score & biomarkers; genomic alterations; DNA scars; imaging; and circulating tumor markers), and investigates the respective roles of the debulking surgery and tumor primary chemosensitivity relative to the success of the comprehensive medical-surgical treatment. The tumor primary chemosensitivity exhibits a major independent prognostic impact on the feasibility of complete interval debulking surgery after neoadjuvant chemotherapy, risk of subsequent platinum-resistant relapse, efficacy of subsequent maintenance therapies with bevacizumab or PARP inhibitors, progression-free survival, overall and long-term survival. While both the completeness of the surgery and the tumor primary chemosensitivity are undoubtedly major prognostic factors, the impact of the surgery may differ according to the primary chemosensitivity. This assumption raises a potential new concept: in patients with advanced ovarian carcinomas, the maximum tumor debulking should ideally be both biological (induced by systemic treatments) and physical (induced by surgery) for maximizing patient survival. Besides BRCA and HRD biomarkers, future trials and algorithms may integrate indicator(s) of the tumor primary chemosensitivity for guiding more subtly the surgical and medical management in first-line setting. Moreover, such a parameter would help in the development of novel approaches meant to reverse the resistance to chemotherapy and PARP inhibitors.
]. The backbone of the standard first-line treatment has historically relied on two components, with the combination of debulking surgery and systemic medical therapy.
The strong prognostic value of the completeness of the debulking surgery has been reproducibly reported, and integrated in the disease management guidelines. Cytoreductive surgery is recommended when the likelihood of achieving complete debulking without any macroscopic residual disease is sufficiently high, either as a primary debulking surgery (PDS), or as an interval debulking surgery (IDS) after neoadjuvant chemotherapy, depending on the initial resectability evaluation [
ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: society of gynecologic oncology and American society of clinical oncology clinical practice guideline.
The effect of liberal vs restrictive use of neoadjuvant chemotherapy for ovarian cancer on postoperative mortality and long-term survival: a quasi-experimental study.
2020 society of gynecologic oncology annual meeting on women’s cancer abstract 165 presented March 30. 2020
The systemic treatment includes 6 cycles of carboplatin and paclitaxel given as adjuvant or peri-operative chemotherapy, or as an exclusive treatment in patients who are not operated. Chemotherapy can be associated with the anti-angiogenic monoclonal antibody bevacizumab continued as a maintenance treatment for a total of 15 months. Inhibitors of poly(ADP-ribose) polymerase (PARP) administered alone, or in combination with bevacizumab, represent a recent milestone as maintenance first-line treatment [
ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: society of gynecologic oncology and American society of clinical oncology clinical practice guideline.
]. The prognostic impact of the tumor primary (intrinsic) chemosensitivity on the feasibility of the IDS and the success of the first-line treatment has been poorly addressed, as recently acknowledged by European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO) [
ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
]. It is not considered as a decisional tool for guiding the disease management, regarding surgery, or selecting the best subsequent maintenance treatment in between PARP inhibitors or bevacizumab. With the major improvements recently observed in systemic treatments, legitimate questions can be raised about the respective roles of medical treatment and surgery.
The present review describes the main indicators of the tumor primary chemosensitivity reported so far, with their strengths and limitations. Moreover, it examines available data about the respective roles of the debulking surgery and tumor primary chemosensitivity relative to the success of the first-line treatment, and to patient prognosis.
Results
Indicators of tumor primary chemosensitivity
Integrating information about the tumor primary sensitivity to systemic treatments in the decision process requires objective measurable markers, that would be available in the first weeks of treatment (Table 1). The initial attempts relying on in-vitro chemotherapy sensitivity testings were not successful, due to the complexity of producing patient ovarian cancer cell cultures, and the heterogeneity of response patterns [
]. More recently, promising outcomes were reported in small studies with patient-derived xenograft (PDX) models, that were described as potentially useful to predict the efficacy of platinum-based chemotherapy, or other chemotherapy regimens [
]. For example, high consistency was found between clinical response to platinum-based chemotherapy and PDX response to cisplatin in a pilot study of 10 patients with platinum-sensitive or platinum–resistant/refractory ovarian cancers [
]. However, the routine implementation of this approach suffers from several limitations, including time-consumption for patients & research team, inconsistent engraftment rates, need for adequate facilities, high cost, loss of immune systems, and uncontrolled impact of the tumor microenvironment [
Table 1Description of the main indicators of the tumor primary chemosensitivity in the literature. OS: overall survival; PFS: progression-free survival; HR: homologous recombination.
Main classes of indicators of the tumor primary chemosensitivity reported in the literature
Potential utility for disease management in first-line setting
Association to the tumor radiological response during chemotherapy
Association to the probability of complete interval debulking surgery
Association to the risk of subsequent platinum- resistant relapse
Association to the progression-free survival (PFS)
Association to the efficacy of maintenance treatment
Association to the overall survival (OS)
Association to the probability of disease cure
Limitations for implementation in routine in the management of ovarian cancers
Ex-vivo assays
In-vitro assays for anti-mitograms on cell cultures
Association to the efficacy of platinum-based chemotherapy or other chemotherapy
Complexity of the methodology. Limited power of small studies. Time required for tumor growth. Cost of the approach. Inconsistent engraftment rates. Poor assessment of the impact of the immune system impact, and of the microenvironment.
Pathology examination
Chemotherapy response score (CRS) on surgery specimen
ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: a systematic review and meta-analysis of individual patient data.
Chemotherapy response score: development and validation of a system to quantify histopathologic response to neoadjuvant chemotherapy in tubo-ovarian high-grade serous carcinoma.
CRS3 significantly associated with improved PFS compared to CRS1/2
CRS3 significantly associated with improved PFS compared to CRS1/2
Requirement of the tumor tissue from omentum obtained at IDS, thereby limiting the possibility of adjustment of medical-surgical management before surgery. Inconsistent outcomes about the prognostic value regarding OS for CRS1 or 2.
Level of Tumor Infiltrating Lymphocytes (TIL) infiltrate
Prognostic impact of human leukocyte antigen class I expression and association of platinum resistance with immunologic profiles in epithelial ovarian cancer.
Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs.
Higher overall response and complete response rate during neoadjuvant platinum-based chemotherapy
BRCA2 mutation associated with longer platinum-free duration
Higher PFS in patients with BRCA mutations and HRD-positive tumors
Higher benefit from PARP inhibitors with BRCA mutations and HRD-positive tumors
Higher OS in patients with BRCA mutations
BRCA mutation status: Cost and availability of the assays. HR panels: Difficulties for building a validated panel with HR-related genes due to many uncertainties about the impacts of many genes. Genomic scar approach: No demonstration of the predictive value of genomic scar-based approaches regarding chemosensitivity in ovarian cancer patients.
Higher percentage of patients with platinum-resistant diseases
Lower OS in patients with CCEN1 amplification
Limited power of small studies. Complexity of methodology for assessing CCNE1 amplification, which cannot be replaced by expression by immunohistochemistry.
Large-scale integrated analysis of ovarian cancer tumors and cell lines identifies an individualized gene expression signature for predicting response to platinum-based chemotherapy.
Higher percentage of patients experiencing partial/complete response among low-risk group with the 97-gene signature
DRDscore associated with the likelihood of subsequent platinum-resistant relapse
Higher OS in patients with low-risk disease compared to high-risk disease with the 97-gene signature
Requirement for tumor tissue, limiting the possibility of adjustment of medical-surgical management before surgery. Cost and complexity of the methodology.
Imaging
Radiological response during neoadjuvant chemotherapy
Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial.
1027PEarly prediction of the platinum-resistant relapse risk using the CA125 modeled kinetic parameter KELIM: a pooled analysis of AGO-OVAR 7 & 9; ICON 7 (AGO/GINECO/ MRC CTU/GCIG trials).
L. Van Wagensveld, O. Colomban, M.A. Van der AA, M. Tod, et al., The prognostic value of chemosensitivity, estimated by the modeled CA-125 KELIM, in ovarian cancer patients treated with neo-adjuvant chemotherapy in the Netherlands, in: Proceedings of ESMO 2020 Virtual Meeting Abs 847P, 2020.
Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: exploratory analyses of ICON-8 trial.
Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance – a study of the OVCAD consortium.
Prospective study of the efficacy and utility of TP53 mutations in circulating tumor DNA as a non-invasive biomarker of treatment response monitoring in patients with high-grade serous ovarian carcinoma.
Exploratory analysis of TP53 mutations in circulating tumour DNA as biomarkers of treatment response for patients with relapsed high-grade serous ovarian carcinoma: a retrospective study.
Association between decline in HE4 and radiological response, and chemoresistance
Decrease during neoadjuvant chemotherapy associated with higher probability of optimal IDS Higher concentrations in patients with post-operative residual lesions
Higher concentration associated with worse PFS in multivariate analyses
Higher concentration associated with worse OS
Limited power of small studies. Contradictory outcomes. Not recommended according to ESGO-ESMO conference consensus.
The pathological chemotherapy response score (CRS) is another approach, which was developed to enable reproducible reporting of the histopathological changes in IDS specimens after neoadjuvant chemotherapy. The CRS ranging from 1 (no or minimal tumor response) to 3 (total or near-total tumor response) has been reported in several studies, including an individual patient data meta-analysis with the results from 800 patients treated at different centers worldwide [
Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: a systematic review and meta-analysis of individual patient data.
]. The score identifies about one-third of all patients (CRS3) who experienced improved progression-free survival (PFS) & overall survival (OS), and has potential for incorporation into clinical trial design as an early endpoint [
ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: a systematic review and meta-analysis of individual patient data.
Chemotherapy response score: development and validation of a system to quantify histopathologic response to neoadjuvant chemotherapy in tubo-ovarian high-grade serous carcinoma.
]. This promising indicator of the tumor primary chemosensitivity is however limited by inconsistent outcomes across studies, restricted applicability to patients treated with neo-adjuvant chemotherapy, and the requirement of a tumor specimen from omentum obtained at IDS, thereby reducing the possibility of medical-surgical treatment adjustment before IDS attempt.
The level of tumor-infiltrating lymphocytes (TILs) was shown to be a valid prognostic factor for prolonged survival in several studies [
], including a meta-analysis with 1815 patients demonstrating the significant association between lack of intra-epithelial TILs and worse survival (pooled hazard-ratio, 2.24, 95% CI; 1.71–2.91) [
]. More specifically, in a study investigating the omentum specimen of 306 patients treated with primary debulking surgery, high numbers of CD8(+) TILs and a high CD8(+)/FoxP3(+) ratio were associated with increased disease specific-free survival, and proved to be independent prognostic factors in multivariate analyses [
]. Another study confirmed that high intra-epithelial infiltrate with CD8(+) TILs (but not with CD3(+)) was an independent favorable prognostic factor for disease-free survival on the tumor samples from 540 patients [
]. Two other retrospective studies with 134 and 122 patients suggested that low CD3+ and CD8+ TILs numbers were more likely to be associated with aggressive diseases (correlation with high Ki67 expression, P = 0.041). A direct correlation was found between low intra-epithelial TIL infiltrate and chemoresistant diseases, characterized by early progressive disease after first-line treatment (positive vs. negative: 9.0% vs. 97.7%; P < 0.001) [
Prognostic impact of human leukocyte antigen class I expression and association of platinum resistance with immunologic profiles in epithelial ovarian cancer.
]. The prognostic value of TILs regarding the benefit from platinum-based chemotherapy and PARPi warrants further investigation. The implementation of this approach in routine for adjusting the disease management would be limited by the need for tumor samples, obtained from biopsy or debulking surgery specimen.
In a review analysis published in 2012, baseline tumor biomarkers, including gene alterations or tumor cell protein expressions (p53, ERCC1, c-erbB-2 …), were not found to be relevant predictors of the likelihood of complete surgery [
]. Later, a study used oligonucleotide microarrays and quantitative-PCR of 12 candidate genes in order to assess genome-wide copy number variations potentially associated to primary resistance to treatment in 118 ovarian cancer samples. Amplification of CCNE1 (cyclin E1, a regulatory subunit of cyclin-dependent kinase 2 thought to control the transition of quiescent cells into the cell cycle) was found to be associated with chemoresistance [
]. In line with these outcomes, CCNE1 amplification was associated with platinum-resistance, along with poor overall survival after adjusting for age and disease stage, in two other studies involving 579 patients (hazard-ratio = 1.62, 95% CI 1.04–2.53, P = 0.033) [
]. As a consequence, CCNE1 amplification may be a relevant predictive factor of the tumor primary chemosensitivity. Additional data on larger datasets are needed to understand the potential use of this biomarker for ovarian cancer management adjustment. The routine implementation of this approach would be limited by the methodology complexity for identifying CCNE1 amplification, since Chan et al showed that amplification could not be replaced by CCNE1 expression assessed by immunohistochemistry [
Germline or somatic BRCA mutations were found to be associated with higher tumor responses to platinum-based regimen, higher efficacy of neoadjuvant chemotherapy, better prognosis, and higher efficacy of PARP inhibitors in many publications [
]. A systematic review and meta-analysis of 34 studies with 18,396 patients showed that BRCA1/2 mutations was associated with better OS and PFS (OS: hazard-ratio, 0.67, 95% CI, 0.57 to 0.78, P < 0.001; PFS: hazard-ratio, 0.62, 95% CI, 0.53 to 0.73, P = 0.261), which may be partly explained by the higher chemosensitivity of their diseases [
]. Indeed, a study involving 316 patients treated with adjuvant platinum-based chemotherapy for ovarian cancers showed that those with BRCA2 mutations experienced higher likelihood of complete/partial response at the end of chemotherapy compared to those with wild-type BRCA tumors (100% vs 85%, P = 0.05), but also longer platinum-free duration (18.0 vs 11.7 months, P = 0.02), longer PFS (hazard-ratio = 0.40, 95% CI 0.22–0.74) and OS (hazard-ratio = 0.33, 95% CI 0.16–0.69) [
]. Similar outcomes were reported in 225 ovarian cancer patients treated with neo-adjuvant chemotherapy, as complete clinical responses (and pathological responses) were observed in 34% (and 46%) of patients with BRCA-mutated cancers, against 4% (and 25%) of patients with BRCA-wild type ovarian cancers [
]. Despite these outcomes suggesting the strong predictive role of BRCA mutation regarding the benefit from platinum-based chemotherapy, the role of the BRCA mutational status as a decisional tool in the disease management with chemotherapy and/or surgery in first-line setting has not been really addressed yet. Interestingly, in the platinum-sensitive relapse setting, a retrospective study based on real-life data reported by Estati et al suggested that there was no survival gain from secondary cytoreductive surgery in 140 patients with BRCA mutations compared to those with no mutations [
]. These data would be consistent with the findings of GOG-0213 phase III trial, which compared secondary surgical cytoreduction followed by platinum-based chemotherapy or platinum-based chemotherapy alone in 485 patients with resectable diseases to no macroscopic residual diseases. No benefit from secondary debulking surgery was found in the whole population (OS: hazard-ratio, 1.29, 95% CI 0.97–1.72, P = 0.008), especially in 142 patients with very platinum-sensitive diseases, characterized by platinum-free interval > 12 months (OS: hazard-ratio, 1.43, 95% CI 1.03–2.00) [
]. However these data about the lack of benefit from secondary cytoreductive surgery should be considered with caution, because the first one was a retrospective study with all inherent biases of such investigations; while the quality & completeness of secondary surgery in the second one could not be adequately assessed. Moreover, the final analysis of AGO DESKTOP III/ENGOT-ov20, which compared chemotherapy alone versus cytoreductive surgery followed by the same chemotherapy in patients with platinum-sensitive recurrent ovarian cancers and positive AGO score, demonstrated a benefit in OS (the primary endpoint), especially in patients who could benefit from complete resection (hazard-ratio, 0.57, 95% CI 0.43–0.76) [
Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: final analysis of AGO DESKTOP III/ENGOT-ov20.
]. These findings highlight the major role of selection criteria for identifying the best candidates for surgery.
Beyond BRCA mutation, tumor homologous recombination deficiency (HRD) has been reported as a strong indicator of the DNA-damaging chemotherapy efficacy [
]. Alterations of HR genes, such as PALB2, RAD51, ATM, ATR were reported as being associated with platinum-sensitivity, but their utility for adjusting disease management has never been assessed [
]. DNA sequencing presents a number of limitations for assessing HRD status. Indeed, about half of HRD-positive ovarian cancers harbor known mutations in HR genes, and the remainders exhibits epigenetic silencing or inactivation of HR-associated genes, along with variants of uncertain significance (VUS). To date, the most efficient strategy to investigate HRD status is to assess DNA scars, such as loss-of-heterozygosity (LOH), or combined markers collectively assessed in Myriad Mychoice with LOH, large-scale transitions and telomere allelic imbalance [
Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs.
Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer.
], the predictive value of these assays regarding response rate, probability of complete IDS, PFS or OS in first-line setting has not been reported in ovarian cancer patients. Another approach for assessing HRD status relies on functional assays, able to inform on HR activity. Immunofluorescence of RAD51, meant to explore the capacity to recruit nuclear RAD51 foci during S/G2 phase in the presence of double strand DNA damage, may represent a very promising strategy. It was shown to be an indicator of HR activity in endometrial carcinomas [
]. In a study involving the tumor samples of 33 patients, significant correlation was found between the RAD51 foci score and platinum-sensitivity, since 80% of samples with low-score were from platinum-sensitive patients, and most of samples with high-score were from patients who did not respond to platinum [
]. Moreover, the functional HR score was associated with tumor response to chemotherapy, subsequent platinum-free interval (179 days for favorable score, and 53 days for unfavorable score), and overall survival (hazard-ratio, 0.081 for HR score <35 vs. ≥35, 95% CI 0.011–0.57, P < 0.01) [
]. In line with these outcomes, a post-hoc analysis of CHIVA trial (where 185 patients were treated with carboplatin-paclitaxel +/- nintedanib) revealed that the overall response rate to chemotherapy was higher in patients with RAD51 positive tumors compared to those with RAD51 negative tumors (n = 139 patients, 68% versus 37%, P = 0.04), as was the median progression-free survival (20.8 vs 14.1 months, P = 0.02) [
]. If the predictive value of this biomarker was confirmed, it would easily assessable on patient tumor samples, at low cost. Moreover, unlike genomic scars, which are definitive and do not inform on the HR efficiency after multiple lines of treatment, functional assays are dynamic and can be repeated to assess the HR activity at different times of the disease management [
Large-scale integrated analysis of ovarian cancer tumors and cell lines identifies an individualized gene expression signature for predicting response to platinum-based chemotherapy.
]. The Cancer Genome Atlas (TCGA) signatures identified four subgroups of ovarian cancers (differentiated, immune-reactive, mesenchymal, proliferative) associated with overall survival differences [
]. However, the TCGA signature was not related to response to chemotherapy. The 97-gene signature based on 7 microarray datasets and a TCGA RNA-seq dataset, classifies patients as having low-risk of high-risk diseases. The risk group was found to be highly associated with overall survival in multivariate analyses (hazard-ratio, 1.749 1.385–2.209, P = 2.6E-6). Moreover, low-risk patients were more likely to experience complete/partial response to platinum-based chemotherapy than high-risk patients (68.3% vs 46.0%, P < 0.01) [
]. Other signatures were developed for predicting the risk of primary platinum-resistance. For example, the University of Peking used whole exome sequencing and whole genome sequencing to build a DRD score that was able to predict the likelihood of platinum-resistance after first-line treatment in 99 patients (sensitivity, specificity, and accuracy of 90.91%, 96.77%, and 95.24%, respectively) [
]. Complex by essence, these gene signatures appear promising, and their reproducibility and potential impact on disease management will have to be assessed.
Although relevant in clinical trials in patients with measurable lesions, imaging-based approaches relying on the tumor radiological response are still limited by the poor sensitivity of the current techniques for assessing peritoneal micro-infiltrative diseases frequently developed in ovarian cancer patients [
]. Conflicting outcomes were reported about the predictive value of the radiological response regarding the probability of complete IDS, or patient prognosis [
]. A recent analysis of the ICON-8 phase III trial dataset on 1566 patients confirmed that the radiological response assessed with the Response Evaluation Criteria in Solid Tumors (RECIST) was not an appropriate parameter to assess the efficacy of the neoadjuvant chemotherapy and predict the benefit from IDS [
Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial.
The strong association between ovarian cancer tumor burden and serum concentrations of CA-125 for each individual led the scientific community to assess the early longitudinal kinetics of CA-125 during the first cycles of chemotherapy, as a reflection of chemotherapy efficacy. The Gynecologic Cancer Intergroup (GCIG) defined the CA-125 response as a 50% reduction in CA-125 levels maintained for at least 28 days, in patients treated for recurrent diseases [
Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG).
]. Different studies, including a recent analysis of the ICON-8 phase III trial dataset showed that this criterion was inadequate for assessing the efficacy of the neoadjuvant chemotherapy and predicting the benefit from IDS [
Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial.
The modeled CA-125 ELIMination rate constant K (KELIM), which is calculated with the mathematical equation driving the CA-125 longitudinal kinetics (≥3 values) during the first 3–4 cycles of neo-adjuvant or adjuvant chemotherapy, has been developed to obtain an accurate characterization of the CA-125 dynamics. The reliability of KELIM as an independent indicator of tumor platinum-based chemosensitivity has been reproducibly shown in many studies, including 895 patients treated for platinum-sensitive relapses in the phase III trial CALYPSO [
L. Van Wagensveld, O. Colomban, M.A. Van der AA, M. Tod, et al., The prognostic value of chemosensitivity, estimated by the modeled CA-125 KELIM, in ovarian cancer patients treated with neo-adjuvant chemotherapy in the Netherlands, in: Proceedings of ESMO 2020 Virtual Meeting Abs 847P, 2020.
Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: exploratory analyses of ICON-8 trial.
Prognostic value and association with veliparib benefit of modeled CA-125 elimination kinetics (KELIM) in patients with newly diagnosed ovarian cancer: analysis from the VELIA/GOG-3005 study.
Proceedings of IGCS 2020 virtual meeting abs 1102. 2020
]. These studies have confirmed the capacity of KELIM to reproducibly predict: (1) the likelihood of complete resection at IDS in the neo-adjuvant setting [
L. Van Wagensveld, O. Colomban, M.A. Van der AA, M. Tod, et al., The prognostic value of chemosensitivity, estimated by the modeled CA-125 KELIM, in ovarian cancer patients treated with neo-adjuvant chemotherapy in the Netherlands, in: Proceedings of ESMO 2020 Virtual Meeting Abs 847P, 2020.
Prognostic value and association with veliparib benefit of modeled CA-125 elimination kinetics (KELIM) in patients with newly diagnosed ovarian cancer: analysis from the VELIA/GOG-3005 study.
Proceedings of IGCS 2020 virtual meeting abs 1102. 2020
1027PEarly prediction of the platinum-resistant relapse risk using the CA125 modeled kinetic parameter KELIM: a pooled analysis of AGO-OVAR 7 & 9; ICON 7 (AGO/GINECO/ MRC CTU/GCIG trials).
Prognostic value and association with veliparib benefit of modeled CA-125 elimination kinetics (KELIM) in patients with newly diagnosed ovarian cancer: analysis from the VELIA/GOG-3005 study.
Proceedings of IGCS 2020 virtual meeting abs 1102. 2020
L. Van Wagensveld, O. Colomban, M.A. Van der AA, M. Tod, et al., The prognostic value of chemosensitivity, estimated by the modeled CA-125 KELIM, in ovarian cancer patients treated with neo-adjuvant chemotherapy in the Netherlands, in: Proceedings of ESMO 2020 Virtual Meeting Abs 847P, 2020.
The impact of chemosensitivity assessed by modeled CA-125 KELIM on the likelihood of long progression-free survivorship (PS) after 1st line treatment in ovarian cancer: an analysis of 4,450 patients.
Proceedings of ESMO 2020 virtual meeting Abs 815MO. 2020
]. These data confirmed that the longitudinal kinetics of CA-125 during the first 3 cycles of chemotherapy, captured by KELIM, is the reflection of an intrinsic property of the tumor cells related to the sensitivity to chemotherapy independently on the received regimen. Indeed, all analyses showed that the addition of third drug (chemotherapy, or anti-angiogenic drugs) to carboplatin-paclitaxel, or the changes of the administration schedule (weekly versus every 3 weeks), did not alter the CA-125 KELIM values, and that KELIM was prognostic and strongly related to overall survival regardless of the received regimen. An online calculator of KELIM is available at http://www.biomarker-kinetics.org/CA-125-neo for neoadjuvant chemotherapy, and at http://www.biomarker-kinetics.org/CA-125 for adjuvant chemotherapy, making this algorithm available to any clinician. Among limitations, KELIM is assessable only for patients who have abnormal values of CA-125 at baseline (typically > 35 IU/mL, depending on the used immunoasssay), and has not been prospectively validated.
Fig. 1Reproducible outcomes for the prognostic value of favorable KELIM (vs unfavorable KELIM) regarding progression-free survival (A), and overall survival (B), across 5 large studies. Forest plot of hazard-ratios (HR) and 95% confidence intervals (CI).
Other circulating tumor markers are being developed for assessing the tumor primary chemosensitivity. Many studies assessed the utility of circulating tumor cells (CTCs), and reported that CTC numbers were associated with patient prognosis in terms of PFS and OS [
Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance – a study of the OVCAD consortium.
]. For example, in a large study with 153 patients treated with first-line chemotherapy, the persistence of CTCs 6 months after the start of the medical-surgical treatment was associated with lower PFS and OS (OS: hazard-ratio, 3.30, 95% CI 1.38–7.88, P = 0.007; PFS: hazard-ratio, 5.67, 95% CI 1.56–20.61, P = 0.008) [
]. However, the lack of standardization of methodology, the heterogeneity in the thresholds for positivity across studies, and the absence of reproducible outcomes on several datasets still limit the spread of this approach in routine [
]. The frequent TP53 mutations found in high grade serous ovarian cancers drove the development of strategies based on circulating tumor DNA (ctDNA) dynamics for characterizing the treatment efficacy. Significant associations between ctDNA kinetics and response to adjuvant chemotherapy, risk of relapse, or survival were reported in small studies, and will have to be validated in larger cohorts [
Prospective study of the efficacy and utility of TP53 mutations in circulating tumor DNA as a non-invasive biomarker of treatment response monitoring in patients with high-grade serous ovarian carcinoma.
Exploratory analysis of TP53 mutations in circulating tumour DNA as biomarkers of treatment response for patients with relapsed high-grade serous ovarian carcinoma: a retrospective study.
]. Several studies also reported the potential utility of HE4 kinetics during chemotherapy as a relevant marker of the tumor chemosensitivity, of the medical-surgical treatment efficacy, and of the patient survival [
]. For example, a retrospective study with 90 ovarian cancer patients suggested that baseline HE4 levels were predictive of platinum-sensitivity (ROC AUC, 0.64, P = 0.035), and optimal IDS (ROC AUC, 0.70, P = 0.0038) with equivalent discriminative power compared to CA-125 concentrations (AUC, 0.65, P = 0.018, and 0.69, P = 0.040, respectively) [
]. Future studies will tell us whether HE4 could substitute to CA125 as a potential predictor of response to chemotherapy.
Respective roles of the surgery and of the tumor primary chemosensitivity
Upon assessment by an expert surgeon, debulking surgery is recommended upfront as a PDS, or after 3–4 cycles of neoadjuvant chemotherapy as IDS when the disease is not considered resectable at baseline [
ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
]. If the tumor response to chemotherapy is insufficient, and complete IDS is not felt to be feasible with an acceptable operative morbidity, or when the patient shape is not fit for debulking surgery, the management of the patients should rely on medical treatments only [
ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: society of gynecologic oncology and American society of clinical oncology clinical practice guideline.
]. The prognosis of patients with advanced ovarian cancers is assumed to decrease incrementally along this pathway, the highest survival being expected in patients treated with complete PDS, and the worse prognosis in those who cannot be operated on. In most first-line treatment guidelines, besides disease FIGO stage, the timing and the completeness of the surgery are considered as the main drivers of the prognosis of advanced ovarian cancer patients [
ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: society of gynecologic oncology and American society of clinical oncology clinical practice guideline.
Although surgery undoubtedly has a major role in the management of ovarian cancer patients, the prognosis of patients cannot be unequivocally explained by disease stage and surgery outcome alone.
In that context, integrating the tumor primary chemosensitivity as an additional parameter to take into consideration may be of high interest. This is already the case in patients with recurrent diseases, since the 6 month cut-off point of platinum-free interval (calculated as the time between the last dose of platinum-based chemotherapy and the date of the relapse) has been used as a surrogate of potential response to platinum rechallenge, and the main factor for designing trials in recurrent ovarian carcinomas [
The effect of liberal vs restrictive use of neoadjuvant chemotherapy for ovarian cancer on postoperative mortality and long-term survival: a quasi-experimental study.
2020 society of gynecologic oncology annual meeting on women’s cancer abstract 165 presented March 30. 2020
], is ideal for assessing the potential utility of the tumor primary chemosensitivity in the disease management. Several studies done with different indicators showed that the likelihood of complete surgery is logically impacted by the tumor sensitivity to the neoadjuvant chemotherapy, thereby suggesting they could be useful tools for assessing the feasibility and utility of IDS [
L. Van Wagensveld, O. Colomban, M.A. Van der AA, M. Tod, et al., The prognostic value of chemosensitivity, estimated by the modeled CA-125 KELIM, in ovarian cancer patients treated with neo-adjuvant chemotherapy in the Netherlands, in: Proceedings of ESMO 2020 Virtual Meeting Abs 847P, 2020.
Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: exploratory analyses of ICON-8 trial.
](Table 1). Moreover, this therapeutic sequence enables to understand the relative contributions of surgery and medical therapy in the overall success of the first-line treatment, and identify the potential predominant driver(s) of the patient prognosis. Such an information is potentially of high interest to know the weight to attribute to each of them for guiding more subtly the overall treatment strategy for each patient. For example, the feasibility and the utility of the IDS could be differentially considered depending on the tumor primary chemosensitivity observed during the first 3 neoadjuvant chemotherapy cycles, especially when the completeness of the planned IDS procedure is uncertain, or the risk of morbidity/sequelae related to the surgical procedure is expected to be high.
Interestingly, multivariate logistic regression models were used to assess the respective contributions of surgery and chemosensitivity, assessed by KELIM, in the overall success of the first-line treatment. The analyses of CHIVA dataset, The Netherlands Cancer Registry and ICON-8 trial confirmed that both the completeness of debulking surgery and the tumor primary chemosensitivity were major and independent prognostic factors of the overall survival [
L. Van Wagensveld, O. Colomban, M.A. Van der AA, M. Tod, et al., The prognostic value of chemosensitivity, estimated by the modeled CA-125 KELIM, in ovarian cancer patients treated with neo-adjuvant chemotherapy in the Netherlands, in: Proceedings of ESMO 2020 Virtual Meeting Abs 847P, 2020.
Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: exploratory analyses of ICON-8 trial.
]. For example, ICON-8 dataset analysis clearly identified three prognostic subgroups of patients regarding OS according to the completeness of PDS and KELIM: (1) good prognosis in patients operated with complete PDS and experiencing favorable KELIM (median OS: not reached (NR) 95% CI (NR)); (2) intermediate prognosis in patients operated with incomplete PDS or unfavorable KELIM (median OS: 43.5 months 95% CI 33.6-NR, and 41.0 months 95% CI 37.8-NR, respectively); and 3) poor prognosis in patients operated with incomplete PDS and unfavorable KELIM (median OS: 28.3 months, 95% CI 21.3–41.1) [
Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: exploratory analyses of ICON-8 trial.
]. These data suggest the complementary roles of both the chemosensivity and the completeness of surgery in the prognosis of patients. In other words, to maximize the patient prognosis, both components of the backbone should be satisfactory.
These analyses also showed that their respective impacts were different according to the chemosensitivity. Indeed, the benefit offered by complete IDS relative to the risk of subsequent platinum-resistant relapse, and survival, was maximum in patients with poorly chemosensitive diseases, in contrast to patients with highly chemosensitive diseases, whose prognostic was mainly driven by the chemosensitivity [
1027PEarly prediction of the platinum-resistant relapse risk using the CA125 modeled kinetic parameter KELIM: a pooled analysis of AGO-OVAR 7 & 9; ICON 7 (AGO/GINECO/ MRC CTU/GCIG trials).
The impact of chemosensitivity assessed by modeled CA-125 KELIM on the likelihood of long progression-free survivorship (PS) after 1st line treatment in ovarian cancer: an analysis of 4,450 patients.
Proceedings of ESMO 2020 virtual meeting Abs 815MO. 2020
]. For example, Fig. 2 displaying the probability of platinum-resistant relapse according to KELIM and to the completeness of IDS in CHIVA trial, suggests that the negative prognostic impact of incomplete surgery decreases as KELIM increases [
]. This hypothesis was corroborated by the ICON-8 trial dataset analysis, which showed that the benefit from complete IDS compared to incomplete IDS appeared maximum in patients exhibiting unfavorable KELIM (hazard-ratio, 0.53, 95% CI 0.39–0.72) with respect to those with favorable KELIM (hazard-ratio, 0.73, 95% CI 0.56–0.94) [
Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: exploratory analyses of ICON-8 trial.
]. Consistently, a study assessing the prognostic value of TIL infiltrate in 134 patients suggested that patients with aggressive tumor behavior with low frequency of intraepithelial CD8+ T cells or high Ki67 expression, assumed to be less sensitive to platinum-based chemotherapy, were more likely to draw benefit from optimal surgical cytoreduction compared to non-optimal surgery in terms of survival (five-year OS rates, 41.2% and 25.1%, P = 0.002), whilst the survival curves for those who had optimal and suboptimal debulking were not significantly different among patients with a high frequency of intraepithelial CD8+ T cells [
Fig. 2Assessment of the respective contributions of surgery and of the tumor primary chemosensitivity relative to the success of the first-line treatment in CHIVA trial. Probability of subsequent platinum-resistant relapse according to the completeness of interval debulking surgery and the tumor primary chemosensitivity measured during neoadjuvant chemotherapy (adapted from You et al.
Assessment of the tumor primary chemosensitivity may also be interesting for selecting the appropriate maintenance therapy between PARP inhibitor and bevacizumab, especially in patients with high-risk diseases (incompletely resected stage III, or stage IV disease) characterized by homologous recombination proficiency (HRP). In line with the efficacy of bevacizumab in patients with platinum-resistant recurrent diseases [
], bevacizumab seems to be more effective in patients with poorly chemosensitive and high-risk diseases in the first-line setting. Indeed, in the pre-planned analysis of the subgroup of patients with high-risk diseases in ICON-7 trial (incomplete PDS for stage III, or stage IV diseases), bevacizumab was associated with improvements of 5.4 months in PFS (hazard-ratio, 0.73; 95% CI, 0.61–0.88), and of 4.8 months in OS (hazard-ratio, 0.78, 95% CI, 0.63–0.97) [
Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.
]. A subsequent additional analysis of this dataset showed that, among these patients with high-risk diseases, only those with unfavorable KELIM < 1 actually derived an OS benefit from bevacizumab (median OS, 29.7 months with bevacizumab versus 20.6 months with placebo), compared to those with favorable KELIM ≥ 1 who had the same OS regardless of bevacizumab administration (median OS, 48.2 versus 46.6 months) [
]. The mesenchymal subtype, known to be poorly sensitive to platinum-based chemotherapy, was associated with a non-significantly higher benefit from bevacizumab with a 8.2 months median PFS improvement, compared to the immunoreactive, and differentiated subtypes (hazard-ratio, 0.78, 95% CI, 0.44– 1.40, P = 0.41)[
Large-scale integrated analysis of ovarian cancer tumors and cell lines identifies an individualized gene expression signature for predicting response to platinum-based chemotherapy.
]. These data suggest that indicators of the tumor primary chemosensitivity could potentially help select patients with maximum survival benefit from bevacizumab among those with high-risk disease, a subpopulation representing 55% to 83% of patients across series. These data are of interest because poorly chemosensitive diseases, frequently characterized by HRP features, are less sensitive to PARP inhibitors, as seen in PRIMA trial [
]. In that context, indicators of the tumor primary chemosensitivity might also inform on the benefit to expect from PARP inhibitors. The predictive value of BRCA mutational and HRD status was reported in many trials and reviews [
]. Its predictive value in ovarian cancers is being assessed on the data from PAOLA-1 trial. In addition to HR-related biomarkers, other early indicators of the chemotherapy activity may provide information on the efficacy to expect with subsequent PARP inhibitor prescription. For example, CCNE1 amplification is thought be a predictor of PARP inhibitor resistance [
An ancillary post-hoc analysis of VELIA trial showed a strong association between veliparib-related PFS benefit and KELIM, and suggested that KELIM might be useful for selecting the patients who will or will not benefit from this PARP inhibitor [
Prognostic value and association with veliparib benefit of modeled CA-125 elimination kinetics (KELIM) in patients with newly diagnosed ovarian cancer: analysis from the VELIA/GOG-3005 study.
Proceedings of IGCS 2020 virtual meeting abs 1102. 2020
These findings suggest that KELIM might help identify the patients the more likely to benefit from PARP inhibitor or from bevacizumab among those with HRP-associated diseases, along with the patients prone to experience poor survival and limited benefit from PARP inhibitors among those with BRCA mutated diseases, as observed by the teams already assessing KELIM in routine. Translational studies are ongoing to assess the validity of this hypothesis.
Conclusions
Among the two backbone components of the first-line medical and surgical treatment for advanced ovarian carcinomas, the major therapeutic and prognostic role of debulking surgery has been well established, and integrated in the disease management guidelines. Many recent data have suggested that the tumor primary chemosensitivity also has a major impact on the feasibility of interval debulking surgery, the success of the first-line medical & surgical treatment, the efficacy of maintenance therapy, and the overall prognosis of patients. As a consequence, both the completeness of the debulking surgery & the tumor primary chemosensitivity play complementary prognostic roles; and ideally both of them must be satisfactory to maximize patient survival. S
Moreover, several studies assessing the prognostic value of tumor primary chemosensitivity (levels of TILs infiltrate, KELIM, and BRCA mutation) suggested that the prognostic impact of the surgery completeness relative to the success of the comprehensive medical-surgical treatment, may differ according to the primary chemosensitivity [
Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: exploratory analyses of ICON-8 trial.
]. This assumption raises a potential new concept: in patients with advanced ovarian carcinomas, the maximum tumor debulking should ideally be both biological (induced by systemic treatments) and physical (induced by surgery) for maximizing patient survival. And the lack of biological debulking related to poor tumor chemosensitivity, should absolutely be compensated by the physical debulking of complete surgery.
In addition to biological markers including BRCA mutational and HRD status, integrating an(some) indicator(s) of the tumor primary chemosensitivity as relevant prognostic factor(s) in future clinical trials may be useful to prospectively validate the major and complementary role of the tumor primary chemosensitivity, and to build subtler medical-surgical management algorithms in patients with advanced ovarian cancers.
In most studies performed so far, the patients with poorly chemosensitive diseases had poor OS regardless of the completeness of surgery. Beyond anti-angiogenic treatments, these patients deserve innovative therapeutic strategies, since they are not likely to benefit from PARP inhibitors [
Prognostic value and association with veliparib benefit of modeled CA-125 elimination kinetics (KELIM) in patients with newly diagnosed ovarian cancer: analysis from the VELIA/GOG-3005 study.
Proceedings of IGCS 2020 virtual meeting abs 1102. 2020
]. The next step is the development of prospective clinical trials meant to improve the management of patient with poorly chemosensitive diseases (such as those with unfavorable KELIM assessed during the first 3 cycles of adjuvant or neo-adjuvant chemotherapy). For example, it would be warranted to compare the efficacy of maintenance treatment with bevacizumab or PARP inhibitors in patients with HRP-associated diseases and poorly chemosensitive diseases in a randomized phase III trial. It would also be relevant to assess the efficacy of innovative treatments, such as cell cycle checkpoint inhibitors, immunotherapy, or anti-angiogenic drugs, meant to reverse the chemoresistance in patients with poorly chemosensitive diseases [
], as a way of improving their very poor prognosis.
Author contributions
All authors contributed to the design of the paper, data collection, interpretation, and analysis, and writing of the manuscript, and all approved the final version.
SP: Honoraria from AstraZeneca, Clovis, MSD, PharmaMar, Roche and Tesaro
EPL: Honoraria from Roche, GSK, Pfizer, Astra-Zeneca, Incyte, Clovis
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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2020 society of gynecologic oncology annual meeting on women’s cancer abstract 165 presented March 30. 2020
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Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: exploratory analyses of ICON-8 trial.
Prognostic value and association with veliparib benefit of modeled CA-125 elimination kinetics (KELIM) in patients with newly diagnosed ovarian cancer: analysis from the VELIA/GOG-3005 study.
Proceedings of IGCS 2020 virtual meeting abs 1102. 2020
1027PEarly prediction of the platinum-resistant relapse risk using the CA125 modeled kinetic parameter KELIM: a pooled analysis of AGO-OVAR 7 & 9; ICON 7 (AGO/GINECO/ MRC CTU/GCIG trials).
The impact of chemosensitivity assessed by modeled CA-125 KELIM on the likelihood of long progression-free survivorship (PS) after 1st line treatment in ovarian cancer: an analysis of 4,450 patients.
Proceedings of ESMO 2020 virtual meeting Abs 815MO. 2020
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