ABSTRACT
The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional 'window of opportunity' endpoints should be included.
Subject(s)
Neoplasms, Glandular and Epithelial/therapy , Ovarian Neoplasms/therapy , Research Design , Carcinoma, Ovarian Epithelial , Female , HumansABSTRACT
BACKGROUND: The current literature indicates that a considerable number of patients in ovarian carcinoma clinical trials have histopathological diagnoses in conflict with inclusion criteria. It has been suggested that specialised pathology review prior to randomisation should become the standard procedure in study protocols. We hypothesised that our new, internet-based high-throughput infrastructure would be capable of providing specialised pathology review within 10 working days (w.d.). METHODS: Patients scheduled for the AGO OVAR17 ovarian carcinoma chemotherapy trial were registered for expert pathologic case review using a new internet-based central pathology review platform prior to randomisation. All original slides were requested from local pathologists. Slides were scanned and uploaded to a secured internet server. A network of experienced gynaecological pathologists was connected to the server through a custom-designed software platform. If deemed necessary by the expert pathologists, immunohistochemistry was available through a collaborating pathology lab. RESULTS: A total of 880 patients with an original diagnosis of ovarian epithelial carcinoma were registered for expert pathology review from October 2011 to July 2013. For case review, five gynaecopathologists from Austria, Switzerland and Germany were available online. Median number of w.d. required to complete the whole process from patient registration to transmission of final review diagnoses was 4 (range 2-31) (w.d.), and in 848 out of 880 (97.5%) cases, it amounted to ⩽10 w.d. In 2.5% (n=22) of cases, a major diagnostic discrepancy of potential clinical relevance was found leading to exclusion from the chemotherapy trial. CONCLUSIONS: Our results show that the use of a new internet-based infrastructure makes timely specialised case review, prior to patient randomisation feasible within ⩽10 w.d. Our new approach helped to protect against overtreatment with chemotherapy of patients with ovarian borderline tumours and inadequate treatment of patients with ovarian metastases, as a result of their inappropriate entry into a clinical trial designed for patients with primary ovarian carcinoma.
Subject(s)
Health Resources/statistics & numerical data , Internet , Neoplasm Staging/standards , Ovarian Neoplasms/pathology , Ovarian Neoplasms/therapy , Pathology, Clinical/methods , Quality of Health Care , Female , Health Resources/organization & administration , Humans , Neoplasm Staging/methods , Pathology, Clinical/organization & administration , Patient Selection , Randomized Controlled Trials as Topic/standards , Research DesignABSTRACT
OBJECTIVES: We evaluated in a large study meta-database of prospectively randomised phase III trials the prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients < and >40 years of age with advanced epithelial ovarian cancer. METHODS: A total of 5055 patients of the AGO, GINECO, NSGO intergroup studies AGO-OVAR 3, 5, 7 and 9 were merged to identify 294 patients <40 years and 4761 patients ≥40 years. We conducted survival analyses and Cox proportional hazard regression models and additionally analysed a very homogeneous subcohort of 405 patients with serous epithelial ovarian cancer, excellent performance status, who had received complete macroscopic upfront cytoreduction and ≥5 chemotherapy cycles. RESULTS: For patients <40 years, the median PFS was 28.9 months and the median OS was 75.3 months, while the median PFS for patients ≥40 years was 18.1 months and the median OS was 45.7 months. Independent prognostic factors were similar in both age groups. In a multivariate analysis including prognostic factors potentially leading to confounding, young age appeared to improve PFS (hazard ratio [HR], 0.86; 95% confidence interval [CI]: 0.72-1.03) and OS (HR, 0.73; 95% CI: 0.59-0.91). The observed effect was even stronger in the subcohort of optimally treated patients with SEOC: PFS (HR, 0.34; 95% CI: 0.19-0.59) and OS (HR, 0.23; 95% CI: 0.09-0.56). DISCUSSION: Prognostic factors were similar in both age groups. Young age appeared a strong independent protective prognostic factor for PFS and OS in the subcohort.
Subject(s)
Neoplasms, Glandular and Epithelial/mortality , Ovarian Neoplasms/mortality , Adult , Age Factors , Age of Onset , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ovarian Epithelial , Clinical Trials, Phase III as Topic , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/mortality , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Prognosis , Prospective Studies , Retrospective StudiesABSTRACT
The adsorption of thymine, a pyrimidine based nucleobase, was studied on the (110) termination of rutile titanium dioxide in order to understand the thermal stability and gross structural parameters of the interaction between a strongly polar adsorbate and a highly corrugated transition metal oxide surface. Near-edge X-ray absorption fine structure (NEXAFS), X-ray photoelectron spectroscopy (XPS), temperature programmed XPS and temperature programmed desorption indicated the growth of a room temperature stable bilayer, which could only be removed by annealing to 450 K. The remaining first layer was remarkably robust, surviving annealing up to 550 K before undergoing N-H bond scission. The comparison to XPS of a sub-monolayer exposure of 1-methyluracil shows that the origin of the room temperature stable bilayer is not intermolecular interactions. This discovery, alongside the deprotonation of one of the first layer's pyrimidinic nitrogen atoms at room temperature, suggests that the thymine molecules in the first layer bind to the undercoordinated surface Ti atoms, and the second layer thymine molecules coordinate with the bridging oxygen atoms which protrude above the Ti surface plane on the (110) surface. The NEXAFS results indicate an almost upright orientation of the molecules in both layers, with a 30 ± 10° tilt away from the surface normal.
ABSTRACT
Despite the recent publication of two randomized controlled phase III trials addressing neoadjuvant chemotherapy in advanced ovarian cancer, the optimal timing of multimodal management in primary therapy is still under debate. As both studies met their primary end point by demonstrating non-inferiority, neoadjuvant chemotherapy followed by interval debulking surgery has been proposed to be an alternative standard for primary ovarian cancer treatment. Nevertheless, significant questions remain unanswered in both trials. Especially, the radicality of surgical therapy was below expectation with the median operating times of <3 h and complete gross resection in <20% of the patients. Consecutively, survival rates of patients undergoing primary debulking surgery were low. Since the primarily surgical question of 'primary versus interval-surgery' can only be answered if the key criteria 'complete gross resection' are present in a considerable percentage of patients, additional studies are needed and neoadjuvant chemotherapy should not be used to reduce surgical radicality for ovarian cancer treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Ovarian Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Chemotherapy, Adjuvant , Clinical Trials, Phase III as Topic , Female , Humans , Neoadjuvant Therapy , Ovarian Neoplasms/mortality , Survival AnalysisABSTRACT
The AGO Kommission Ovar already published a statement in 2013, warning about the uncritical use of hyperthermic intraperitoneal chemotherapy (HIPEC) outside controlled studies. This statement has now been updated after the most recent literature was reviewed by AGO Kommission Ovar, the AGO Study Group, NOGGO, AGO Austria and AGO Switzerland. The authors conclude that HIPEC remains experimental. Its use is not recommended and should be rejected outside of prospective controlled trials.
ABSTRACT
BACKGROUND: Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure. METHODS: Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS). RESULTS: For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation. CONCLUSION: Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.
Subject(s)
Cystadenoma, Serous/diagnosis , Cystadenoma, Serous/pathology , Gynecologic Surgical Procedures , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Cystadenoma, Serous/epidemiology , Cystadenoma, Serous/surgery , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/surgery , Prognosis , Young AdultABSTRACT
BACKGROUND: Retrospective studies have shown that a significant number of ovarian borderline tumors, ovarian metastases, and nonepithelial tumors were erroneously diagnosed as ovarian carcinomas. This may lead to unnecessary morbidity, suboptimal therapeutic modalities, and unintended bias in clinical trials. The aim of this study was to investigate the frequency and clinical significance of such diagnostic discrepancies. MATERIAL AND METHODS: Original histological slides from patients with ovarian carcinomas included in phase III chemotherapy trials of the Working Group on Gynecological Oncology (AGO) were reviewed by at least two specialized pathologists. Diagnostic discrepancies were classified as being either clinically relevant (major) or clinically not relevant (minor). RESULTS: A total of 454 out of 533 patients from the AGO OVAR11 (ICON7) trial gave consent to the second opinion on the pathology results. All of the 104 institutes of pathology responsible for the original diagnoses contributed to the study. The first diagnosis and the second opinion pathology review were identical in 295 out of 454 (65%) cases. In 128 cases (28.2%) a minor discrepancy was found and 31 cases (6.8%) were shown to have a major discrepancy. CONCLUSION: The assumption of a significant number or erroneous diagnoses in chemotherapy trials of ovarian carcinomas was confirmed. A pathology review seems therefore desirable and may help to reduce unnecessary morbidity and optimize therapeutic strategies. Moreover, improvement of quality in therapy trials may become possible. In another study a new concept allowing a rapid pathology review before randomization of patients has now been successfully tested and it may well have potential to form the basis for modern networking consultation pathology.
Subject(s)
Diagnostic Errors , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Ovary/pathology , Referral and Consultation , Adenocarcinoma, Clear Cell/drug therapy , Adenocarcinoma, Clear Cell/pathology , Carcinoma, Endometrioid/drug therapy , Carcinoma, Endometrioid/pathology , Colonic Neoplasms/pathology , Disease Progression , Female , Germany , Humans , Neoplasm Staging , Ovarian Neoplasms/secondary , Patient Selection , Prospective StudiesABSTRACT
Histological grading of ovarian cancer has prognostic relevance and implications for treatment decisions. No standardized grading system has been established so far. Several grading systems are currently being used, including the FIGO, WHO, and Silverberg grading systems which cannot be directly translated into each other. Furthermore, individual grading criteria are not uniformly applicable to different histological subtypes. For serous ovarian cancer a binary grading system is now in use as the distinction between low-grade versus high-grade carcinomas reflects the different pathogenesis of these entities. Uniform guidelines for grading ovarian cancer are necessary and should ideally reflect the prognosis. This article provides an overview of commonly used grading systems and their prognostic value. The article demonstrates that a type-specific grading of ovarian cancer should be performed and recommendations for grading the various histological subtypes are given.
Subject(s)
Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/pathology , Carcinoma, Ovarian Epithelial , Cell Transformation, Neoplastic/classification , Cell Transformation, Neoplastic/pathology , Female , Humans , Neoplasm Grading , Neoplasms, Glandular and Epithelial/classification , Neoplasms, Glandular and Epithelial/therapy , Ovarian Neoplasms/classification , Ovarian Neoplasms/therapy , Ovary/pathology , PrognosisABSTRACT
BACKGROUND: Approximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. METHODS: Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis. RESULTS: A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS. CONCLUSIONS: Despite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.
Subject(s)
Age Factors , Ovarian Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: The majority of women with ovarian cancer develop recurrent disease. For patients with a platinum-free interval of >6 months, platinum-based chemotherapy is a treatment of choice. The benefit of platinum-based combination chemotherapy in randomized trials varies, and a meta-analysis was carried out to gain more secure information on the size of the benefit of this treatment. MATERIALS AND METHODS: We initiated a systematic review and meta-analysis following a pre-specified protocol to determine whether combination chemotherapy is superior to single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. RESULTS: A total of five potentially eligible randomized trials were identified that had used combination-platinum chemotherapy versus single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. For one trial (190 patients), adequate contact with the investigators could not be established. Therefore, four trials that randomly assigned 1300 patients were included, with a median follow-up of 36.1 months. Overall survival (OS) analyses were based on 865 deaths and demonstrated evidence for the benefit of combination-platinum chemotherapy (HR = 0.80; 95% CI, 0.64-1.00; P = 0.05). Progression-free survival (PFS) analyses were based on 1167 events and demonstrated strong evidence for the benefit of combination-platinum chemotherapy (HR = 0.68; 95% CI, 0.57-0.81; P < 0.001). There was no evidence of a difference in the relative effect of combination-platinum chemotherapy on either OS or PFS in patient subgroups defined by previous paclitaxel (Taxol) treatment (OS, P = 0.49; PFS, P = 0.66), duration of treatment-free interval (OS, P = 0.86; PFS, P = 0.48) or the number of previous lines of chemotherapy (OS, P = 0.21; PFS, P = 0.27). CONCLUSIONS: In this individual patient data (IPD) meta-analysis, we have demonstrated that combination-platinum chemotherapy improves OS and PFS across all subgroups. This provides the strongest evidence to date of the benefit of combination-platinum over single-agent platinum.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carboplatin/administration & dosage , Cisplatin/administration & dosage , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Neoplasm Recurrence, Local/mortality , Ovarian Neoplasms/mortality , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. PATIENTS AND METHODS: The nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). RESULTS: The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65-0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). CONCLUSIONS: This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.
Subject(s)
Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Platinum/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Clinical Trials as Topic , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/chemically induced , Neoplasm Recurrence, Local/genetics , Neoplasm Staging , Nomograms , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Platinum/adverse effects , Platinum/toxicity , Prognosis , Sensitivity and Specificity , Treatment OutcomeABSTRACT
BACKGROUND AND AIMS: Surgery followed by platinum-taxane chemotherapy is the current standard approach to treat advanced ovarian cancer. The impact of the time interval between surgery and initiation of chemotherapy for clinical outcome has not been clarified yet. METHODS: Individual patient data analysis of 3326 patients from three prospective randomised phase III trials conducted between 1995 and 2002 to investigate platinum-taxane based chemotherapy regimens in advanced ovarian cancer. Time to chemotherapy (TTC) was analysed and correlated with outcome. RESULTS: Median TTC was 19 days (range 1-56). The effect of TTC differed significantly for patients with or without residual disease for progression-free (PFS; interaction p=0.004) and for overall survival (OS; interaction p=0.028). A delayed start of chemotherapy was associated with earlier disease recurrence (HR 1.038, 95% CI 0.973; 1.106, p=0.257 per week delay) and a significantly decreased OS (HR 1.087, 95% CI 1.005; 1.176 p=0.038) in patients with no residual tumour after surgery. In contrast, in patients with residual disease, a longer TTC was significantly associated with later progression (HR 0.931, 95% CI 0.895; 0.969, p<0.001) and no effect towards OS (HR 0.983, 95% CI 0.940; 1.028, p=0.452). CONCLUSIONS: Our results provide evidence that early initiation of chemotherapy might result in slightly improved survival in patients with complete cytoreduction while patients with residual disease after surgery did not benefit from earlier chemotherapy. A prospective study randomising patients to different time intervals could clarify the definitive relevance of the time between surgery and chemotherapy.
Subject(s)
Antineoplastic Agents/administration & dosage , Ovarian Neoplasms/mortality , Ovarian Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Clinical Trials, Phase III as Topic , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Ovariectomy , Prognosis , Proportional Hazards Models , Time , Young AdultABSTRACT
BACKGROUND: Despite recent progress in the treatment of ovarian cancer, the majority of patients eventually relapse. There is little information on the effectiveness of chemotherapy in higher treatment lines. PATIENTS AND METHODS: Characterization of the second to sixth line therapy and its effects on survival was carried out, based on data of n = 1620 patients from three large randomized phase III trials investigating primary therapy. RESULTS: Median progression-free survival (PFS) after the first, second, third, fourth and fifth relapse was 10.2 [95% confidence interval (CI) 9.6-10.7], 6.4 (5.9-7.0), 5.6 (4.8-6.2), 4.4 (3.7-4.9) and 4.1 (3.0-5.1) months, respectively. Median overall survival (OS) after the first, second, third, fourth and fifth relapse was 17.6 (95% CI 16.4-18.6), 11.3 (10.4-12.9), 8.9 (7.8-9.9), 6.2 (5.1-7.7) and 5.0 (3.8-10.4) months, respectively. The most frequent second and third line chemotherapy was platinum combination (n = 313, 24.5%) and topotecan (n = 118, 23.6%), respectively. Relapse treatment improved PFS and OS at the second to fourth recurrence, although frequently not performed according to the standard of care. In multivariate analysis, platinum sensitivity and optimal primary tumor debulking were revealed as independent prognostic factors for PFS up to third relapse. CONCLUSION: A maximum of three lines of subsequent relapse treatment seems to be beneficial for patients with recurrent ovarian cancer. Optimal primary tumor debulking and platinum sensitivity remain independent prognostic factors even after more frequent relapses.
Subject(s)
Antineoplastic Agents/therapeutic use , Organoplatinum Compounds/therapeutic use , Ovarian Neoplasms/drug therapy , Taxoids/therapeutic use , Female , Humans , Recurrence , Survival AnalysisABSTRACT
BACKGROUND: CA-125 as a tumour progression criterion in relapsing ovarian cancer (ROC) trials remains controversial. CALYPSO is a large randomised trial incorporating CA-125 (GCIG criteria) and symptomatic deterioration in addition to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (radiological) to determine progression. METHODS: In all, 976 patients with platinum-sensitive ROC were randomised to carboplatin-paclitaxel (C-P) or carboplatin-pegylated liposomal doxorubicin (C-PLD). CT-scan and CA-125 were performed every 3 months until progression. RESULTS: In all, 832 patients (85%) progressed, with 60% experiencing a first radiological progression, 10% symptomatic progression, and 28% CA-125 progression without evidence of radiological or symptomatic progression. The benefit of C-PLD vs C-P in progression-free survival was not influenced by type of first progression (hazard ratio 0.85 (95% confidence interval (CI): 0.66-1.10) and 0.84 (95% CI: 0.72-0.98) for CA-125 and RECIST, respectively). In patients with CA-125 first progression who subsequently progressed radiologically, a delay of 2.3 months was observed between the two progression types. After CA-125 first progression, median time to new treatment was 2.0 months. In all, 81%of the patients with CA-125 or radiological first progression and 60% with symptomatic first progression received subsequent treatment. CONCLUSION: CA-125 and radiological tests performed similarly in determining progression with C-PLD or C-P. Additional follow-up with CA-125 measurements was not associated with overtreatment.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , CA-125 Antigen/analysis , Ovarian Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Disease Progression , Disease-Free Survival , Doxorubicin/adverse effects , Doxorubicin/analogs & derivatives , Female , Humans , Ovarian Neoplasms/diagnostic imaging , Paclitaxel/administration & dosage , Polyethylene Glycols/adverse effects , Recurrence , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer. METHODS: Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model. RESULTS: Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1-1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (≤23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model. CONCLUSION: This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer.
Subject(s)
Adenocarcinoma, Clear Cell/mortality , Adenocarcinoma, Mucinous/mortality , Cystadenocarcinoma, Serous/mortality , Endometrial Neoplasms/mortality , Neoplasm Recurrence, Local/mortality , Ovarian Neoplasms/mortality , Ovariectomy , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Clear Cell/surgery , Adenocarcinoma, Mucinous/pathology , Adenocarcinoma, Mucinous/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , Cystadenocarcinoma, Serous/pathology , Cystadenocarcinoma, Serous/surgery , Endometrial Neoplasms/pathology , Endometrial Neoplasms/surgery , Female , Follow-Up Studies , Humans , International Agencies , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/surgery , Neoplasm Staging , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , Survival Rate , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n=955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n=340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. RESULTS: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Carboplatin/therapeutic use , Disease-Free Survival , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Middle Aged , Ovarian Neoplasms/pathology , Prognosis , Proportional Hazards ModelsABSTRACT
OBJECTIVE: The aim of this study was to select the best catumaxomab regimen for further investigation in ovarian cancer based on confirmed tumour response. METHODS: Randomised open-label phase IIa study in women with platinum-resistant or -refractory epithelial ovarian cancer. Catumaxomab (6-hour intraperitoneal infusion on days 0, 3, 7 and 10) was administered at a low (10, 10, 10 and 10 µg) or high dose (10, 20, 50 and 100 µg). Responders were patients with either a complete (CR) or partial (PR) response. RESULTS: Forty-five patients were randomised to receive either low dose (23) or high dose (22). There were no responders in the low-dose versus one patient (5%) in the high-dose group with a PR. In the low-dose group, two patients (9%) had stable disease compared with five patients (23%) in the high-dose group. Catumaxomab was well tolerated and there was no difference between the dose groups in the incidence of treatment-induced adverse events, the most common of which were gastrointestinal and injection-site reactions. CONCLUSION: Catumaxomab had modest activity in platinum-resistant ovarian cancer. The high-dose regimen was associated with a slightly better therapeutic index than the low dose regimen.
Subject(s)
Antibodies, Bispecific/administration & dosage , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Ovarian Epithelial , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Female , Humans , Infusions, Parenteral , Middle Aged , Organoplatinum Compounds/pharmacologyABSTRACT
BACKGROUND: For the adjuvant setting of advanced ovarian cancer (AOC) after primary radical surgery the combination of paclitaxel and platinum in a 3-week schedule has emerged as the current standard. In preclinical studies additional anti-angiogenic effects of low dose paclitaxel infusion were demonstrated. A sequential schedule of carboplatin and paclitaxel has the potential to improve the therapeutic index. METHODS: In this multicenter phase II trial four cycles of carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles of weekly paclitaxel at a dose of 80 mg/m(2) (d1/q7d) were applied after primary radical surgery. Eligible were all optimally or sub-optimally debulked patients with FIGO IA-IV ovarian cancer. All patients with hemoglobin levels <12 mg/dl received erythropoietin additionally. RESULTS: Between July 2003 and May 2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (range: 23-80 years). A median number of 16 courses (range 1-16) were applied. The incidence of non-hematological toxicities was very low. Only 41% of patients experienced alopecia (grade 1-2). Neurotoxicity (grade 3-4) was not observed. Grade 3-4 hematological toxicity (43% of all patients) included thrombocytopenia (17%), anemia (3%), leucopenia (23%), and neutropenic fever (0%). Ninety-seven percent received erythropoietin. Thromboembolic events (4%) were not increased in patients who received erythropoietin. After a median time of 23 months (range: 1-42 months) 32 patients had died, and the median overall survival was not reached. The progression-free survival was 25.4 months (95% CI: 18.8-40+). CONCLUSION: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted.