Clinical impact of CA-125 ELIMination rate constant K (KELIM) on surgical strategy in advanced serous ovarian cancer patients.

OBJECTIVES: The modeled CA-125 elimination constant K (KELIM) is a pragmatic early marker of tumor chemosensitivity in ovarian cancer patients treated with neoadjuvant chemotherapy before interval surgery. The primary objective of this study was to assess the prognostic value of KELIM regarding the feasibility of complete surgery, and secondary objectives were to assess the prognostic value of KELIM for the risk of a platinum resistant relapse, progression free survival, and overall survival. METHODS: The study was based on a retrospective cohort of 284 patients treated for an advanced serous high grade ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV, with neoadjuvant chemotherapy, followed by interval surgery, in a comprehensive cancer center. CA-125 concentrations at baseline and during neoadjuvant chemotherapy were collected. The KELIM predictive value regarding the tumor radiological response rate, likelihood of complete surgery, risk of subsequent platinum resistant relapse, progression free survival, and overall survival were assessed with univariate and multivariate tests. RESULTS: In 232 patients, KELIM was an independent and major predictor of the probability of complete surgery and survival. The final logistic regression model, including KELIM (odds ratio (OR) 0.36, 95% confidence interval (CI)0.16 to 0.73, p=0.006) and complete surgery (no vs yes, OR 0.29, 95% CI 0.15 to 0.53, p<0.001), highlighted the complementary impact of chemosensitivity and surgical outcome relative to the complete surgery. In the multivariate analysis, KELIM and complete surgery were significantly associated with a lower risk of early relapse. In the case of an unfavorable KELIM, when surgical efforts allowed complete cytoreduction, median overall survival was similar to that reported in the case of a favorable KELIM (46.3 months (range 34.6-60.3) vs 46.5 months (range 40.6-68.7), respectively). CONCLUSION: Primary tumor chemosensitivity, assessed by the modeled CA-125 KELIM, calculated during neoadjuvant chemotherapy, is a major parameter to consider for decision making regarding interval surgery. Complementary to the RECIST score and laparoscopy, this non-invasive tool, available online, helps tailor the interval surgery strategy according to patient tumor chemosensitivity.

Avelumab in patients with gestational trophoblastic tumors with resistance to polychemotherapy: Cohort B of the TROPHIMMUN phase 2 trial.

PURPOSE: There is a need for innovative treatments in women with gestational trophoblastic tumors (GTT) resistant to chemotherapy. The TROPHIMMUN trial assessed the efficacy of avelumab in patients with resistance to single-agent chemotherapy (cohort A), or to polychemotherapy (cohort B). Cohort B outcomes are reported here. METHODS: In the cohort B of this phase 2 multicenter trial (NCT03135769), women with GTT progressing after polychemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. The primary endpoint was the rate of hCG normalization enabling treatment discontinuation (2-stage Simon design). RESULTS: Between February 2017 and August 2020, 7 patients were enrolled. Median age was 37 years (range: 29-47); disease stage was I or III in 42.9% and 57.1%; FIGO score was 9-10 in 28.6%, 11 in 28.6%, and 16 in 14.3%, respectively. Median follow-up was 18.2 months. One patient (14.3%) experienced hCG normalization enabling treatment discontinuation. However, resistance to avelumab was observed in the remaining 6 patients (85.7%). The cohort B was stopped for futility. Grade 1-2 treatment-related adverse events occurred in 57.1%, most commonly fatigue (42.9%), nausea, diarrhea, infusion-related reaction, muscle pains, dry eyes (each 14.3%). The median resistance-free survival was 1.4 months (95% CI 0.7-5.3). CONCLUSIONS: Although avelumab is active in patients with single-agent chemotherapy-resistant GTT (cohort A), it was associated with limited efficacy in patients with resistance to polychemotherapy (cohort B). The prognosis of patients with polychemotherapy resistance remains poor, and innovative immunotherapy-based therapeutic combinations are needed.

NIRVANA-1: maintenance therapy with niraparib versus niraparib-bevacizumab in patients with advanced ovarian cancer.

Following the results of the PRIMA and PAOLA-1 trials, the most effective maintenance strategy for International Federation of Gynecology and Obstetrics stage III patients is still debated, raising the question which of those two maintenance strategies is the most effective: PARP inhibitors alone or PARP inhibitors in combination with bevacizumab. The ongoing NIRVANA-1 study will try to answer this question by assessing the efficacy and safety of niraparib + bevacizumab in comparison with niraparib alone after adjuvant chemotherapy for completely resected stage III patients. Stratification factors include tumor BRCA status, International Federation of Gynecology and Obstetrics stage (IIIA vs IIIB/IIIC) and the use of hyperthermic intraperitoneal chemotherapy during surgery - within the OVHIPEC-2 trial. The primary end point will be progression-free survival rate at 24 months. Safety, median progression-free survival and overall survival will also be studied.

In many patients with ovarian cancer who are treated with platinum-based chemotherapy after surgery, the tumor comes back several months later. In order to minimize this risk, one treatment approach that has shown promising results is PARP inhibitors. This treatment works by inhibiting cancer cells' ability to repair themselves after DNA damage. One of the PARP inhibitors approved by medical authorities is niraparib, used as a solo therapy after surgery and chemotherapy. Nevertheless, the most effective maintenance strategy for patients in this setting is still debated. In a worldwide clinical trial called NIRVANA-1, researchers are investigating how niraparib would work if combined with another treatment called bevacizumab, which stops the growth of new blood vessels in tumors. Patients who participate in this trial will be randomly assigned to one of two treatment groups: the combination of niraparib + bevacizumab or niraparib by itself. The main purpose of NIRVANA-1 is to understand whether the combination of niraparib and bevacizumab prevents the cancer from returning in patients with completely resected stage III ovarian cancer. The trial will also assess the safety of this combination compared with niraparib alone. At the time of this writing, NIRVANA-1 is open for new patients to join. Sponsored by ARCAGY-GINECO, the NIRVANA-1 trial is currently recruiting patients from France, Spain, Italy, Belgium, Japan and Korea. The duration of the inclusion period is estimated to be around 36 months. The study is registered on ClinicalTrial.gov with registration number NCT05183984.

Low probability of disease cure in advanced ovarian carcinomas before the PARP inhibitor era.

BACKGROUND: In ovarian carcinomas, the likelihood of disease cure following first-line medical-surgical treatment has been poorly addressed. The objective was to: (a) assess the likelihood of long-term disease-free (LDF) > 5 years; and (b) evaluate the impact of the tumour primary chemosensitivity (assessed with the modelled CA-125 KELIM) with respect to disease stage, and completeness of debulking surgery. METHODS: Three Phase III trial datasets (AGO-OVAR 9; AGO-OVAR 7; ICON-7) were retrospectively investigated in an "adjuvant dataset", whilst the Netherlands Cancer Registry was used in a "neoadjuvant dataset". The prognostic values of KELIM, disease stage and surgery outcomes regarding the likelihood of LDF were assessed using univariate/multivariate analyses. RESULTS: Of 2029 patients in the "adjuvant dataset", 82 (4.0%) experienced LDF (Stage I-II: 25.9%; III: 2.1%; IV: 0.5%). Multivariate analyses identified disease stage and KELIM (OR = 4.24) as independent prognostic factors. Among the 1452 patients from the "neoadjuvant dataset", 36 (2.4%) had LDF (Stage II-III: 3.3%; IV: 1.3%). Using multivariate tests, high-risk diseases (OR = 0.18) and KELIM (OR = 2.96) were significant. CONCLUSION: The probability of LDF > 5 years after first-line treatment in 3486 patients (<4%) was lower than thought. These data could represent a reference for future studies meant to assess progress related to PARP inhibitors.

Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer.

BACKGROUND: Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS: Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).

Changes in the Use of Comprehensive Geriatric Assessment in Clinical Trials for Older Patients with Cancer over Time.

BACKGROUND: The objective of this study was to describe the implementation of comprehensive geriatric assessment (CGA) in clinical trials dedicated to older patients before and after the creation of the International Society of Geriatric Oncology in the early 2000s. SUBJECTS, MATERIALS, AND METHODS: All phase I, II, and III trials dedicated to the treatment of cancer among older patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. We considered that a CGA was performed when the authors indicated an intention to do so in the Methods section of the article. We collected each geriatric domain assessed using a validated tool even in the absence of a clear CGA, including nutritional, functional, cognitive, and psychological status, comorbidity, comedication, overmedication, social status and support, and geriatric syndromes. RESULTS: A total of 260 clinical trials dedicated to older patients were identified over the two time periods: 27 phase I, 193 phase II, and 40 phase III trials. CGA was used in 9% and 8% of phase II and III trials, respectively; it was never used in phase I trials. Performance status was reported in 67%, 79%, and 75% of phase I, II, and III trials, respectively. Functional assessment was reported in 4%, 11%, and 13% of phase I, II, and III trials, respectively. Between the two time periods, use of CGA increased from 1% to 11% (p = .0051) and assessment of functional status increased from 3% to 14% (p = .0094). CONCLUSION: The use of CGA in trials dedicated to older patients increased significantly but remained insufficient. IMPLICATIONS FOR PRACTICE: This article identifies the areas in which research efforts should be focused in order to offer physicians well-addressed clinical trials with results that can be extrapolated to daily practice.

Non-pegylated liposomal doxorubicin (NPLD, Myocet®) + carboplatin in patients with platinum sensitive ovarian cancers: A ARCAGY-GINECO phase IB-II trial.

BACKGROUND: Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to 2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin. METHODS: MYCA was a multicenter 2-step phase Ib-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m2 during phase Ib step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months. RESULTS: From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3-39.7); the median PFS was 10.0 months (95% CI, 8.6-11.0). The median overall survival was 28.1 months (95% CI, 22.3-32.5); and the objective response rate was 58% (95% CI, 47-68). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia. CONCLUSION: Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments.

Progression-free survival and safety at 3.5 years of follow-up: results from the randomized phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer - a plain language summary.

What is this summary about? This PLSP provides a short summary of an original scientific article that presented results from the PRIMA study after 3.5 years of follow-up time. The original article was published in the European Journal of Cancer in 2023.The PRIMA study included adult patients with newly diagnosed advanced high-risk ovarian cancer whose tumors shrunk or became undetectable after treatment with chemotherapy with or without surgery. The PRIMA study evaluated how well the drug niraparib, also known as Zejula, worked at delaying or preventing ovarian cancer from coming back (recurring) or getting worse (progressing) compared with placebo (a substance with no effects that a doctor gives to a patient instead of a drug). The first results from the PRIMA study were published in 2019, when patients had participated in the PRIMA study for about 1.2 years.The article this PLSP is based on reports longer-term data from the PRIMA study, when patients had participated in the PRIMA study for about 3.5 years. Patients were monitored (or followed) for a longer time to understand how well niraparib continued to work and to evaluate whether the safety of niraparib changed with additional time being monitored.What were the results? Patients who took niraparib had more time before their cancer came back or got worse than patients who took placebo. In terms of safety, no new types of side effects with niraparib treatment were observed with additional time being monitored as part of the PRIMA study.What do the results mean? These results support that niraparib remains an important treatment option to help delay the cancer from coming back or getting worse in patients with newly diagnosed advanced ovarian cancer that responded to initial treatment.Clinical Trial Registration: NCT02655016 (PRIMA study) (ClinicalTrials.gov).

Impact of geriatric assessment for the therapeutic decision-making of breast cancer: results of a French survey. AFSOS and SOFOG collaborative work.

BACKGROUND: Cancer management in the elderly is often considered as suboptimal, highly variable, and rarely evidence-based. Data are needed to understand decision-making processes in this population. MATERIALS AND METHODS: A survey was performed in France to describe decision-making in gynaecologic patients over 70. It followed a three-step method: (1) 101 representative physicians questioned about treatment decision criteria; (2) simplified individual data were collected; (3) as well as detailed data patients receiving chemotherapy. This analysis refers to breast cancer subgroup of patients. RESULTS: Main decision criteria were performance status, comorbidities, and renal function. In adjuvant setting, the main concern was life expectancy, whereas it was quality of life in metastatic setting. Of the 631 patients entered in the simplified analysis, 41% had been evaluated by a geriatrician, 67% received chemotherapy. In the detailed analysis, patients older than 75 were more likely to receive a monochemotherapy and to be treated with weekly/divided dose. In adjuvant setting, respectively, 19, 55, and 26% of the patients were treated with regimen validated in the elderly, validated in a younger population, and not validated. A G-CSF was prescribed in 48% of the patients, as primary prophylaxis in 78 and in 41% of patients with a risk of febrile neutropenia < 10%. CONCLUSION: Geriatric covariates become an increasing concern in the decision-making process. This survey also suggests an insufficient use of validated chemotherapy regimens. To date, age remains a risk factor for heterogeneity in oncologic practice justifying a persistent effort for elaborating and disclosing specific recommendations.

Long-term survival in patients with epithelial ovarian cancer following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

OBJECTIVE: Despite a high response rate to first-line therapy, prognosis of epithelial ovarian carcinoma (EOC) remains poor. The objective of the present study was to evaluate the frequency of long-term survivors and to identify the prognostic factors associated with long-term survival in a French cohort of 566 patients. METHODS: Patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for EOC in 13 French centers between 1991 and 2010 were included. Long-term survivors were defined as patients who survived more than 5 years after HIPEC and CRS, irrespective of relapse. RESULTS: Seventy-eight long-term survivors were analyzed. The median follow-up was 74 months. Median age at the time of first HIPEC was 55.4 years (range [22.6-77.6]. Seven patients had advanced EOC and 71 patients had recurrent EOC (37 patients had platinum-resistant EOC and 32 had platinum-sensitive disease). More than half of the long-term survivors had high-grade serous ovarian cancer (HGSOC). In univariate analysis, age ≥50 years (p = .004), peritoneal cancer index (PCI) ≤ 8 (p = .049) and CA-125 < 100 (p = .02) were associated with long-term survival. There was a trend towards an association between higher CC-score and long-term survival (p = .057). CONCLUSION: Age ≥50 years, PCI ≤8 and CA125 < 100 were associated with long-term survival in univariate analysis. There was a trend towards the significance of CC-score. Platinum-status was not associated with long-term survival.

Total Hip Arthroplasty for Periacetabular Metastatic Disease. An Original Technique of Reconstruction According to the Harrington Classification.

BACKGROUND: Periacetabular metastatic disease requires complex acetabular reconstruction. The complication rate for these frail patients is high. Various cement-rebar reinforced techniques allowing cemented total hip arthroplasty (THA) have been described. The optimal procedure has not yet been identified. METHODS: A continuous series of 131 THAs performed in 126 patients with periacetabular metastatic disease was prospectively included in this study. After bone metastasis curettage and cementation, an original technique of acetabular reconstruction was performed using a dual mobility cup cemented into an acetabular reinforcement device (ie, Kerboull cross-plate or Burch-Schneider antiprotrusio cage) according to the Harrington classification. Functional outcome for independent ambulation in the community, pain relief, and occurrence of dislocation or mechanical failure of the acetabular reconstruction were assessed. RESULTS: At a mean follow-up of 33 ± 17 months, the improvement in the preoperative to postoperative functional outcome and pain relief was significant (P < .001). The dislocation rate was 2%. Two of the 3 cases of dislocation occurred in acetabular reconstructions associated with a proximal femoral arthroplasty. No mechanical failure or aseptic loosening of the acetabular reconstruction was observed. CONCLUSION: This study emphasized that our original technique combining bone metastasis curettage and cementation, acetabular reinforcement device and cemented dual mobility cup was effective to restore a painless functional independence and ensure a durable acetabular reconstruction able to face to adjuvant radiation therapy and mechanical solicitations for long survivors. In addition, dual mobility cup limited the risk of dislocation in patients undergoing THA for periacetabular metastatic disease.

EVESOR, a model-based, multiparameter, Phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib.

AIM: This novel multiparameter Phase I study aimed to optimize doses/dosing schedules of everolimus and sorafenib drug combination, based on modeling/simulation (NCT01932177). PATIENTS & METHODS: About 26 patients with solid tumors were treated in four different dosing schedules. Everolimus once daily + sorafenib twice daily were given continuously in arms A and B, and intermittently in arms C (alternating every other week) and D (everolimus continuous and sorafenib 3 days on/4 days off). RESULTS: Continuous schedules exhibited higher toxicity risks than intermittent schedules (64.1 vs 35.9%; p < 0.0001), and trends for lower disease control rates (80 vs 100%). No significant pharmacokinetic interaction was identified. CONCLUSION: Feasibility of EVESOR trial is demonstrated. Intermittent schedules might provide better tolerance and efficacy than continuous schedules.

PD-L1 Expression in Premalignant and Malignant Trophoblasts From Gestational Trophoblastic Diseases Is Ubiquitous and Independent of Clinical Outcomes.

OBJECTIVE: Recently reported expression of programmed cell death 1 ligand 1 (PD-L1) in gestational trophoblastic diseases (GTDs) suggests that the immune tolerance of pregnancy might be hijacked during neoplastic process. We assessed PD-L1 protein expression in premalignant and malignant GTD lesions and analyzed associations with disease severity and chemotherapy outcomes. METHODS: We included 83 GTD whole-tissue sections from 76 patients in different treatment settings. PD-L1 protein expression was assessed with immunohistochemistry in each trophoblast subtype with the Allred total score (ATS), which combines intensity and proportion expression on a 0- to 8-point scale. Peritumoral immune infiltrate was scored on hematoxylin-eosin-safran-stained slides. RESULTS: PD-L1 expression was ubiquitous and strong in all GTD trophoblast subtypes. For invasive moles, ATS scores were maximal at 8 in 100%, 100%, and 75% of syncytiotrophoblast, villous cytotrophoblast, and extravillous cytotrophoblast specimens, respectively. For choriocarcinomas, ATS was 8 in 80% of specimens. Immune infiltrates were moderate to severe in 61%, 100%, and 100% of peritumoral zones of choriocarcinoma, epithelioid trophoblastic tumor, and invasive moles, respectively. Because of the homogeneous pathological findings, no significant differences in PD-L1 expression profiles or peritumoral immune infiltrates were found regarding FIGO (International Federation of Gynecology Obstetrics) prognostic score, fatal outcome, or chemosensitivity. CONCLUSIONS: We confirm that PD-L1 is constitutively expressed in all GTD premalignant and malignant trophoblast subtypes, independently from FIGO score, chemoresistance, or fatal outcomes, thereby suggesting a crucial role for PD-L1 in the development and tolerance of GTD. Assessment of anti-PD-L1 drug in GTD patients has been activated.

Revisiting dosing regimen using PK/PD modeling: the MODEL1 phase I/II trial of docetaxel plus epirubicin in metastatic breast cancer patients.

The MODEL1 trial is the first model-driven phase I/II dose-escalation study of densified docetaxel plus epirubicin administration in metastatic breast cancer patients, a regimen previously known to induce unacceptable life-threatening toxicities. The primary objective was to determine the maximum tolerated dose of this densified regimen. Study of the efficacy was a secondary objective. Her2-negative, hormone-resistant metastatic breast cancer patients were treated with escalating doses of docetaxel plus epirubicin every 2 weeks for six cycles with granulocyte colony stimulating factor support. A total of 16 patients were treated with total doses ranging from 85 to 110 mg of docetaxel plus epirubicin per cycle. Dose escalation was controlled by a non-hematological toxicity model. Dose densification was guided by a model of neutrophil kinetics, able to optimize docetaxel plus epirubicin dosing with respect to pre-defined acceptable levels of hematological toxicity while ensuring maximal efficacy. The densified treatment was safe since hematological toxicity was much lower compared to previous findings, and other adverse events were consistent with those observed with this regimen. The maximal tolerated dose was 100 mg given every 2 weeks. The response rate was 45 %; median progression-free survival was 10.4 months, whereas 54.6 months of median overall survival was achieved. The optimized docetaxel plus epirubicin dosing regimen led to fewer toxicities associated with higher efficacy as compared with standard or empirical densified dosing. This study suggests that model-driven dosage adjustment can lead to improved efficacy-toxicity balance in patients with cancer when several anticancer drugs are combined.

Prognostic factors for overall survival in elderly patients with advanced ovarian cancer treated with chemotherapy: Results of a pooled analysis of three GINECO phase II trials.

BACKGROUND: The GINECO led three multicentric prospective phase II studies, Elderly Woman Ovarian Trials 1 (EWOT1), EWOT2, and EWOT3, to evaluate the impact of geriatric covariates on the outcome of elderly patients treated with six courses of first-line chemotherapy for FIGO stage IIIIV ovarian cancer. This pooled analysis was designed to evaluate the validity of the geriatric vulnerability parameters identified in EWOT3 (Falandry et al., 2013). PATIENTS AND METHODS: From 1997 to 2011, 266 patients were recruited: 83 in EWOT1, 72 in EWOT2, and 111 in EWOT3, which evaluated respectively a 4-weekly carboplatin-cyclophosphamide regimen, a 3-weekly standard carboplatin-paclitaxel doublet and a carboplatin monotherapy. All patients were analyzed in this pooled analysis for treatment completion, toxicity, and overall survival. RESULTS: The global treatment completion rate was 73% and ranged from 68% in EWOT2 to 74% in EWOT3. Toxicities were generally manageable: neutropenia was more frequent in EWOT2 and thrombopenia in EWOT1 and EWOT3. In multivariate analysis, covariates associated with decreased survival were: being "depressed" according to the investigators' assessment, hypoalbuminemia <35g/L, and FIGO stage IV. In addition, a Hospital Anxiety and Depression Scale (HADS) score>14 and Instrumental Activities of Daily Living (IADL) score<25 confirmed a deleterious impact in the EWOT2+EWOT3 population subanalysis. CONCLUSIONS: Despite moderate heterogeneity among the studies, this pooled analysis confirmed the deleterious effects on overall survival of emotional disorders ("depressed", as assessed by investigators or the HADS score), and decreased functionality (IADL score), in addition to FIGO stage.

Routine Clinical Practice for Patients With Recurrent Ovarian Carcinoma: Results From the TROCADERO Study.

OBJECTIVE: Treatment options for patients with recurrent ovarian carcinoma are diverse, and different therapies are recommended based on platinum-free interval (PFI). Data examining the association between platinum sensitivity, treatment strategy, and outcomes are limited, particularly for partially platinum-sensitive (PPS) patients. This study characterized clinical features and outcomes in patients with recurrent ovarian carcinoma in the context of sensitivity to platinum-based therapy. METHODS: Anonymized case records were obtained from eligible European medical sites. Eligible patients were 18 years or older with epithelial ovarian carcinoma who had received 1 or more platinum-based therapies and had 1 or more subsequent relapses. Patient records were categorized by PFI and analyzed based on demographic and clinical data using descriptive statistics. RESULTS: There was no difference between PFI in PPS patients receiving platinum versus nonplatinum therapy (8.9 [range, 6.0-12.0] and 8.3 [range, 6.0-11.3] months, respectively). Overall survival in patients with platinum-sensitive, PPS, platinum-resistant, and platinum-refractory disease was 43.0 (95% confidence interval [95% CI], 25.1-42.3), 20.5 (95% CI, 17.7-24.8), 12.7 (95% CI, 10.4-14.2), and 9.8 (95% CI, 6.6-14.9) months, respectively. Among PPS patients, overall survival was 23.5 (95% CI, 18.4-37.3) and 18.7 (95% CI, 11.0-23.5) months for those who received platinum and nonplatinum-based therapy, respectively. No demographic or clinical characteristics were identified that indicated a difference between PPS patients who received platinum-based therapy versus those who did not. CONCLUSIONS: Partially platinum-sensitive patients with recurrent ovarian carcinoma who received platinum-based therapy had improved outcomes compared with those who did not. No clear demographic criteria for choosing platinum- versus nonplatinum-based therapy for PPS patients were identified from patient records.

Motivations of patients seeking supportive care for cancer from physicians prescribing homeopathic or conventional medicines: results of an observational cross-sectional study.

BACKGROUND & AIMS: The motivations of patients who consult a homeopathic (GP-Ho) or conventional (GP-CM) general practitioner for supportive care during cancer treatment have not been widely studied. We investigated the reasons why cancer patients consult a GP-Ho versus a GP-CM for supportive care and the GPs' motivations for their prescriptions. METHODS: This observational survey was carried out in France between October 2008 and October 2011. GPs across France were randomly selected and asked to recruit four cancer patients each. At inclusion, the sociodemographic and clinical (including psychological) characteristics and medical history of the patients were recorded by the GPs and the patients noted their quality of life (QoL) and anxiety/depression using the Quality of Life Questionnaire-C30 (QLQ-C30) and Hospital Anxiety and Depression Scale (HADS) self-questionnaires. The main motivations of the patients regarding the type of GP consultation and the main reasons for the GPs' prescriptions were recorded. RESULTS: Six hundred and forty four patients were included in the analysis: 399 consulted a GP-CM (n = 112) and 245 a GP-Ho (n = 73). Patients consulting a GP-Ho were more often female [OR = 1.93; 95%CI: 1.11-3.35; p = 0.02], employed in a professional capacity [OR = 6.57; 95%CI: 1.96-21.99; p = 0.002], have a shorter time since cancer diagnosis [OR = 2.19; 95%CI: 1.24-3.87; p = 0.007], have received targeted anticancer therapy [OR = 3.70; 95%CI: 1.67-8.18; p = 0.001] and have a high QLQ-C30 score for constipation [OR = 1.01; 95%CI: 1.00-1.02; p = 0.001]. Patients mainly consulted a GP-Ho to receive overall care (73.5% vs. 64.9%; p = 0.024) and medicines to prevent anticancer treatment-related side-effects (63.7% vs. 41.4%; p < 0.0001). In contrast, patients consulted a GP-CM to receive psychological care (50.1% vs. 40.8%; p = 0.021) and more information regarding the oncologists' strategic decisions (p < 0.0001). There was a significantly greater prescription of psychotropic drugs by GP-CM (53.7% vs. 22.4%, p < 0.0001). CONCLUSIONS: Patients consulting a GP-Ho or GP-CM had different motivations for seeking supportive care. There was a significantly greater prescription of psychotropic drugs by GP-CM.

Multiparameter Phase I trials: a tool for model-based development of targeted agent combinations--example of EVESOR trial.

Optimal development of targeted drug combinations is one of the future challenges to be addressed. Computerization and mathematical models able to describe biological phenomena and to simulate the effects of changes in experimental conditions may help find solutions to this issue. We propose the concept of 'multiparameter trials', where biological, radiological and clinical data required for modeling purpose are collected and illustrated by the ongoing academic EVESOR trial. The objective of the model-based work would be the determination of the optimized doses and dosing schedules of everolimus and sorafenib, offering the maximization of the predicted modeled benefit/toxicity ratio in patients with solid tumors. It may embody the 'proof of concept' of model-based drug development of anticancer agent combinations.

Dynamic modeling in ovarian cancer: an original approach linking early changes in modeled longitudinal CA-125 kinetics and survival to help decisions in early drug development.

OBJECTIVE: Early prediction of the expected benefit of treatment in recurrent ovarian cancer (ROC) patients may help in drug development decisions. The actual value of 50% CA-125 decrease is being reconsidered. The main objective of the present study was to quantify the links between longitudinal assessments of CA-125 kinetics and progression-free survival (PFS) in treated recurrent ovarian cancer (ROC) patients. METHODS: The CALYPSO randomized phase III trial database comparing two platinum-based regimens in ROC patients was randomly split into a "learning dataset" and a "validation dataset". A parametric survival model was developed to associate longitudinal modeled CA-125 changes (ΔCA125), predictive factors, and PFS. The predictive performance of the model was evaluated with simulations. RESULTS: The PFS of 534 ROC patients were properly characterized by a parametric mathematical model. The modeled ΔCA125 from baseline to week 6 was a better predictor of PFS than the modeled fractional change in tumor size. Simulations confirmed the model's predictive performance. CONCLUSIONS: We present the first parametric survival model quantifying the relationship between PFS and longitudinal CA-125 kinetics in treated ROC patients. The model enabled calculation of the increase in ΔCA125 required to observe a predetermined benefit in PFS to compare therapeutic strategies in populations. Therefore, ΔCA125 may be a predictive marker of the expected gain in PFS and an early predictive tool in drug development decisions.

Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas.

Vulvovaginal melanomas are rare tumors that account for a small fraction of all vulvovaginal cancers. Biologically, they seem to be similar to mucosal and acral melanomas of other sites. There are limited data specific to vulvovaginal melanomas, especially regarding systemic therapies. Most treatment decisions are based on extrapolation from data regarding cutaneous melanomas of other sites. It is reasonable to follow already established guidelines from other professional groups and societies. Outcomes tend to be worse compared with cutaneous melanomas likely because of the later presentation and physical biological characteristics of these tumors.