Primary surgery followed by platinum-taxane based chemotherapy has been the standard therapy in advanced ovarian cancer. However, the prognostic role of complete and so-called optimal and suboptimal ...debulking and its interaction with biological factors has not been not fully defined.
Exploratory analysis was conducted of 3 prospective randomized trials (AGO-OVAR 3, 5, and 7) investigating platinum-taxane based chemotherapy regimens in advanced ovarian cancer conducted between 1995 and 2002.
A total of 3126 patients were analyzed. Approximately one-third each fulfilled criteria for complete resection (group A), small residual tumor burden of 1-10 mm (group B), or macroscopic residual disease exceeding 1 cm in diameter (group C). Multivariate analysis showed improved progression-free and overall survival for group A with complete resection compared with groups B or C (P<.0001). The impact of so-called optimal debulking as in group B showed a smaller prognostic impact compared with group C. Further independent prognostic factors for overall survival were age, performance status, grade, FIGO stage, and histology, namely the mucinous subtype. An interaction between residual tumor and some biologic factors was demonstrated.
The goal of primary surgery should be complete resection. The prognostic impact of tumor biology seemed to be partially overruled by residual tumor and further evaluation of biologic factors should stratify for residual tumor.
The aim of this randomized, phase II trial was to explore the activity and safety of adding bevacizumab to paclitaxel once per week in treatment of angiosarcomas (AS).
Patients were treated with ...paclitaxel alone (90 mg/m(2) per week for six cycles of 28 days each; arm A) or with paclitaxel combined with bevacizumab (10 mg/kg once every 2 weeks; arm B). In the combination treatment arm, bevacizumab was administered after the six cycles of chemotherapy as maintenance therapy (15 mg/kg once every 3 weeks) until intolerance or progression occurred. Stratification factors were superficial versus visceral AS and de novo versus radiation-induced AS. The primary end point was the 6-month progression-free survival (PFS) rate, which was based on RECIST, version 1.1. Statistical assumptions were P0 = 20%, P1 = 40%, a = 10%, and b = 20%. P0 was the PFS rate at 6 months defining inactive drug, and P1 was the PFS rate at 6 months defining promising drug.
A total of 52 patients were enrolled, and 50 were randomly assigned in 14 centers. The most common primary sites were the breast (49%) and skin (12%). There were 17 (34%) visceral and 24 (49%) radiation-induced AS. The performance status was 0 in 24 patients (49%) and 1 in the remaining 25 patients (51%). The median follow-up time was 14.5 months. Both treatment regimens were considered active, with 6-month PFS rates of 54% (14 of 26) in arm A and 57% (14 of 24) in arm B. The median overall survival rates were 19.5 months in arm A and 15.9 months in arm B. Toxicity was higher with the combination arm and included one fatal drug-related toxicity (intestinal occlusion).
The primary objective was met in both treatment arms. However, the present data do not support additional clinical investigation of combined paclitaxel/bevacizumab for the treatment of advanced AS.
Background
The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype‐specific prospective controlled data lacking, this study retrospectively evaluated doxorubicin plus ...dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first‐line treatments for advanced/metastatic leiomyosarcoma treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC‐STBSG) sites.
Methods
The inclusion criteria were a confirmed histological diagnosis, treatment between January 2010 and December 2015, measurable disease (Response Evaluation Criteria in Solid Tumors 1.1), an Eastern Cooperative Oncology Group performance status ≤2, and an age ≥ 18 years. The endpoints were progression‐free survival (PFS), overall survival (OS), and overall response rate (ORR). PFS was analyzed with methods for interval‐censored data. Patients were matched according to their propensity scores, which were estimated with a logistic regression model accounting for histology, grade, age, sex, performance status, tumor site, and tumor extent.
Results
Three hundred three patients from 18 EORTC‐STBSG sites were identified. One hundred seventeen (39%) received doxorubicin plus dacarbazine, 71 (23%) received doxorubicin plus ifosfamide, and 115 (38%) received doxorubicin. In the 2:1:2 propensity score–matched population (205 patients), the estimated median PFS was 9.2 months (95% confidence interval CI, 5.2‐9.7 months), 8.2 months (95% CI, 5.2‐10.1 months), and 4.8 months (95% CI, 2.3‐6.0 months) with ORRs of 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone, respectively. PFS was significantly longer with doxorubicin plus dacarbazine versus doxorubicin (hazard ratio HR, 0.72; 95% CI, 0.52‐0.99). Doxorubicin plus dacarbazine was associated with longer OS (median, 36.8 months; 95% CI, 27.9‐47.2 months) in comparison with both doxorubicin plus ifosfamide (median, 21.9 months; 95% CI, 16.7‐33.4 months; HR, 0.65; 95% CI, 0.40‐1.06) and doxorubicin (median, 30.3 months; 95% CI, 21.0‐36.3 months; HR, 0.66; 95% CI, 0.43‐0.99). Adjusted analyses retained an effect for PFS but not for OS. None of the factors selected for multivariate analysis had a significant interaction with the received treatment for both PFS and OS.
Conclusions
This is the largest retrospective study of first‐line treatment for advanced leiomyosarcoma. In the propensity score–matched population, doxorubicin and dacarbazine showed favorable activity in terms of both ORR and PFS and warrants further evaluation in prospective trials.
In this propensity score‐adjusted, multi‐institutional series, doxorubicin and dacarbazine show better outcomes for the first‐line treatment of advanced leiomyosarcoma and warrant further studies. This series represents a benchmark for the future development of trials for leiomyosarcoma.
Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of ...avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer.
JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints.
Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6–21·9) for the combination group, 17·4 months (15·2–21·3) for the PLD group, and 18·2 months (15·8–21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3–5·1) in the combination group, 3·5 months (2·1–4·0) in the PLD group, and 1·9 months (1·8–1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 repeated 93·1% CI 0·59–1·24, one-sided p=0·030; avelumab vs PLD: 1·68 1·32–2·60, one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7–18·7) in the combination group, 13·1 months (11·8–15·5) in the PLD group, and 11·8 months (8·9–14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 repeated 88·85% CI 0·74–1·24, one-sided p=0·21; avelumab vs PLD: 1·14 0·95–1·58, one-sided p=0·83). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 10% in the combination group vs nine 5% in the PLD group vs none in the avelumab group), rash (11 6% vs three 2% vs none), fatigue (ten 5% vs three 2% vs none), stomatitis (ten 5% vs five 3% vs none), anaemia (six 3% vs nine 5% vs three 2%), neutropenia (nine 5% vs nine 5% vs none), and neutrophil count decreased (eight 5% vs seven 4% vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction).
Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer.
Pfizer and Merck KGaA, Darmstadt, Germany.
Spatial inequalities in health result from different exposures to health risk factors according to the features of geographical contexts, in terms of physical environment, social deprivation, and ...health care accessibility. Using a common geographical referential, which combines indices measuring these contextual features, could improve the comparability of studies and the understanding of the spatial dimension of health inequalities.
We developed the Geographical Classification for Health studies (GeoClasH) to distinguish French municipalities according to their ability to influence health outcomes. Ten contextual scores measuring physical and social environment as well as spatial accessibility of health care have been computed and combined to classify French municipalities through a K-means clustering. Age-standardized mortality rates according to the clusters of this classification have been calculated to assess its effectiveness.
Significant lower mortality rates compared to the mainland France population were found in the Wealthy Metropolitan Areas (SMR = 0.868, 95% CI 0.863-0.873) and in the Residential Outskirts (SMR = 0.971, 95% CI 0.964-0.978), while significant excess mortality were found for Precarious Population Districts (SMR = 1.037, 95% CI 1.035-1.039), Agricultural and Industrial Plains (SMR = 1.066, 95% CI 1.063-1.070) and Rural Margins (SMR = 1.042, 95% CI 1.037-1.047).
Our results evidence the comprehensive contribution of the geographical context in the constitution of health inequalities. To our knowledge, GeoClasH is the first nationwide classification that combines social, environmental and health care access scores at the municipality scale. It can therefore be used as a proxy to assess the geographical context of the individuals in public health studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study examined the types of discordance occurring in the diagnosis of soft tissue and visceral sarcomas, gastrointestinal stromal tumors (GIST), and desmoid tumors, as well as the economic ...impact of diagnostic discrepancies.
We carried out a retrospective, multicenter analysis using prospectively implemented databases performed on a cohort of patients within the French RRePS network in 2010. Diagnoses were deemed to be discordant based on the 2013 World Health Organization (WHO) classification. Predictive factors of discordant diagnoses were explored. A decision tree was used to assess the expected costs of two strategies of disease management: one based on revised diagnoses after centralized histological review (option 1), the other on diagnoses without centralized review (option 2). Both were defined based on the patient and the disease characteristics, according to national or international guidelines. The time horizon was 12 months and the perspective of the French National Health Insurance (NHI) was retained. Costs were expressed in Euros for 2013. Sensitivity analyses were performed using low and high scenarios that included ± 20% estimates for cost.
A total of 2,425 patients were included. Three hundred forty-one patients (14%) had received discordant diagnoses. These discordances were determined to mainly be benign tumors diagnosed as sarcomas (n = 124), or non-sarcoma malignant tumors diagnosed as sarcomas (n = 77). The probability of discordance was higher for a final diagnosis of desmoid tumors when compared to liposarcomas (odds ratio = 5.1; 95%CI 2.6-10.4). The expected costs per patient for the base-case analysis (low- and high-case scenarios) amounted to €8,791 (€7,033 and €10,549, respectively) for option 1 and €8,904 (€7,057 and €10,750, respectively) for option 2.
Our findings highlight misdiagnoses of sarcomas, which were found to most often be confused with benign tumors. Centralized histological reviews are likely to provide cost-savings for the French NHI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Soft Tissue and Uterine Leiomyosarcoma George, Suzanne; Serrano, César; Hensley, Martee L ...
Journal of clinical oncology,
01/2018, Letnik:
36, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Leiomyosarcoma (LMS) is one of the most common subtypes of soft tissue sarcoma in adults and can occur in almost any part of the body. Uterine leiomyosarcoma is the most common subtype of uterine ...sarcoma. Increased awareness of this unique histology has allowed for the development of drugs that are specific to LMS and has begun to shed light on the similarities and possible unique aspects of soft tissue and uterine LMS. In this review, we summarize the current understanding of the epidemiology, diagnosis, genomics, and treatment options for LMS.
In patients with advanced ovarian cancer, the modelled CA-125 ELIMination rate constant K (KELIM) is an early indicator of the tumour intrinsic chemosensitivity. We assessed the prognostic and ...surrogate values of KELIM with respect to those of surgery outcome (based on post-operative residual lesions) in the Gynaecologic Cancer Intergroup (GCIG) individual patient data meta-analysis MAOV (Meta-Analysis in OVarian cancer) built before the emergence of poly(ADP-ribose) polymerase (PARP) inhibitors.
The dataset was split into learning and validation cohorts (ratio 1:2). The individual modelled KELIM values were estimated, standardised by the median value, then scored as unfavourable (<1.0) or favourable (≥1.0). Overall survival (OS) and progression-free survival (PFS) analyses were performed with a two-step meta-analytic approach and surrogacy through a two-level meta-analytic model.
KELIM was assessed in 5884 patients from eight first-line trials (learning, 1962; validation, 3922). A favourable KELIM score was significantly associated with longer OS (validation set, median, 78.8 versus 28.4 months, hazard-ratios HR 0.46, 95% confidence interval CI, 0.41-0.50, C-index 0.68), and longer PFS (validation set, median 30.5 versus 9.8 months, HR 0.49, 95% CI, 0.45-0.54, C-index 0.68), as were International Federation of Gynaecology and Obstetrics (FIGO) stage and debulking surgery outcome. Three prognostic groups were identified based on the surgery outcome and KELIM score, with large differences in OS (105.1, ∼45.0, and 22.1 months) and PFS (58.1, ∼15.0, and 8.0 months). Surrogacy for OS and for PFS was not established.
KELIM is an independent prognostic biomarker for survival, complementary to surgery outcome, representing a new determinant of first-line treatment success.
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