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1.
Ann Surg Oncol ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33768396

RESUMO

BACKGROUND: Most frequent borderline ovarian tumors are serous and mucinous subtypes. Less frequent borderline diseases are endometrioid, clear-cell, and Brenner tumors (BBOT). Very little is known about the latter subtype, and most studies include very short series or case reports. The aim of this study is to determine the prognosis of a continuous series of BBOT and analyze data published in the literature on this rare entity. PATIENTS AND METHODS: A retrospective review of patients with BBOT treated or referred to our institutions was conducted. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion. RESULTS: Overall, 17 patients were identified. Median age was 62 (range 42-85) years. Six patients underwent unilateral salpingo-oophorectomy, and 11 bilateral salpingo-oophorectomy +/- hysterectomy and/or staging surgery. In total, 16 patients had unilateral tumor, and all patients had stage I disease. Stromal microinvasion was observed in three cases. Median follow-up was 60 months (range 7-118 months). One patient developed a recurrence in contralateral ovary after unilateral salpingo-oophorectomy. One patient had previous history of urothelial tumor. CONCLUSIONS: Peritoneal staging surgery is not required because all patients reported had stage I disease. One recurrence occurred. When reviewing all the 82 cases reported in the literature (including ours), 9% had previous history or synchronous urothelial tumor, suggesting the need to carefully check for urological disease in patients with BBOT.

2.
J Natl Cancer Inst ; 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33693762

RESUMO

BACKGROUND: Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction, however the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined PORTEC-1,-2 and -3 trial cohort. METHODS: After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into three groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were two-sided. RESULTS: Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to ≤ 60 or ≤ 70 years would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses. Five-year recurrence-free survival (RFS) was 91.7% (95% confidence interval [CI] = 83.1-100%; hazard ratio [HR] = 0.45, 95%CI =0.16-1.24, p = .12) for LS, 95.5% (95% CI = 90.7-100%; HR = 0.17, 95% CI = 0.05-0.55, p = .003) for 'other' versus 78.6% (95% CI = 73.8-83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95%CI = 0.0-24.7%), 1.5% (95%CI = 0.0-4.3%) and 7.0% (95%CI = 3.0-10.9%) within the LS, 'other' and MLH1-hypermethylated MMRd-EC groups. CONCLUSION: The LS prevalence in the PORTEC-trial population was 2.8%, and among MMRd-ECs 9.5%. Patients with LS-associated ECs showed a trend towards better RFS and higher risk for second cancers compared to patients with MLH1-hypermethylated MMRd-EC.

3.
Gynecol Oncol ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33752918

RESUMO

OBJECTIVE: To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2. METHODS: Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model. RESULTS: Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05). CONCLUSION: The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.

4.
BMC Cancer ; 21(1): 135, 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33549033

RESUMO

BACKGROUND: The identification of factors responsible for false negative (FN) rate at 18F- Fluorodeoxyglucose (FDG) Positron Emission Tomography /Computed Tomography (PET/CT) in para-aortic (PA) lymph nodes in the presurgical staging of patients with locally advanced cervical cancer (LACC) is challenging. The aim of this study was to evaluate the impact of PET/CT technology. METHODS: A total of 240 consecutive patients with LACC (International Federation of Gynecology and Obstetrics, FIGO, stage IB2-IVA) and negative Magnetic Resonance Imaging (MRI) and/or Computed Tomography (CT) and negative 18F-FDG PET/CT in the PA region, undergoing laparoscopic PA lymphadenectomy before chemoradiotherapy were included. The FN rate in patients studied with Time of flight (TOF) PET/CT (TOF PET) or non-Time of flight PET/CT (no-TOF PET) technology was retrospectively compared. RESULTS: Patients presented with FIGO stage IB (n = 78), stage IIA-B (n = 134), stage III (n = 18) and stage IVa (n = 10), squamous cell carcinoma (n = 191) and adenocarcinoma (n = 49). 141/240 patients were evaluated with no-TOF PET/CT and 99/240 with TOF PET/CT. Twenty-two patients (9%) had PA nodal involvement at histological analysis and considered PET/CT FN findings. The FN rate was 8.5% for no-TOF PET and 10% for TOF PET subgroup respectively (p = 0.98). Ninety patients (38%) presented with pelvic node uptakes at PET/CT. The FN rate in the PA region was 18% (16/90) and 4% (6/150) in patients with and without pelvic node involvement at PET/CT respectively (19 vs 3% for no-TOF PET and 17 vs 5% for TOF PET subgroup). CONCLUSIONS: In LACC, FN rate in PA lymph nodes detection is a clinical issue even for modern PET/CT, especially in patients with pelvic uptake. Surgical lymphadenectomy should be performed in case of negative PET/CT at PA level in these patients, while it could be discussed in the absence of pelvic uptake.

5.
Lancet Haematol ; 8(2): e122-e134, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33347814

RESUMO

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy and acceptable safety in a range of neoplasms, particularly in ovarian cancers. However, some concerns have emerged regarding rare and delayed adverse events including cases of myelodysplastic syndrome and acute myeloid leukaemia, for which data are scarce. The aim of this study was to estimate the risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitors, via a systematic review and safety meta-analysis, and to describe clinical features of PARP inhibitor-related myelodysplastic syndrome and acute myeloid leukaemia cases reported in WHO's pharmacovigilance database (VigiBase). METHODS: We systematically reviewed randomised controlled trials (RCTs) comparing PARP inhibitor therapy versus control treatments (placebo and non-placebo) in adults (age ≥18 years) treated for cancer in MEDLINE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry with ongoing surveillance up to May 31, 2020. The date range for included studies was not restricted. By a stepwise method to capture all available adverse events, we first extracted data on myelodysplastic syndrome and acute myeloid leukaemia cases from ClinicalTrials.gov. If cases were not available, we extracted them from published manuscripts, or subsequently contacted corresponding authors or sponsors to provide data. RCTs without available data from ClinicalTrials.gov, publications, or corresponding authors or sponsors were excluded. The primary outcome was the summary risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibition versus placebo treatment in RCTs. We used a fixed-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% CIs. In a separate observational, retrospective, cross-sectional pharmacovigilance study of VigiBase, cases of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitor therapy were extracted on May 3, 2020, and clinical features summarised with a focus on median duration of PARP inhibitor exposure, median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death. Our systematic review and safety meta-analysis were registered with PROSPERO, CRD42020175050. Our retrospective pharmacovigilance study was registered on ClinicalTrials.gov, NCT04326023. FINDINGS: For our safety meta-analysis, initial searches identified 1617 citations, and 31 RCTs were systematically reviewed for eligibility. 28 RCTs with available adverse events were analysed (18 placebo and ten non-placebo RCTs), with 5693 patients in PARP inhibitor groups and 3406 patients in control groups. Based on the 18 placebo RCTs (n=7307 patients), PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukaemia compared with placebo treatment (Peto OR 2·63 [95% CI 1·13-6·14], p=0·026) with no between-study heterogeneity (I2=0%, χ2 p=0·91). The incidence of myelodysplastic syndrome and acute myeloid leukaemia across PARP inhibitor groups was 0·73% (95% CI 0·50-1·07; I2=0%, χ2 p=0·87; 21 events out of 4533 patients) and across placebo groups was 0·47% (0·26-0·85; I2=0%, χ2 p=1·00; three events out of 2774 patients). All 28 RCTs were rated as having unclear risk of bias. In VigiBase, 178 cases of myelodysplastic syndrome (n=99) and acute myeloid leukaemia (n=79) related to PARP inhibitor therapy were extracted. In cases with available data, median treatment duration was 9·8 months (IQR 3·6-17·4; n=96) and median latency period since first exposure to a PARP inhibitor was 17·8 months (8·4-29·2; n=58). Of 104 cases that reported outcomes, 47 (45%) resulted in death. INTERPRETATION: PARP inhibitors increased the risk of myelodysplastic syndrome and acute myeloid leukaemia versus placebo treatment. These delayed and often lethal adverse events should be studied further to improve clinical understanding, particularly in the front-line maintenance setting. FUNDING: None.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Razão de Chances , Efeito Placebo , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Trombocitopenia/etiologia , Resultado do Tratamento
6.
Artigo em Inglês | MEDLINE | ID: mdl-33221969

RESUMO

BACKGROUND: This ancillary study aimed to evaluate 18F-FDG PET parameter changes after one cycle of treatment compared to baseline in patients receiving first-line neoadjuvant anti-angiogenic nintedanib combined to paclitaxel-carboplatin chemotherapy or chemotherapy plus placebo and to evaluate the ability of 18F-FDG PET parameters to predict progression-free survival (PFS), overall survival (OS), and success of second-look surgery. MATERIALS AND METHODS: Central review was performed by two readers blinded to the received treatment and to the patients' outcome, in consensus, by computing percentage change in PET metrics within a volume of interest encompassing the entire tumor burden. EORTC and PERCIST criteria were applied to classify patients as responders (partial metabolic response and complete metabolic response) or non-responders (stable metabolic disease and progressive metabolic disease). Also analyzed was the percentage change in metabolic active tumor volume (MATV) and total lesion glycolysis (TLG). RESULTS: Twenty-four patients were included in this ancillary study: 10 received chemotherapy + placebo and 14 chemotherapy + nintedanib. PERCIST and EORTC criteria showed similar discriminative power in predicting PSF and OS. Variation in MATV/TLG did not predict PFS or OS, and no optimal threshold could be found for MATV/TLG for predicting survival. Complete cytoreductive surgery (no residual disease versus residual disease < 0.25 cm/0.25-2.5 cm/> 2.5 cm) was more frequent in responders versus non-responders (P = 0.002 for PERCIST and P = 0.02 for EORTC criteria). No correlation was observed between the variation of PET data and the variation of CA-125 blood level between baseline sample and that performed contemporary to the interim PET, but a statistically significant correlation was observed between ΔSULpeak and ΔCA-125 between baseline sample and that performed after the second cycle. CONCLUSION: 18F-FDG PET using EORTC or PERCIST criteria appeared to be a useful tool in ovarian cancer trials to analyze early tumor response, and predict second-look surgery outcome and survival. An advantage of PERCIST is the correlation of ΔSULpeak and ΔCA-125, PET response preceding tumor markers response by 1 month. Neither MATV nor TLG was useful in predicting survival. TRIAL REGISTRATION: NCT01583322 ARCAGY/ GINECO GROUP GINECO-OV119, 24 April 2012.

7.
Gynecol Oncol ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33162175

RESUMO

BACKGROUND: The disappointing activity of single agent immune-checkpoint inhibitors in epitherlial ovarian cancer (EOC) has been attributed in part to its unique tumor microenvironment (TME). IDO, PDL1, LAG3 and TIM3 have been implicated in the immunotolerance of EOC. We investigated the expression of these co-regulators, their change with neoadjuvant chemotherapy (NACT), and their association with outcome. METHOD: We identified 98 patients with EOC treated with NACT and performed IDO, PDL1, LAG3 and TIM3 immunohistochemistry on samples obtained before and after NACT. The cut-off threshold to consider a positive sample was set at 5%. RESULTS: In our cohort, TIM3 was the most prevalent co-regulator, with more than 75% of the samples being TIM3 positive. In comparison, only 22%, 28% and 17% of the samples were considered IDO, PDL1 and LAG3 positive. More than half of ovarian tumors expressed 2, 3 or even all 4 co-inhibitory molecules. However, biomarkers were not correlated with each other. NACT had a marked impact on immune co-regulator expression with over 70% of patients showing a change in biomarker status from negative to positive or vice versa. There was no significant difference in the pattern of co-regulator expression between platinum-sensitive and resistant patients. Co-expression of multiple inhibitory molecules did not appear to affect overall and progression-free survival. CONCLUSION: TIM3 is the most abundant co-inhibitory molecule in OC and may represent an attractive target. In addition, OC frequently co-expressed 2 or more markers supporting ICI combinatorial approaches. Finally, NACT significantly altered the expression of immunosuppressive molecules suggesting that the choice of ICI combinations should be adapted to the composition of the post-NACT immune TME.

8.
Ann Surg Oncol ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33140251

RESUMO

OBJECTIVE: The aim of this study was to assess the outcomes of a large series of patients treated conservatively for stage II or III serous borderline tumors of the ovary (SBOTs) with a long-term follow-up. METHODS: Patients with SBOTs and peritoneal implants, treated in or referred to our institution, were retrospectively reviewed. Outcomes of patients treated conservatively (preservation of the uterus and at least a part of one ovary) to promote subsequent fertility were specifically analyzed. RESULTS: Between 1971 and 2017, 212 patients were identified and followed-up. Among these patients, 65 underwent conservative treatment; eight patients had invasive implants. Among patients treated conservatively, 38 (58%) patients recurred. Twenty-eight recurrences were observed under the form of borderline tumor on the spared ovary and/or noninvasive implants, but eight patients had a recurrence under the form of invasive disease. Compared with radical surgery, the use of conservative treatment (p < 0.0001) was a prognostic factor on disease-free survival (DFS), but without an impact on overall survival (OS). Nevertheless, three deaths occurred. Twenty-four pregnancies (13 spontaneous) were observed in 20 patients (29 patients wanted to become pregnant). CONCLUSION: In this series collecting the largest number of patients undergoing conservative surgery for stage II/III SBOTs, spontaneous pregnancies can be achieved after conservative treatment of advanced-stage disease, but the recurrence rate is high and three deaths were observed. These patients were spared their fertility but with a high rate of recurrence. Uncertainties regarding the safety of conservative treatment should be exposed to these patients.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33129910

RESUMO

PURPOSE: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). METHODS AND MATERIALS: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. RESULTS: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. CONCLUSIONS: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

10.
Virchows Arch ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33009577

RESUMO

The morphological distinction between the various types of mucinous ovarian tumors has major prognostic implications but may be challenging. The aims of our study were to describe inter-observer reproducibility in the morphological diagnosis of mucinous ovarian tumors, to evaluate the clinical relevance of possible diagnostic discrepancies, and to identify molecular abnormalities correlated with the histological type. Seventy-nine ovarian mucinous borderline tumors (MOB) and either expansile or infiltrative carcinomas (MOC) were independently reviewed by two gynecological pathologists. Molecular analysis was performed in 32 cases. Concordance between the two pathologists was reached in 67 cases (k: 0.78). The main discrepancies (8/12) were the evaluation of nuclear grade 3 or that of microfoci (< 5 mm) of infiltrative-type carcinoma in an otherwise typical expansile MOC. Our follow-up analysis showed that infiltrative MOC had a lower overall survival (OS) (p < 0.0024) and progression-free survival (PFS) (p = 0.0060) as compared with MOB and expansile MOC. The presence of nuclear grade 3 or microfoci (< 5 mm) of infiltrative-type pattern of invasion in an otherwise typical expansile MOC did not alter the prognosis as compared with expansile MOC without these features, in terms of OS (p < 0.0028) and PFS (p = 0.0074). KRAS mutations were more frequent in MOB (71%), than in expansile (50%) and infiltrative MOC (14%). In contrast, the prevalence of TP53 mutation was lower in MOB (43%), than in expansile (58%) and infiltrative MOC (71%). Our results confirm that in MOC, the expansile pattern of invasion is associated with a better prognosis than extensive (> 5 mm) infiltrative-type pattern of invasion. No specific or sensitive molecular profile might help in the differential diagnosis of mucinous ovarian tumors.

11.
Gynecol Oncol ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33059915

RESUMO

OBJECTIVE: In young women, EOC is a rare disease with an uncertain genetic and biological substrate. METHODS: We report a long follow-up of EOC patients treated at Gustave Roussy between 1990 and 2009. We matched young patients aged ≤30 years to randomly selected older patients aged ≥40 years according to known prognostic factors (i.e. FIGO stage, histology and surgical residual disease) and the date of diagnosis with a threshold at the year 2000 to balance the treatment procedures. RESULTS: EOC was diagnosed in 68 patients aged ≤30 years matched with 111 patients aged ≥40 years. Low-grade (LG) (i.e. serous and endometrioid) (52%, n = 35) and mucinous (i.e. 23%, n = 16 infiltrative and 12% n = 8 expansile) tumors are prevalent. High-grade (HG) tumors are rare (7%, n = 5). Early stage diseases (53%, n = 36 FIGO I/II) are predominant. Response to platinum based chemotherapy is observed to be inferior in young patients as compared to matched older patients (ORR, 29 vs 84% p = 0.0002). For HG tumors the PFS is of 0% at 5 and 10 years in younger as compared to 30% in older patients. No difference in PFS (median 4.9 vs 9.8 ms, p = 0.58) and OS (not reached vs 15.3 ms, p = 0.47) is found overall among younger and older patients respectively. The median follow-up was 72 months (range, 11-288 months). No genetic abnormalities were found. CONCLUSIONS: Young EOC patients are most often diagnosed at an early FIGO stage with LG serous or mucinous histology. Tumors are significantly more resistant to platinum-based chemotherapy in younger patients.

12.
Bull Cancer ; 107(10): 1006-1018, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-32958220

RESUMO

Endometrial cancer is a common cancer in older women and is often associated with comorbidities. Management of metastatic disease and/or relapse requires a multidisciplinary approach. Recent advances in the understanding of oncogenesis and molecular classification of endometrial cancers offer new therapeutic perspectives. These first recommendations, established following the methodology of Nice-Saint-Paul recommendations for clinical practice (RPC), aims to integrate molecular advances in diagnostic and therapeutic management. In 2020, the histological diagnosis of endometrial cancer is based on morphology and immunohistochemistry, including at least p53, oestrogen and progesterone receptors. Deficiency in the DNA mismatch repair system (MMR) must be assessed in all advanced endometrial tumors for oncogenetic and theranostic purposes. It can be sought initially by an analysis in immunohistochemistry with the 4 markers (MLH1, MSH2, MSH6, PMS2). Medical treatment depends on histological type, presence of hormone receptors and patient's profile to refer to chemotherapy (carboplatin-paclitaxel) or hormone therapy (for example of the progestogen type); in the event of MMR-deficiency, immunotherapy trial is the best option. As part of overall management of advanced endometrial cancer, radiotherapy (and surgery in rare cases) must be discussed, in particular in the event of loco-regional only relapse or oligometastatic disease.


Assuntos
Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/terapia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/terapia , Árvores de Decisões , Neoplasias do Endométrio/secundário , Feminino , Humanos
13.
J Clin Oncol ; 38(29): 3388-3397, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32749941

RESUMO

PURPOSE: The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. METHODS: Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated (POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis. RESULTS: Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC (P < .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (P = .019); 100% versus 97% for patients with POLEmut EC (P = .637); 68% versus 76% (P = .428) for MMRd EC; and 80% versus 68% (P = .243) for NSMP EC. CONCLUSION: Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.

14.
J Clin Oncol ; 38(30): 3528-3537, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32749942

RESUMO

PURPOSE: In SOLO1, maintenance olaparib (300 mg twice daily) significantly improved progression-free survival (PFS) for patients with newly diagnosed BRCA1- and/or BRCA2-mutated advanced ovarian cancer compared with placebo (hazard ratio [HR], 0.30; 95% CI, 0.23 to 0.41; median not reached v 13.8 months). We investigated PFS in SOLO1 for subgroups of patients based on preselected baseline factors. PATIENTS AND METHODS: Investigator-assessed PFS subgroup analyses of SOLO1 included clinical response after platinum-based chemotherapy (complete [CR] or partial response [PR]), surgery type (upfront or interval surgery), disease status after surgery (residual or no gross residual disease), and BRCA mutation status (BRCA1 or BRCA2). Additionally, we evaluated PFS in patients with stage III disease who underwent upfront surgery and had no gross residual disease. We also report objective response rate. RESULTS: The risk of disease progression or death was reduced with olaparib compared with placebo by 69% (HR, 0.31; 95% CI, 0.21 to 0.46) and 63% (HR, 0.37; 95% CI, 0.24 to 0.58) in patients undergoing upfront or interval surgery; 56% (HR, 0.44; 95% CI, 0.25 to 0.77) and 67% (HR, 0.33; 95% CI, 0.23 to 0.46) in patients with residual or no residual disease after surgery; 66% (HR, 0.34; 95% CI, 0.24 to 0.47) and 69% in women with clinical CR or PR at baseline (HR, 0.31; 95% CI, 0.18 to 0.52); and 59% (HR, 0.41; 95% CI, 0.30 to 0.56) and 80% (HR 0.20; 95% CI, 0.10 to 0.37) in patients with a BRCA1 or BRCA2 mutation, respectively. CONCLUSION: Patients with newly diagnosed advanced ovarian cancer achieve substantial benefit from maintenance olaparib treatment regardless of baseline surgery outcome, response to chemotherapy, or BRCA mutation type.

15.
Gynecol Oncol ; 159(2): 534-538, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32828580

RESUMO

OBJECTIVE: To define a prognostic score based on pretreatment values of leucocyte, platelet and hemoglobin in locally advanced cervical cancer (LACC). MATERIAL AND METHODS: We conducted a prospective study of 238 patients for LACC with negative PET imaging in the para-aortic (PA) area and who were undergoing laparoscopic PA lymphadenectomies. All patients were treated with chemo-radiation and brachytherapy. RESULTS: Patients had clinical International Federation of Gynecology and Obstetrics stages IB2 (n = 76), IIA (n = 13), IIB (n = 122), III (n = 18) or IVA (n = 9). We identified three biological parameters (at the time of diagnosis) with three cut-offs which impacted disease free survival (DFS) and overall survival (OS): <12 g/dL for hemoglobin, >10,000/µL for leucocyte and >300 × 109/L for platelet. A score is calculated, as shown in the table below, by adding the scores of all three biological parameters together (with a maximum score of three). DFS at 36 months was 87.3% [78.3-97.4], 58% [45-74.6], 79.1% [71.1-88], 58% [45-74.6] and 56.8% [37.8-85.4] for scores of 0, 1, 2 and 3 respectively. OS at 36 months was 92.6% [84.9-100], 84% [76.6-92.1], 62.5% [48.9-79.9] and 67% [46.8-96] for scores of 0, 1, 2 and 3 respectively. CONCLUSION: This score includes three biomarkers with easily remembered cut-offs that allow us to identify, at the time of diagnosis, those patients with a high risk of relapse (scores of two or three) and those requiring dose escalation.

16.
J Clin Oncol ; 38(30): 3494-3505, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32840418

RESUMO

PURPOSE: To investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo. PATIENTS AND METHODS: Patients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ≥ 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥ 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as µTOX × TOX + TWiST, with µTOX calculated using EQ-5D-3L data. RESULTS: The visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib. CONCLUSION: The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32852603

RESUMO

BACKGROUND: At diagnosis, tumor-infiltrating lymphocytes (TILs) are prognostic in epithelial ovarian cancer (EOC). We recently demonstrated that neoadjuvant chemotherapy (NACT) significantly increased stromal TILs. Here, we investigated the impact of NACT on immune subpopulations with a particular focus on the balance of immune-reactive to tolerant subpopulations. MATERIALS AND METHODS: Tissue microarrays of EOC (145 pre-NACT, 139 post-NACT) were analyzed for CD3+, CD8+, FOXP3+, CD68+, and CD163+ by immunohistochemistry and CD4+ cells from deduction. Stromal TILs scored as percentage of stromal area, while intra-epithelial TILs scored as number of TILs in contact with tumor cells/HPF. Differences were evaluated by Wilcoxon or Chi square tests, Wilcoxon signed-rank for paired analyses, and cox model for PFS and OS. RESULTS: NACT significantly increased stromal CD3+ (p = 0.003) and CD8+ (p = 0.001) and intra-epithelial CD8+ (p = 0.022) and CD68+ (p = 0.0003) infiltration in unmatched samples and among paired samples for stromal CD3+ and CD8+. Neither CD3+, CD8+, CD4+, and CD68+ nor CD163+ expression correlated with outcome at diagnosis or post NACT. Using median value as a cut-off, high stromal CD8+/FOXP3+ ratio (HR = 0.59; p = 0.017) and high stromal CD3+/FOXP3+ ratio post NACT were associated with prolonged PFS (p = 0.0226). The more the balance shifted in favor of effector versus regulatory TILs, the better the survival. Similarly, high CD68+/CD163+ ratio post NACT improved PFS (p = 0.0445). CONCLUSION: NACT has a significant impact on the balance of immune-reactive to immune-tolerant subpopulations and a high ratio of CD8+/FOXP3+, CD3+/FOXP3+, and CD68+/CD163+ post NACT was significantly associated with improved outcomes. Whether this could select patients for immunotherapy in the post-operative setting should be investigated.

18.
Gynecol Oncol ; 159(1): 101-111, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32861537

RESUMO

BACKGROUND: In the phase 3 trial ARIEL3, maintenance treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib provided clinical benefit versus placebo for patients with recurrent, platinum-sensitive ovarian cancer. Here, we evaluate the impact of age on the clinical utility of rucaparib in ARIEL3. METHODS: Patients with platinum-sensitive, recurrent ovarian carcinoma with ≥2 prior platinum-based chemotherapies who responded to their last platinum-based therapy were enrolled in ARIEL3 and randomized 2:1 to rucaparib 600 mg twice daily or placebo. Exploratory, post hoc analyses of progression-free survival (PFS), patient-centered outcomes (quality-adjusted PFS [QA-PFS] and quality-adjusted time without symptoms or toxicity [Q-TWiST]), and safety were conducted in three age subgroups (<65 years, 65-74 years, and ≥75 years). RESULTS: Investigator-assessed PFS was significantly longer with rucaparib than placebo in patients aged <65 years (rucaparib n = 237 vs placebo n = 117; median, 11.1 vs 5.4 months; hazard ratio [HR]: 0.33 [95% confidence interval (95% CI) 0.25-0.43]; P < 0.0001) and 65-74 years (n = 113 vs n = 64; median, 8.3 vs 5.3 months; HR 0.43 [95% CI 0.29-0.63]; P < 0.0001) and numerically longer in patients aged ≥75 years (n = 25 vs n = 8; median, 9.2 vs 5.5 months; HR 0.47 [95% CI 0.16-1.35]; P = 0.1593). QA-PFS and Q-TWiST were significantly longer with rucaparib than placebo across all age subgroups. Safety of rucaparib was generally similar across the age subgroups. CONCLUSIONS: Efficacy, patient-centered outcomes, and safety of rucaparib were similar between age subgroups, indicating that all eligible women with recurrent ovarian cancer should be offered this therapeutic option, irrespective of age. https://clinicaltrials.gov/ct2/show/NCT01968213.

19.
Gynecol Oncol ; 159(1): 256-263, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32712155

RESUMO

OBJECTIVE: MicroRNAs (miRNAs) are promising biomarkers in ovarian cancer. Their kinetics during treatment might be useful for monitoring disease burden, and guiding treatments in patients treated with peri-operative chemotherapy and interval debulking surgery (IDS). METHODS: Serial blood samples of patients enrolled in the randomized phase II CHIVA trial, comparing first line carboplatin-paclitaxel +/- nintedanib (NCT01583322) and IDS, were investigated to assess the kinetics of 11 relevant miRNAs. Their prognostic/predictive values regarding the likelihood of complete IDS, and the patient survival, were assessed and compared to those of CA125 kinetics. The selection of the miRNAs (miR-15b-5p, miR-16-5p, miR-20a-5p, miR-21-5p, miR-93-5p, miR-122-5p, miR-150-5p, miR-195-5p, miR-200b-3p, miR-148b-5p and miR-34a-5p) was based on the expression levels found with a large explorative panel, and on the literature data. RESULTS: 756 serial blood samples from 119 patients were analyzed for a total of 8172 miRNA assays, and 1299 CA125 values. The longitudinal kinetics of the miRNA expressions were highly inconsistent, and were not related to CA125 dynamics. The miRNA changes during neoadjuvant treatment were not found associated with RECIST tumor response or IDS outcomes. Decreases of miR-34a-5p and miR-93-5p were associated with PFS benefit (p = .009) and OS benefits (p < .001), respectively, using univariate tests. CONCLUSIONS: The longitudinal kinetics of miRNA expressions during neoadjuvant treatment in ovarian cancer patients were inconsistent, and were not found to be associated with tumor burden changes. Although some prognostic value could be discussed, no predictive value regarding tumor responses or IDS quality could be identified.

20.
Cells ; 9(6)2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575483

RESUMO

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive malignancy that occurs in young women, is characterized by recurrent loss-of-function mutations in the SMARCA4 gene, and for which effective treatments options are lacking. The aim of this study was to broaden the knowledge on this rare malignancy by reporting a comprehensive molecular analysis of an independent cohort of SCCOHT cases. We conducted Whole Exome Sequencing in six SCCOHT, and RNA-sequencing and array comparative genomic hybridization in eight SCCOHT. Additional immunohistochemical, Sanger sequencing and functional data are also provided. SCCOHTs showed remarkable genomic stability, with diploid profiles and low mutation load (mean, 5.43 mutations/Mb), including in the three chemotherapy-exposed tumors. All but one SCCOHT cases exhibited 19p13.2-3 copy-neutral LOH. SMARCA4 deleterious mutations were recurrent and accompanied by loss of expression of the SMARCA2 paralog. Variants in a few other genes located in 19p13.2-3 (e.g., PLK5) were detected. Putative therapeutic targets, including MAGEA4, AURKB and CLDN6, were found to be overexpressed in SCCOHT by RNA-seq as compared to benign ovarian tissue. Lastly, we provide additional evidence for sensitivity of SCCOHT to HDAC, DNMT and EZH2 inhibitors. Despite their aggressive clinical course, SCCOHT show remarkable inter-tumor homogeneity and display genomic stability, low mutation burden and few somatic copy number alterations. These findings and preliminary functional data support further exploration of epigenetic therapies in this lethal disease.

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