ABSTRACT
BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Endometrial Neoplasms , Microsatellite Instability , Mutation , Paclitaxel , Humans , Female , Antibodies, Monoclonal, Humanized/therapeutic use , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Middle Aged , Paclitaxel/therapeutic use , Paclitaxel/administration & dosage , Aged , Carboplatin/administration & dosage , Carboplatin/pharmacology , Carboplatin/therapeutic use , Immunotherapy/methods , PTEN Phosphohydrolase/genetics , Adult , Progression-Free Survival , Biomarkers, Tumor/genetics , Tumor Suppressor Protein p53/genetics , DNA-Binding Proteins/genetics , High-Throughput Nucleotide Sequencing , Transcription Factors , Class I Phosphatidylinositol 3-KinasesABSTRACT
BACKGROUND: The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. PATIENTS AND METHODS: Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. RESULTS: The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. CONCLUSIONS: Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.
Subject(s)
Mangifera , Ovarian Neoplasms , Female , Humans , Bevacizumab/therapeutic use , Carboplatin/therapeutic use , Homologous Recombination , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Paclitaxel/therapeutic use , Platinum/therapeutic use , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/therapeutic useABSTRACT
Marfan syndrome is an autosomal dominant disorder of the connective tissue caused by mutations of the fibrillin-1 gene (FBN1) that primarly involves the cardiovascular, skeletal and ocular systems. We investigated 72 children affected by Marfan syndrome in order to identify possible correlations between some musculoskeletal features and specific mutations of fibrillin-1 gene. The following FBN-1 gene mutations have been observed: a missense mutation in 21 children, a stop mutation in 9, a splice mutation in 15 and other mutations in the remaining 27 patients. We observed a statistical significant association between chest asymmetry and splice mutation (p=0.031) and between scoliosis >20° or thoracolumbar kyphosis and stop mutation (p=0.039). However, we did not find a true genotype-phenotype correlation between the fibrillin-1 gene mutations observed and the prognosis of the disease. Future studies are necessary to demonstrate further genotype-phenotype correlations in order to identify early prognostic markers of Marfan syndrome and to plan the most appropriate clinical management accordingly.
Subject(s)
Marfan Syndrome , Orthopedics , Child , Fibrillin-1/genetics , Fibrillins , Humans , Marfan Syndrome/genetics , Microfilament Proteins/genetics , Mutation , PhenotypeABSTRACT
OBJECTIVE: Increased Vascular Endothelial Growth Factor Receptor (VEGF) expression in endometrial cancer (EC) is associated with a poor prognosis. Preliminary clinical data reported Bevacizumab effectiveness in EC both as single agent and in combination with chemotherapy. METHODS: In a phase II trial, patients with advanced (FIGO stage III-IV) or recurrent EC were randomized to receive Carboplatin-Paclitaxel standard dose for 6-8 cycles vs Carboplatin-Paclitaxel and Bevacizumab 15 mg/kg in combination with chemotherapy and maintenance until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS). RESULTS: 108 patients were randomized; PFS (10.5 vs 13.7 months, HR 0.84 p = 0.43), overall response rate (ORR 53.1% vs 74.4%) and overall survival (OS) (29.7 vs 40.0 months, HR 0.71 p = 0.24) resulted in a non-significant increase in Bevacizumab treated patients. The PFS increase became significant when an exploratory analysis with the Breslow test was used. Moreover, patients treated with Bevacizumab experienced a significant increase in 6-month disease control rate (70.4% vs 90.7%). Cardiovascular events were more frequent in the experimental arm ("de novo" grade ≥2 hypertension 21% vs 0% and grade ≥2 thromboembolic events 11% vs 2% in the Bevacizumab vs standard treatment arm, respectively). CONCLUSIONS: Bevacizumab combined with chemotherapy in the treatment of advanced/recurrent EC failed to demonstrate a significant increase in PFS in the MITO END-2 trial. Nevertheless, these preliminary data suggests some effectiveness of the antiangiogenic agent which merits further exploration in a larger population with a better molecular characterization.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Endometrial Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/administration & dosage , Bevacizumab/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Endometrial Neoplasms/pathology , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Progression-Free Survival , Prospective StudiesABSTRACT
Safinamide (Xadago) is a novel dual-mechanism drug that has been approved in the European Union and United States as add-on treatment to levodopa in Parkinson's disease therapy. In addition to its selective and reversible monoamine oxidase B inhibition, safinamide through use-dependent sodium channel blockade reduces overactive glutamatergic transmission in basal ganglia, which is believed to contribute to motor symptoms and complications including levodopa-induced dyskinesia (LID). The present study investigated the effects of safinamide on the development of LID in 6-hydroxydopamine (6-OHDA)-lesioned rats, evaluating behavioral, molecular, and neurochemical parameters associated with LID appearance. 6-OHDA-lesioned rats were treated with saline, levodopa (6 mg/kg), or levodopa plus safinamide (15 mg/kg) for 21 days. Abnormal involuntary movements, motor performance, molecular composition of the striatal glutamatergic synapse, glutamate, and GABA release were analyzed. In the striatum, safinamide prevented the rearrangement of the subunit composition of N-methyl-d-aspartate receptors and the levodopa-induced increase of glutamate release associated with dyskinesia without affecting the levodopa-stimulated motor performance and dyskinesia. Overall, these findings suggest that the striatal glutamate-modulating component of safinamide's activity may contribute to its clinical effects, where its long-term use as levodopa add-on therapy significantly improves motor function and "on" time without troublesome dyskinesia.
Subject(s)
Alanine/analogs & derivatives , Benzylamines/pharmacology , Dyskinesia, Drug-Induced/drug therapy , Excitatory Amino Acid Agents/pharmacology , Levodopa/pharmacology , Signal Transduction/drug effects , Alanine/pharmacology , Animals , Antiparkinson Agents/pharmacology , Corpus Striatum/drug effects , Disease Models, Animal , Dopamine Agents/pharmacology , Male , Oxidopamine/pharmacology , Parkinson Disease/drug therapy , Rats , Rats, Sprague-DawleyABSTRACT
In patients with recurrent ovarian cancer, the choice of second-line therapy is complex. Several factors have to be considered, such as platinum-free interval (PFI), residual toxicity from the previous treatments, BRCA1/2 gene mutation status. Trebectedin is a minor groove DNA binder derived from a marine organism that has shown efficacy in different settings in ovarian cancer therapy. It has been approved in the treatment of partially platinum sensitive (PPS) (PFI between 6 and 12 months) relapsed ovarian cancer according to the statistically significant progression-free survival (7.3 versus 5.8 months) and overall survival (22.2 versus 18.9 months) benefit compared with single-agent pegylated liposomal doxorubicin (PLD) in the OVA 301 phase III trial. This drug has been shown to prolong the time to first subsequent treatment and improve the efficacy of further platinum-based chemotherapy. The role of trabectedin/PLD followed by platinum combination compared with the reverse sequence in PPS is actually in evaluation in the INOVATYON phase III study, which will clarify the best sequence to be adopted in this setting. Trabectedin has been shown to be active in patient carriers of BRCA mutations, probably for its mechanism of action directly affecting DNA and it is actually tested as a single agent in some phase III trials in BRCA mutated and BRCAness ovarian cancer patients. Trabectedin is also active on the immune system. There is, therefore, the rational for new trials of a combination with immune checkpoint inhibitors.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Standard of Care , Trabectedin/therapeutic use , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Humans , Middle AgedABSTRACT
Background: MITO-8 showed that prolonging platinum-free interval by introducing non-platinum-based chemotherapy (NPBC) does not improve prognosis of patients with partially platinum-sensitive recurrent ovarian cancer. Quality of life (QoL) was a secondary outcome. Patients and methods: Ovarian cancer patients recurring or progressing 6-12 months after previous platinum-based chemotherapy (PBC) were randomized to receive PBC or NPBC as first treatment. QoL was assessed at baseline, third and sixth cycles, with the EORTC C-30 and OV-28 questionnaires. Mean changes and best response were analysed. Progression-free survival, response rate, and toxicity are also reported for proper interpretation of data. All analyses were based on intention-to-treat. Results: Out of the 215 patients, 151 (70.2%) completed baseline questionnaire, balanced between the arms; thereafter, missing rate was higher in the NPBC arm. At mean change analysis, C30 scores were prevalently worse in the NPBC than PBC arm, statistical significance being attained for emotional functioning, global health status/QoL, fatigue, and dyspnoea (effect sizes ranging from 0.30 to 0.51). Conversely, as for OV28 scale, the other chemotherapy side-effects item was significantly worse with PBC at three and six cycles, with a larger effect size (0.70 and 0.54, respectively). At best response analysis, improvement of emotional functioning and pain and worsening of peripheral neuropathy and other chemotherapy side-effects were significantly more frequent in the PBC arm. Progression-free survival (median 9 versus 5 months, P = 0.001) and objective response rate (51.6% versus 19.4%, P = 0.0001) were significantly better with PBC. Allergy, blood cell count, alopecia, nausea, musculoskeletal, and neurological side-effects were more frequent and severe with PBC; hand-foot skin reaction, rash/desquamation, mucositis, and vascular events were more frequent with NPBC. Conclusion: MITO-8 QoL analysis shows that deterioration of some functioning and symptom scales is lower with PBC, with improvement of emotional functioning and pain, despite worsening of toxicity-related items. ClinicalTrials.gov: NCT00657878.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug-Related Side Effects and Adverse Reactions/epidemiology , Neoplasm Recurrence, Local/drug therapy , Organoplatinum Compounds/adverse effects , Ovarian Neoplasms/drug therapy , Quality of Life , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cross-Over Studies , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/psychology , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/psychology , Organoplatinum Compounds/administration & dosage , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Ovarian Neoplasms/psychology , Prognosis , Progression-Free Survival , Severity of Illness Index , Surveys and Questionnaires/statistics & numerical data , Survival AnalysisABSTRACT
OBJECTIVE: Hypersensitivity reactions (HSR) are frequently reported in patients rechallenged with carboplatin for recurrent ovarian cancer (ROC) and represent a critical issue, since discontinuation of the platinum-based therapy could affect prognosis. Several strategies to allow platinum rechallenge have been described, with controversial outcomes. The aim of this study is to illustrate a 10-year experience with cisplatin in patients with a previous HSR to carboplatin or at risk for allergy. METHODS: A retrospective review of all patients with platinum sensitive ROC retreated with carboplatin was performed between January 2007 and May 2016 at the Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples. RESULTS: Among 183 patients, 49 (26.8%) presented HSR to carboplatin, mainly during second line therapy. Mean number of cycles before HSR was 8 (range 3-17). G2, G3 and G4 reaction were detected in 83%, 15% and 2% of patients, respectively. In a multivariate analysis including age, hystotype, BRCA status, previous known HSR, and combination drug administered, only the type of carboplatin-based doublet used as 2nd line therapy was found to significantly affect HSR development, with a protective effect of PLD (pegylated liposomal doxorubicin) (p = 0.014, OR = 0.027). Thirty seven patients (77%) with a previous HSR to carboplatin were rechallenged with cisplatin. Treatment was generally well tolerated. 5 patients (13.1%) experienced mild HSR to cisplatin, successfully managed in all cases. 14 patients were treated with cisplatin even without a carboplatin-related HSR due to other allergies. Among these, only one developed HSR (7.1%). CONCLUSIONS: Cisplatin rechallenge is a feasible approach in patients experiencing HSR to carboplatin to maintain the beneficial effect of platinum while reducing hypersensitivity-related risks.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/adverse effects , Cisplatin/administration & dosage , Drug Hypersensitivity/etiology , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/immunology , Cisplatin/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Female , Humans , Middle Aged , Paclitaxel/administration & dosage , Polyethylene Glycols/administration & dosage , Retrospective Studies , GemcitabineABSTRACT
BACKGROUND: Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype. PATIENTS AND METHODS: A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [single-nucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed. RESULTS: Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1-2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported. CONCLUSIONS: Our data prospectively confirmed that the signature of 'repeated platinum sensitivity' identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum. EUDRACT NUMBER: 2011-001298-17.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Dioxoles/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Tetrahydroisoquinolines/therapeutic use , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/adverse effects , Dioxoles/adverse effects , Disease-Free Survival , Female , Humans , Middle Aged , Platinum Compounds/therapeutic use , Prospective Studies , Tetrahydroisoquinolines/adverse effects , TrabectedinABSTRACT
Non-Muscle-Invasive-Bladder-Cancer represents 75-85% of the new bladder cancer cases per year. Trans-uretral vesical resection is the milestone for diagnosis and therapy. After primary treatment, recurrence is frequent depending on the presence of several established risk factors: multiplicity, T dimension, prior recurrence. In some patients disease progress to an advanced stage. Adjuvant chemo-immunotherapy has been widely used depending on the risk category assigned on the basis of the risk factors for recurrence. In low risk categories a one shot treatment with chemotherapy is considered the standard treatment without any maintenance therapy. In intermediate risk patients, adjuvant induction therapy and maintenance chemotherapy or immunotherapy for at least one year is recommended. In high risk patients adjuvant induction and maintenance immunotherapy until 3 years is considered the best strategy. In this review data on the different drugs used in this setting will be discussed.
Subject(s)
Antineoplastic Agents/therapeutic use , Immunotherapy/methods , Urinary Bladder Neoplasms/therapy , Antineoplastic Agents/administration & dosage , Chemotherapy, Adjuvant/methods , Combined Modality Therapy , Disease Progression , Humans , Neoplasm Invasiveness , Neoplasm Recurrence, Local/prevention & control , Neoplasm Staging , Risk Factors , Time Factors , Urinary Bladder Neoplasms/epidemiology , Urinary Bladder Neoplasms/pathologyABSTRACT
The activity of heparanase is responsible for heparan sulfate cleavage, thus resulting in the release of heparan sulfate-bound growth factors. Since heparanase activity is upregulated in several tumor types and is implicated in the malignant behavior, the enzyme is regarded as a promising target for antitumor therapy. Based on previous evidence that the heparanase inhibitor SST0001, a non-anticoagulant N-acetylated glycol split heparin, is effective against an Ewing's sarcoma model, the present study was performed to extend the preclinical evaluation of SST0001 to a panel of pediatric sarcoma models, representative of various tumor histotypes (soft tissue and bone sarcomas) and to further elucidate its mode of action. SST0001 treatment downregulated several angiogenic factors in the conditioned media of sarcoma cells, inhibited the pro-invasive effect of heparin-binding factors (VEGF, bFGF, HGF, PDGF), and abrogated PDGF receptor tyrosine phosphorylation. Subcutaneous administration of SST0001 was very effective, resulting in a significant growth inhibition (range, 64-95%) of all tested tumor xenografts. The efficacy of SST0001 was enhanced in combination with antiangiogenic agents (bevacizumab, sunitinib) as documented by the high rate of complete response. The synergistic effect of SST0001 in combination with antiangiogenic agents is consistent with the heparanase mode of action and with the relevant role of heparin-binding proangiogenic/growth factors in the malignant behavior of sarcoma cells.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Bone Neoplasms/drug therapy , Heparin/analogs & derivatives , Osteosarcoma/drug therapy , Rhabdomyosarcoma/drug therapy , Angiogenesis Inhibitors/therapeutic use , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab , Bone Neoplasms/blood supply , Bone Neoplasms/pathology , Cell Line, Tumor/drug effects , Child , Drug Synergism , Female , Glucuronidase/antagonists & inhibitors , Glucuronidase/metabolism , Heparin/pharmacology , Heparin/therapeutic use , Humans , Indoles/pharmacology , Indoles/therapeutic use , Mice , Mice, Nude , Neoplasm Invasiveness , Neovascularization, Pathologic/prevention & control , Osteosarcoma/blood supply , Osteosarcoma/pathology , Pyrroles/pharmacology , Pyrroles/therapeutic use , Rhabdomyosarcoma/blood supply , Rhabdomyosarcoma/pathology , Sunitinib , Xenograft Model Antitumor AssaysABSTRACT
Endometrial cancer is a highly curable malignancy when it presents as uterine-confined disease, but the prognosis for metastatic or recurrent endometrial cancer is poor. For those patients which are diagnosed at an early stage, surgery alone may be adequate for cure and clinical outcome is often favorable, with approximately 80 % of cases surviving at 5 years. However, after primary diagnosis and treatment, roughly 20-30% of patients are expected to recur within the following 5 years. Adjuvant treatment for endometrial cancer is not yet clearly defined. FIGO Stage I-III endometrial cancer patients, usually undergo surgery and some of them are offered adjuvant treatment based on risk assessment. Grade, age, stage are considered all independent risk factors for recurrence. Radiotherapy (RT) has been considered the adjuvant treatment of choice for decades, being able to reduce local recurrence rate and improving progression free survival, but without any impact on overall survival. In the last two decades, a shift toward the use of systemic chemotherapy (CT) in addition or instead of radiation has occurred, although few prospective studies have been performed in this field.
Subject(s)
Chemoradiotherapy, Adjuvant/methods , Endometrial Neoplasms/pathology , Endometrial Neoplasms/therapy , Endometrium/pathology , Animals , Antineoplastic Agents/therapeutic use , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/surgery , Endometrium/drug effects , Endometrium/radiation effects , Endometrium/surgery , Female , HumansABSTRACT
BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. PATIENTS AND METHODS: The nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). RESULTS: The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65-0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). CONCLUSIONS: This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.
Subject(s)
Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Platinum/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Clinical Trials as Topic , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/chemically induced , Neoplasm Recurrence, Local/genetics , Neoplasm Staging , Nomograms , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Platinum/adverse effects , Platinum/toxicity , Prognosis , Sensitivity and Specificity , Treatment OutcomeABSTRACT
BACKGROUND: CA-125 as a tumour progression criterion in relapsing ovarian cancer (ROC) trials remains controversial. CALYPSO is a large randomised trial incorporating CA-125 (GCIG criteria) and symptomatic deterioration in addition to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (radiological) to determine progression. METHODS: In all, 976 patients with platinum-sensitive ROC were randomised to carboplatin-paclitaxel (C-P) or carboplatin-pegylated liposomal doxorubicin (C-PLD). CT-scan and CA-125 were performed every 3 months until progression. RESULTS: In all, 832 patients (85%) progressed, with 60% experiencing a first radiological progression, 10% symptomatic progression, and 28% CA-125 progression without evidence of radiological or symptomatic progression. The benefit of C-PLD vs C-P in progression-free survival was not influenced by type of first progression (hazard ratio 0.85 (95% confidence interval (CI): 0.66-1.10) and 0.84 (95% CI: 0.72-0.98) for CA-125 and RECIST, respectively). In patients with CA-125 first progression who subsequently progressed radiologically, a delay of 2.3 months was observed between the two progression types. After CA-125 first progression, median time to new treatment was 2.0 months. In all, 81%of the patients with CA-125 or radiological first progression and 60% with symptomatic first progression received subsequent treatment. CONCLUSION: CA-125 and radiological tests performed similarly in determining progression with C-PLD or C-P. Additional follow-up with CA-125 measurements was not associated with overtreatment.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , CA-125 Antigen/analysis , Ovarian Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Disease Progression , Disease-Free Survival , Doxorubicin/adverse effects , Doxorubicin/analogs & derivatives , Female , Humans , Ovarian Neoplasms/diagnostic imaging , Paclitaxel/administration & dosage , Polyethylene Glycols/adverse effects , Recurrence , Tomography, X-Ray ComputedABSTRACT
Serum cancer antigen 125 (CA125) is widely used in ovarian cancer to monitor the effectiveness of therapy both in first line and recurrence. It is also widely used during follow-up, where it is able to identify a percentage of patients with asymptomatic recurrence. Although a recent Medical Research Council (UK)/European Organisation for Research and Treatment of Cancer trial has demonstrated that early chemotherapy in asymptomatic patients based only on CA125 increase does not prolong survival, we still believe that CA125 monitoring should be prescribed to patients during follow-up. In fact, it can help to identify patients who should undergo radiology in order to select those that can benefit from surgery or from early treatment before the onset of symptoms, which are usually related to an excessive disease burden. The delay of disease symptoms, such as those associated with the appearance of ascites or bowel occlusion, is in our view an important goal of our treatment of recurrence. Moreover, research should be done in patients with asymptomatic CA125 increase in order to identify more effective therapies that will improve survival. Finally, the reliability of CA125 as a surrogate of response under treatment with biological agents should be validated in prospective trials.
Subject(s)
CA-125 Antigen/blood , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Watchful Waiting/methods , Antineoplastic Agents/therapeutic use , Carcinoma, Ovarian Epithelial , Female , Follow-Up Studies , Humans , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/diagnosis , Neoplasms, Glandular and Epithelial/blood , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/blood , Ovarian Neoplasms/pathology , Treatment OutcomeABSTRACT
BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n=955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n=340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. RESULTS: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Carboplatin/therapeutic use , Disease-Free Survival , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Middle Aged , Ovarian Neoplasms/pathology , Prognosis , Proportional Hazards ModelsABSTRACT
PURPOSE: Treatment of patients with recurrent ovarian cancer remains a challenge, and there is a need for new and more effective agents. A phase I-II study was designed to determine the recommended dose (RD) and the anti-tumour effect of a prolonged administration of elacytarabine, the elaidic ester of cytarabine, in patients with refractory/resistant recurrent ovarian cancer. EXPERIMENTAL DESIGN: The primary objective of the dose escalation phase I part was to determine the RD for elacytarabine when given twice for five consecutive days in a 4-week schedule, D1-5 and D8(+2)-12(+2) q4w. Three to six patients were to be enrolled at each dose level. The start dose was elacytarabine 75 mg/m(2)/day. The phase II part was designed as a two-step study based on response. RESULTS: A total of 28 patients entered the study, 17 patients in the phase I part and 11(#) patients in phase II. Three dose levels were tested: 75 mg/m(2)/day in 3 patients, 100 mg/m(2)/day in 7 + 11(#) patients, and 125 mg/m(2)/day in 7 patients. Three (17.6%) patients in phase I experienced a dose limiting toxicity (DLT), all at the 125 mg/m(2)/day dose level, establishing the lower dose of 100 mg/m(2)/day as the RD. The DLTs were neutropenia grade 4 according to the Common Terminology Criteria for Adverse Events (CTCAE) and thrombocytopenia grade 4 (2 patients), and vomiting grade 2 with hospitalisation and hypokalaemia grade 3 (1 patient). The best response was a clinically meaningful stabilization observed in 3 patients. In two of them, the disease stabilization exceeded the previous platinum-free interval (PFI). CONCLUSIONS: The RD for elacytarabine was 100 mg/m(2)/day, D1-5 and D8-12 q4w. The safety profile was comparable to the safety profiles reported in previous clinical studies with elacytarabine in solid tumours. Despite some longer-lasting disease stabilisations, two of them exceeding the previous progression-free interval, further investigations of elacytarabine in the ovarian cancer indication are not warranted.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Cytarabine/analogs & derivatives , Ovarian Neoplasms/drug therapy , Cytarabine/therapeutic use , Female , Humans , Middle AgedABSTRACT
The solute carrier family 11 member A1 (SLC11A1) gene is associated with resistance to infectious diseases. Chromosomal localisation, genomic regions corresponding to functional domains and the genetic variability of microsatellites in the 3' untranslated region (3'-UTR) of this gene were investigated in 427 goats (Capra hircus) of six breeds. Using dual colour fluorescence in situ hybridisation, SLC11A1 was localised to goat chromosome 2. Single strand conformation polymorphism was used to screen for polymorphisms in SLC11A1 exons 2, 10 and 15. There was no variation among goat breeds in the sarcoma homology 3 (SH3) binding motif, the protein kinase C phosphorylation site or the two N-linked glycosylation sites. Exon 15 exhibited variability due to the presence of two polymorphic microsatellites. Genotyping of the upstream guanine-thymine repeat (GTn) at 3'-UTR revealed eight alleles (GT11, GT12, GT14-GT19) in goats, whereas GT13 (present in cattle) was absent. Most goats carried the GT16 allele and no allele was found to be exclusive to only one breed. The coefficient of genetic differentiation value (G(ST)) was 0.084. This microsatellite appears to be an informative DNA marker for genetic linkage analysis in goats.
Subject(s)
Cation Transport Proteins/genetics , Goats/genetics , Animals , Base Sequence , Chromosome Mapping/veterinary , Exons , Gene Frequency , In Situ Hybridization, Fluorescence/veterinary , Microsatellite Repeats , Molecular Sequence Data , Polymorphism, Genetic , Polymorphism, Single-Stranded Conformational , Sequence AlignmentABSTRACT
BACKGROUND: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. PATIENTS AND METHODS: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m(2) or PLD 30 mg/m(2) every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). CONCLUSIONS: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Doxorubicin/analogs & derivatives , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Paclitaxel/therapeutic use , Polyethylene Glycols/therapeutic use , Adult , Aged , Antineoplastic Agents/therapeutic use , Area Under Curve , Carboplatin/administration & dosage , Doxorubicin/administration & dosage , Doxorubicin/therapeutic use , Female , Humans , Middle Aged , Neoplasm Staging , Neoplasms, Glandular and Epithelial/mortality , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Polyethylene Glycols/administration & dosage , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: The increased survival due to the introduction of effective antineoplastic regimens has caused a modification of the natural history of numerous malignancies. Follow-up of neoplastic patients often includes the evaluation of masses in various body sites by fine needle cytology (FNC) in order to rule out cancer recurrence. Besides primary neoplasms, the breast can host a number of metastases: these rarely do have a typical presentation, so FNC is requested for their cytomorphological assessment. PATIENTS AND METHODS: This report describes nine consecutive cases in which a cytopathological diagnosis of metastasis to the breast was carried out on FNC samples. RESULTS: Primary sites were identified on cytomorphological and immunocytochemical bases and were represented by the ovary (three cases), melanoma (two cases), endocervix (one case), endometrium (one case), lung (one case) and prostate (one case). CONCLUSION: The cytopathological diagnosis of metastatic neoplasms to the breast is not always straightforward, especially in the absence of a clinical history of cancer. The usage of improved cytopathological criteria combined with immunocytochemistry may be of great diagnostic help in the identification of breast metastases.