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1.
Genes Chromosomes Cancer ; 63(1): e23206, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37819540

RESUMEN

We present two cases of malignant ossifying fibromyxoid tumor (OFMT) which eluded diagnosis due to compelling clinicopathologic mimicry, compounded by similarly elusive underlying molecular drivers. The first is of a clavicle mass in a 69 year-old female, which histologically showed an infiltrative nested and trabeculated proliferation of monomorphic cells giving rise to scattered spicules of immature woven bone. Excepting SATB2 positivity, the lesion showed an inconclusive immunoprofile which along with negative PHF1 FISH led to an initial diagnosis of high-grade osteosarcoma. Next generation sequencing (NGS) revealed a particularly rare CREBBP::BCORL1 fusion. The second illustrates the peculiar presentation of a dural-based mass in a 52 year-old female who presented with neurologic dyscrasias. Sections showed a sheeted monotonous proliferation of ovoid to spindle cells, but in contrast to Case #1, the tumor contained an exuberance of reticular osteoid and woven bone deposition mimicking malignant osteogenic differentiation. NGS showed a novel CREBZF::PHF1 fusion. Both tumors recurred locally less than 1 year post-operatively. As such we reiterate that careful morphologic examination is axiomatic to any diagnosis in our discipline, but this paradigm must shift to recognize that molecular diagnostics can provide closure where traditional tools have notable limitations.


Asunto(s)
Neoplasias Óseas , Fibroma Osificante , Fibroma , Osteosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Femenino , Humanos , Anciano , Persona de Mediana Edad , Proteínas de Unión al ADN , Fibroma Osificante/diagnóstico , Fibroma Osificante/genética , Fibroma Osificante/patología , Osteogénesis , Proteínas del Grupo Polycomb , Recurrencia Local de Neoplasia , Fibroma/patología , Osteosarcoma/diagnóstico , Osteosarcoma/genética , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico
2.
Oncologist ; 29(1): 67-74, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37449664

RESUMEN

INTRODUCTION: FDA's Project Optimus was developed in part to better identify appropriate dose and schedule of cancer therapeutics. The tabular method to summarize patients' maximum toxicity in a clinical trial does not allow for ready comparison to the treatment's benefit. In this manuscript, we apply a simple tool, the weighted toxicity score (WTS), to trials involving lung cancer immunotherapy and chemotherapy, as well as those cited in a recent publication as examples of trials that represent successful reduction of the appropriate dose of anti-cancer agents. METHODS: PubMed was queried for randomized controlled trials of therapy involving immune checkpoint inhibitors in lung cancer. Trial data from studies highlighting initial success with dose adjustments after FDA approval also were assembled and analyzed according to the WTS procedure described previously, compared to clinical outcomes data. RESULTS: The WTS provided, with the clinical outcome(s), a data pair that leads to easy interpretation of the expected benefit versus relative toxicity of studies involving immunotherapy or chemoimmunotherapy in lung cancers. The WTS was consistent with the conclusions of the primary studies, helping to quantitate the toxicity difference between treatments in a previously unavailable way. CONCLUSION: The WTS provides a tool to show the cost in toxicity of therapy in a randomized clinical trial, with applicability to studies involving chemotherapy, immunotherapy, or kinase-directed therapy. Inclusion of a running tally of WTS during conduct of a trial could serve as one means to adjust dosing or to provide feedback during data safety monitoring of a clinical trial.


Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Antineoplásicos/efectos adversos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Neoplasias Pulmonares/tratamiento farmacológico
3.
Oncologist ; 28(5): 453-459, 2023 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-36724001

RESUMEN

BACKGROUND: Evaluation of prior phase II trials for malignant peripheral nerve sheath tumors (MPNST) may help develop more suitable trial endpoints in future studies. METHODS: We analyzed outcomes of patients with recurrent or unresectable/metastatic MPNST enrolled on prior Sarcoma Alliance for Research through Collaboration (SARC) phase II trials and estimated the progression-free survival (PFS). PFS from SARC006 (NCT00304083), the phase II trial of upfront chemotherapy in chemotherapy naïve patients, was analyzed separately. Impact of baseline enrollment characteristics on PFS was evaluated. RESULTS: Sixty-four patients (29 male, 35 female, median age 39 years (range 15-81)) with MPNST were enrolled on 1 of 5 trials of single agent or combination therapy that were determined to be inactive. Patients had received a median of 1 (range 0-5) prior systemic therapy, and most had undergone prior surgery (77%) and radiation (61%). Seventy-three percent had metastatic disease at enrollment. Median PFS was 1.77 months (95% CI, 1.61-3.45), and the PFS rate at 4 months was 15%. Greater number of prior systemic therapies and worse performance status were associated with inferior PFS. There was no significant difference in PFS based on age at enrollment, treatment trial, response criteria, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. In comparison, on the SARC006 trial the PFS rate at 4 months was 94% in 40 patients. CONCLUSION: These data provide a historical baseline PFS that may be used as a comparator in future clinical trials for patients with MPNST.


Asunto(s)
Neurofibrosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Masculino , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Neurofibrosarcoma/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Supervivencia sin Progresión , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
4.
Ann Surg Oncol ; 30(11): 6886-6893, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37488394

RESUMEN

INTRODUCTION: Management of retroperitoneal sarcoma (RPS) remains controversial, with the mainstay of treatment being surgery. While neoadjuvant radiation demonstrated no improvement in recurrence-free survival in a prospective randomized trial (STRASS), the role of neoadjuvant chemotherapy (NCT) remains unknown and is the subject of ongoing study (STRASS2). METHODS: Patients who underwent surgical resection of high-grade RP leiomyosarcoma (LMS) or dedifferentiated liposarcoma (DDLS) were identified from the National Cancer Database (2006-2019). Predictors of NCT were analyzed using univariate and multivariate logistic regression analyses. Differences in 5-year survival were examined using the Kaplan-Meier (KM) method and by Cox proportional hazard modeling. RESULTS: A total of 2656 patients met inclusion criteria. Fifty-seven percent of patients had DDLS and 43.5% had LMS. Six percent of patients underwent NCT. Patients who received NCT were younger (median age 60 vs 64 years, p < 0.001) and more likely to have LMS (OR 1.4, p = 0.04). In comparing NCT with no-NCT patients, there was no difference in 5-year overall survival (OS) on KM analysis (57.3% vs 52.8%, p = 0.38), nor was any difference seen after propensity matching (54.9% vs 49.1%, p = 0.48, N = 144 per group). When stratified by histology, there was no difference in OS based on receipt of NCT (LMS: 59.8% for NCT group, 56.6% for no-NCT, p = 0.34; DDLS: 54.2% for NCT group, 50.1% for no-NCT, p = 0.99). CONCLUSION: In patients undergoing surgical resection of RP LMS or DDLS, NCT does not appear to confer an OS advantage. Prospective randomized data from STRASS2 will confirm or refute these retrospective data.


Asunto(s)
Leiomiosarcoma , Neoplasias Retroperitoneales , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Persona de Mediana Edad , Estudios de Cohortes , Terapia Neoadyuvante , Estudios Retrospectivos , Pronóstico , Estudios Prospectivos , Sarcoma/tratamiento farmacológico , Sarcoma/cirugía , Sarcoma/patología , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/cirugía , Leiomiosarcoma/patología , Neoplasias Retroperitoneales/tratamiento farmacológico , Neoplasias Retroperitoneales/cirugía , Neoplasias Retroperitoneales/patología
5.
J Surg Oncol ; 128(4): 628-634, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37148468

RESUMEN

INTRODUCTION: Many patients with high-risk soft tissue sarcoma (STS) develop distant metastases. Meta-analyses suggest that chemotherapy confers a small survival benefit, though few studies focus on neoadjuvant chemotherapy (NCT). There has been more frequent use of neoadjuvant radiation therapy (NRT) in STS, but the utility of NCT for these patients remains unclear. METHODS: Patients with stage II-III trunk/extremity STS who underwent NRT and resection were identified using the National Cancer Database (2006-2019). Predictors of NCT were analyzed using logistic regression. Change in rate of NCT use over time was assessed using log-linear regression modeling. Survival was examined using Kaplan-Meier (KM) and Cox proportional hazard modeling. RESULTS: Of 5740 patients, 25% underwent NCT. The overall median age was 62, 55% of patients were male, and 67% had stage III disease. The most common histological subtypes were fibrosarcoma/myxofibrosarcoma (39%) and liposarcoma (16%). Use of NCT decreased by 4.0% per year throughout the study period (p < 0.01). Predictors of NCT included younger age (median 54, IQR 42-64 vs. median 65, IQR 53-75, p < 0.01), treatment at an academic center (odds ratio [OR] 1.5, p < 0.01), and stage III disease (OR 2.2, p < 0.01). Histologic predictors of NCT included synovial sarcoma (52%) and angiosarcoma (45%). With a median follow-up time of 77 months, NCT was associated with improved 5-year survival compared to NRT alone on KM analysis (70% vs. 63%, p < 0.01). This difference persisted on multivariate analysis (hazard ratio 0.86, p = 0.027) and after propensity matching (70% vs. 65%, p = 0.0064). CONCLUSION: Despite risk of distant failure in high-risk STS, use of NCT has decreased over time in patients receiving NRT. In this retrospective analysis, NCT was associated with a modestly improved overall survival.


Asunto(s)
Fibrosarcoma , Liposarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Masculino , Adulto , Persona de Mediana Edad , Femenino , Terapia Neoadyuvante , Estudios Retrospectivos , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Extremidades/patología , Liposarcoma/patología , Fibrosarcoma/patología , Neoplasias de los Tejidos Blandos/patología
6.
Future Oncol ; 19(9): 621-629, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36987836

RESUMEN

Dedifferentiated liposarcoma (DDLPS) is a rare, aggressive liposarcoma associated with poor prognosis. First-line treatment for advanced/metastatic DDLPS is systemic chemotherapy, but efficacy is poor and toxicities substantial. Most DDLPS tumors have amplification of the MDM2 gene, which encodes a negative regulator of the p53 suppressor protein. BI 907828 is a highly potent, oral MDM2-p53 antagonist that inhibits the interaction between p53 and MDM2, thereby restoring p53 activity. BI 907828 has shown promising activity in preclinical studies and in a phase Ia/Ib study in patients with solid tumors, particularly those with DDLPS. This manuscript describes the rationale and design of an ongoing multicenter, randomized, phase II/III trial (Brightline-1; NCT05218499) evaluating BI 907828 versus doxorubicin as first-line treatment for advanced DDLPS.


Dedifferentiated liposarcoma (DDLPS) is a rare, fast-growing cancer that begins in fat cells. Patients with DDLPS that cannot be removed surgically or has spread to other areas of the body are usually treated with chemotherapy at first, but this typically stops working only 2­4 months after the start of treatment and has a lot of side effects. The drug BI 907828 works differently to chemotherapy by specifically targeting a gene called MDM2. This gene is abnormally increased in most DDLPS tumors and causes cancer by shutting down one of the pathways that the body uses to kill cancerous cells. BI 907828 restores this pathway, leading to the targeted destruction of tumor cells. Results from initial studies show that BI 907828 is able to slow the growth of DDLPS, and is now being investigated further, in a study called Brightline-1. Brightline-1, which is currently underway, is comparing BI 907828 with the chemotherapy drug doxorubicin for the initial treatment of DDLPS that is inoperable or has spread to other areas of the body. Clinical Trial Registration: NCT05218499 (ClinicalTrials.gov).


Asunto(s)
Liposarcoma , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Liposarcoma/tratamiento farmacológico , Liposarcoma/genética , Liposarcoma/patología , Doxorrubicina/efectos adversos , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Ensayos Clínicos Fase III como Asunto , Estudios Multicéntricos como Asunto
7.
Genes Chromosomes Cancer ; 61(8): 509-517, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35443099

RESUMEN

The year 2021 marked the centenary of the first publication of a cancer termed diffuse endothelioma of bone by James Ewing. Its unique features were apparent even in the first case series he described. This new diagnosis was clearly distinct from osteogenic sarcoma and myeloma, which were already well recognized at the time. We undertake this summary to better understanding Ewing sarcoma, contrasting the logarithmic evolution of the standard of care of systemic therapy for this and related diagnoses to the exponential understanding of the molecular biology of this family of tumors. We also outline in this manuscript how the finding of genomic relatives within Ewing sarcoma itself and related tumors, first noted nearly 40 years ago, helps us appreciate the need to find therapeutic plans that are specific for each small round blue cell tumor subtype. The advent of next generation sequencing regarding previously unknown small round blue cell tumor subtypes in many ways puts us back in the shoes of James Ewing in 1921, searching anew for clues leading to better treatments for increasingly rare cancer subsets.


Asunto(s)
Sarcoma de Ewing , Sarcoma , Biomarcadores de Tumor/genética , Humanos , Masculino , Proteínas de Fusión Oncogénica/genética , Sarcoma/genética , Sarcoma de Ewing/patología , Translocación Genética
8.
Cancer Immunol Immunother ; 71(4): 807-818, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34415404

RESUMEN

Histiocytic sarcoma (HS) is a rare and aggressive tumor in humans with no universally agreed standard of care therapy. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Previous data allude to the immunogenicity of this disease in both species, highlighting the potential for their successful treatment with immunotherapy. Quantification of CD3 tumor-infiltrating lymphocytes (TIL) in five cases of human HS revealed variable intra-tumoral T cell infiltration. Due to the paucity of human cases and lack of current model systems in which to appraise associations between anti-tumor immunity and treatment-outcome in HS, we analyzed clinical data and quantified TIL in 18 dogs that were previously diagnosed with localized HS and treated with curative-intent tumor resection with or without adjuvant chemotherapy. As in humans, assessment of TIL in biopsy tissues taken at diagnosis reveal a spectrum of immunologically "cold" to "hot" tumors. Importantly, we show that increased CD3 and granzyme B TIL are positively associated with favorable outcomes in dogs following surgical resection. NanoString transcriptional analyses revealed increased T cell and antigen presentation transcripts associated with prolonged survival in canine pulmonary HS and a decreased tumor immunogenicity profile associated with shorter survivals in splenic HS. Based on these findings, we propose that spontaneous canine HS is an accessible and powerful novel model to study tumor immunology and will provide a unique platform to preclinically appraise the efficacy and tolerability of anti-cancer immunotherapies for HS.


Asunto(s)
Enfermedades de los Perros , Sarcoma Histiocítico , Animales , Biopsia , Perros , Sarcoma Histiocítico/genética , Sarcoma Histiocítico/patología , Sarcoma Histiocítico/veterinaria , Linfocitos Infiltrantes de Tumor/patología , Bazo/patología
9.
Curr Treat Options Oncol ; 23(11): 1477-1502, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36178573

RESUMEN

OPINION STATEMENT: Sarcomas are a rare group of tumors with many subtypes, conventionally classified into soft-tissue sarcomas and bone sarcomas. Chemotherapeutic regimens form the mainstay of systemic therapy but are not well defined beyond the first-line setting and clinical outcomes are variable. Tyrosine kinase inhibitors (TKIs), with a broad inhibition profile which have been shown to target tumor angiogenesis, have an established role in the treatment of sarcomas without characteristic driver alterations. One such TKI, regorafenib, has been evaluated in sarcomas and clinical data are discussed in this review. An overview of regorafenib data from five phase 2 and one phase 1b clinical trials in over 10 sarcoma subtypes (both soft-tissue and bone) in adult and pediatric patients is reviewed. Regorafenib demonstrated clinical benefit in patients with non-adipocytic soft-tissue sarcomas, osteosarcoma and Ewing sarcoma who had progressed on prior therapy. Patients with otherwise limited treatment options may therefore benefit from regorafenib therapy.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Humanos , Niño , Compuestos de Fenilurea/efectos adversos , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Inhibidores de Proteínas Quinasas/efectos adversos
10.
N Engl J Med ; 379(25): 2417-2428, 2018 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-30575484

RESUMEN

BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). CONCLUSIONS: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).


Asunto(s)
Antineoplásicos/uso terapéutico , Fibromatosis Agresiva/tratamiento farmacológico , Sorafenib/uso terapéutico , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Método Doble Ciego , Femenino , Fibromatosis Agresiva/mortalidad , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Sorafenib/efectos adversos , Tasa de Supervivencia , Adulto Joven
11.
Cancer ; 126(1): 98-104, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31536651

RESUMEN

BACKGROUND: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS. METHODS: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method. RESULTS: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively. CONCLUSION: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Cardíacas/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Túnica Íntima/efectos de los fármacos , Adulto , Anciano , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cardiotoxicidad , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patología , Humanos , Indazoles , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas c-mdm2/genética , Pirimidinas/administración & dosificación , Sarcoma/genética , Sarcoma/patología , Sulfonamidas/administración & dosificación , Resultado del Tratamiento , Túnica Íntima/patología , Gemcitabina
12.
Oncologist ; 25(11): e1655-e1662, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32701199

RESUMEN

LESSONS LEARNED: The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. BACKGROUND: Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. METHODS: Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. RESULTS: Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92-3.67) months for regorafenib versus 2.07 (95% CI, 1.64-3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16-23.48) months for regorafenib and 4.89 (95% CI, 3.02-9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31-1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. CONCLUSION: Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.


Asunto(s)
Liposarcoma , Compuestos de Fenilurea , Piridinas , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Liposarcoma/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas , Piridinas/uso terapéutico , Resultado del Tratamiento
13.
Future Oncol ; 16(1): 4289-4301, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31778074

RESUMEN

Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195.


Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Crizotinib/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Antineoplásicos/farmacocinética , Biomarcadores de Tumor/metabolismo , Crizotinib/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/patología , Pronóstico , Distribución Tisular
14.
Cancer ; 125(24): 4435-4441, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31503332

RESUMEN

BACKGROUND: The results of the randomized, phase 3 ET743-SAR-3007 trial demonstrated that trabectedin had a significantly longer progression-free survival (PFS) compared with dacarbazine in patients with advanced leiomyosarcoma/liposarcoma after the failure of prior chemotherapy. Patients randomized to trabectedin received a 24-hour intravenous infusion either in an inpatient or outpatient setting. Herein, the authors reported the safety, efficacy, and patient-reported outcomes based on first infusion site of care. METHODS: Patients were randomized 2:1 to trabectedin (at a dose of 1.5 mg/m2 ) or dacarbazine (1 g/m2 over 20-120 minutes) with overall survival (OS) as the primary endpoint and PFS, time to disease progression, objective response rate, duration of response, safety, and patient-reported symptom scoring as secondary endpoints. The setting of the trabectedin infusion was based on institutional preference and categorized based on the setting of the first infusion. RESULTS: Of the 378 patients who were treated with trabectedin, 100 (27%) and 277 (73%), respectively, first received trabectedin in the inpatient and outpatient setting. No differences were observed with regard to PFS or OS based on site of care. The median PFS was 4.1 months versus 4.2 months (hazard ratio, 0.90; P = .49) for inpatients versus outpatients, respectively, and the median OS was 14.3 months versus 13.7 months (hazard ratio, 0.89; P = .40), respectively. Grade 3/4 adverse events (classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) were reported in 87 inpatients (87%) compared with 219 outpatients (79%); grade 3/4 serious adverse events were reported in 43 inpatients (43%) and 92 outpatients (33%). Extravasation occurred in 0 inpatients and 5 outpatients (2%), whereas the incidence of catheter-related complications was similar between groups (16% vs 15%). CONCLUSIONS: Although the majority of patients who were randomized to trabectedin received outpatient therapy, the outcomes of the current study suggested equivalent safety and efficacy in either setting.


Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Pacientes Internos , Leiomiosarcoma/tratamiento farmacológico , Liposarcoma/tratamiento farmacológico , Pacientes Ambulatorios , Trabectedina/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/efectos adversos , Manejo de la Enfermedad , Femenino , Humanos , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/mortalidad , Liposarcoma/diagnóstico , Liposarcoma/mortalidad , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Trabectedina/efectos adversos , Resultado del Tratamiento , Adulto Joven
15.
Cancer ; 125(14): 2445-2454, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31034598

RESUMEN

BACKGROUND: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. METHODS: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m2 gemcitabine on days 1 and 8 and 75 mg/m2 docetaxel on day 8). In part 2, patients were randomized in a double-blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. RESULTS: In part 2 with 209 patients, no significant difference in progression-free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7-6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6-8.3 months) was observed (P = .67; hazard ratio [HR], 1.07; 95% CI, 0.77-1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2-21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P = .32; HR, 1.23; 95% CI, 0.82-1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. CONCLUSIONS: Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft-tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Docetaxel/uso terapéutico , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/sangre , Anticuerpos Monoclonales Humanizados/inmunología , Antígenos CD/sangre , Antígenos CD/inmunología , Antígenos de Neoplasias/sangre , Antígenos de Neoplasias/inmunología , Antimetabolitos Antineoplásicos/administración & dosificación , Biomarcadores de Tumor/sangre , Estudios de Cohortes , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Docetaxel/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Sarcoma/patología , Sarcoma/secundario , Adulto Joven , Gemcitabina
16.
Cancer ; 125(15): 2610-2620, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31173362

RESUMEN

BACKGROUND: We performed a randomized phase 3 study of trabectedin versus dacarbazine in previously-treated patients with liposarcoma/leiomyosarcoma (LPS/LMS). METHODS: Patients were randomized 2:1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every 3 weeks. The primary objective was overall survival (OS). Secondary objectives were progression-free survival, objective response rate, safety, and patient-reported outcomes, all previously reported and demonstrating superior disease control with trabectedin. Results of the final OS analysis in preplanned subgroups of patients with LPS/LMS are presented. RESULTS: At the time of the final OS analysis, 577 patients had been assigned randomly, including 423 (73%) with LMS and 154 (27%) with LPS. The median duration of treatment exposure was higher in the trabectedin arm compared with the dacarbazine arm (4 vs 2 cycles), as was the proportion of patients receiving an extended number of therapy courses (≥6 cycles: 42% vs 22%). This pattern was consistent across histological subgroups: the median number of treatment cycles (4 vs 2 for both subgroups) and proportion of patients with ≥6 treatment cycles (LMS, 43% vs 24%; LPS, 40% vs 16%). Despite improved disease control by trabectedin, no improvement in OS was observed; the final median OS for trabectedin versus dacarbazine was 13.7 versus 13.1 months (P = .49). Sensitivity analyses of OS suggest confounding by post-study anticancer therapies, which were utilized in most patients in both treatment arms (71% vs 69%, respectively). CONCLUSION: The final OS results demonstrated comparable survival between LPS/LMS patients receiving trabectedin or dacarbazine, which is consistent with the interim analysis results. Both LPS and LMS demonstrated improved disease control with trabectedin.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Dacarbazina/uso terapéutico , Leiomiosarcoma/tratamiento farmacológico , Liposarcoma/tratamiento farmacológico , Trabectedina/uso terapéutico , Anciano , Antineoplásicos Alquilantes/farmacología , Femenino , Humanos , Leiomiosarcoma/mortalidad , Leiomiosarcoma/patología , Liposarcoma/mortalidad , Liposarcoma/patología , Masculino , Análisis de Supervivencia , Trabectedina/farmacología
17.
Br J Cancer ; 120(11): 1026-1032, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31065111

RESUMEN

BACKGROUND: This subgroup analysis of a phase 3 study compares outcomes for eribulin versus dacarbazine in patients with leiomyosarcoma. METHODS: Patients ≥18 years old with advanced liposarcoma or leiomyosarcoma, ECOG PS ≤2, and ≥2 prior treatment regimens were randomly assigned (1:1) to eribulin mesylate (1.4 mg/m² intravenously on day 1 and day 8) or dacarbazine (either 850, 1000, or 1200 mg/m² intravenously) every 21 days until disease progression. The primary end point was OS; additional end points were progression-free survival (PFS) and objective response rate (ORR). RESULTS: 309 Patients with leiomyosarcoma were included (eribulin, n = 157; dacarbazine, n = 152). Median age was 57 years; 42% of patients had uterine disease and 57% had nonuterine disease. Median OS was 12.7 versus 13.0 months for eribulin versus dacarbazine, respectively (hazard ratio [HR] = 0.93 [95% CI 0.71-1.20]; P = 0.57). Median PFS (2.2 vs 2.6 months, HR = 1.07 [95% CI 0.84-1.38]; P = 0.58) and ORR (5% vs 7%) were similar between eribulin- and dacarbazine-treated patients. Grade ≥3 TEAEs occurred in 69% of patients receiving eribulin and 59% of patients receiving dacarbazine. CONCLUSIONS: Efficacy of eribulin in patients with leiomyosarcoma was comparable to that of dacarbazine. Both agents had manageable safety profiles.


Asunto(s)
Dacarbazina/uso terapéutico , Furanos/uso terapéutico , Cetonas/uso terapéutico , Leiomiosarcoma/tratamiento farmacológico , Adulto , Anciano , Dacarbazina/efectos adversos , Femenino , Furanos/efectos adversos , Humanos , Cetonas/efectos adversos , Leiomiosarcoma/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos
18.
Oncologist ; 24(6): 857-863, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30126857

RESUMEN

BACKGROUND: Sorafenib and dacarbazine have low single-agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes. MATERIALS AND METHODS: Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3-week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1,000 mg/m2 intravenously (later reduced to 850 mg/m2). Patients were evaluated for response every 6 weeks. The primary objective was to determine the disease control rate (DCR) of sorafenib plus dacarbazine in the selected sarcoma subtypes. RESULTS: The study included 37 patients (19 female); median age was 55 years (range 26-87); and histologies included LMS (22), SS (11), and MPNST (4). The DCR was 46% (17/37). Median progression-free survival was 13.4 weeks. The RECIST response rate was 14% (5/37). The Choi response rate was 51% (19/37). Median overall survival was 13.2 months. Of the first 25 patients, 15 (60%) required dacarbazine dose reductions for hematologic toxicity, with one episode of grade 5 neutropenic fever. After reducing the starting dose of dacarbazine to 850 mg/m2, only 3 of the final 12 (25%) patients required dose reduction. CONCLUSION: This phase II study met its primary endpoint with an 18-week DCR of 46%. The clinical activity of dacarbazine plus sorafenib in patients with these diagnoses is modest. IMPLICATIONS FOR PRACTICE: Metastatic soft tissue sarcomas are a heterogeneous group of relatively rare malignancies. Most patients are treated with cytotoxic chemotherapy or targeted therapy in the form of tyrosine kinase inhibitors. Response rates are relatively low, and there is a need for better therapies. This clinical trial demonstrates that combining a cytotoxic therapy (dacarbazine) with an antiangiogenic small molecule (sorafenib) is feasible and associated with favorable disease-control rates; however, it also increases the potential for significant toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neutropenia Febril/epidemiología , Leiomiosarcoma/tratamiento farmacológico , Neurofibrosarcoma/tratamiento farmacológico , Sarcoma Sinovial/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estudios de Factibilidad , Neutropenia Febril/diagnóstico , Neutropenia Febril/etiología , Femenino , Humanos , Leiomiosarcoma/mortalidad , Leiomiosarcoma/patología , Masculino , Persona de Mediana Edad , Neurofibrosarcoma/mortalidad , Neurofibrosarcoma/patología , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores Sólidos , Sarcoma Sinovial/mortalidad , Sarcoma Sinovial/patología , Índice de Severidad de la Enfermedad , Sorafenib/administración & dosificación , Sorafenib/efectos adversos
19.
Mod Pathol ; 32(12): 1772-1785, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31263176

RESUMEN

Despite advances in our understanding of the underlying molecular drivers of sarcomas, few treatments are available with proven benefit for advanced metastatic sarcomas. Immunotherapy has value in this setting for some types of cancers, but sarcomas, with their multiplicity of rare types, have not been characterized in detail for their expression of targetable immune biomarkers. This study provides the most systematic evaluation to date of tumor-infiltrating lymphocytes and immune checkpoint biomarker expression in sarcomas. We examined by morphology and immunohistochemistry 1072 sarcoma specimens representing 22 types, in addition to 236 benign bone and soft-tissue tumors. Genomically-complex sarcoma types-those driven by mutations and/or copy-number alterations-had much higher numbers of tumor-infiltrating lymphocytes than translocation-associated sarcomas. Prior exposure to radiotherapy was associated with increased immune infiltrates. Higher lymphocytic infiltration was associated with better overall survival among the non-translocation-associated sarcomas. Expression of PD-1 and CD56 were associated with worse overall survival. LAG-3 and TIM-3, two emerging immune checkpoints, were frequently expressed in most sarcoma types. Indeed, most cases positive for PD-(L)1 coexpressed one or both of these novel biomarkers, providing a potential rationale in support for trials targeting LAG-3 and/or TIM-3 in conjunction with PD-1 inhibition.


Asunto(s)
Biomarcadores de Tumor/inmunología , Neoplasias Óseas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Sarcoma/inmunología , Neoplasias de los Tejidos Blandos/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias Óseas/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Adulto Joven
20.
BMC Cancer ; 19(1): 593, 2019 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-31208434

RESUMEN

BACKGROUND: Cancer patients with advanced disease routinely exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates molecular sequencing data with functional assay data to develop patient-specific combination cancer treatments. METHODS: Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the primary murine tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient's epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient's primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay. RESULTS: Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model). CONCLUSIONS: These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.


Asunto(s)
Biología Computacional/métodos , Evaluación Preclínica de Medicamentos/métodos , Quimioterapia Combinada/métodos , Modelos Estadísticos , Medicina de Precisión/métodos , Rabdomiosarcoma Alveolar/tratamiento farmacológico , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Perros , Sinergismo Farmacológico , Femenino , Xenoinjertos , Humanos , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos NOD
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