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PURPOSE: The aim of this study was to determine outcomes and prognostic factors for patients with primary and locally recurrent extra-abdominal desmoid tumors who underwent percutaneous cryoablation, and to compare with patients treated with surgery. METHODS: Group characteristics were compared using Fisher's exact test, and propensity score matching was performed using the nearest-neighbor approach. Kaplan-Meier and log-rank analyses were used to evaluate the variation in first local recurrence and disease control, while multivariate Cox regression was used to identify factors associated with first local recurrence. All statistical tests were two-sided and a p-value of 0.05 was considered statistically significant. RESULTS: Twenty-two cryoablation patients were matched with 33 surgical patients (n = 55). Median follow-up after cryoablation was 16.3 months versus 14.9 months after surgery. Two-year local recurrence-free survival (LRFS) was 59% after cryoablation and 71% after surgery, and median LRFS was 26.6 months after cryoablation but was not reached after surgery. Two-year disease control for all patients was 85%, however median disease control was not reached in either the cryoablation or surgery groups. There was no significant difference in LRFS or disease control between matched cryoablation and surgical patients. No local recurrences occurred after the first cryoablation in patients with zero or one of the following risk factors: tumor size > 5 cm, age ≤ 25 years, or locally recurrent disease. All patients with two or more of these risk factors recurred locally after the first cryoablation. CONCLUSION: Percutaneous cryoablation of primary and locally recurrent extra-abdominal desmoid tumors provides freedom from first local recurrence and long-term disease control comparable with surgery.
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Ablação por Cateter , Criocirurgia , Fibroma , Fibromatose Agressiva , Adulto , Fibromatose Agressiva/cirurgia , Humanos , Fatores de RiscoRESUMO
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neutropenia Febril/epidemiologia , Leiomiossarcoma/tratamento farmacológico , Neurofibrossarcoma/tratamento farmacológico , Sarcoma Sinovial/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Estudos de Viabilidade , Neutropenia Febril/diagnóstico , Neutropenia Febril/etiologia , Feminino , Humanos , Leiomiossarcoma/mortalidade , Leiomiossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Neurofibrossarcoma/mortalidade , Neurofibrossarcoma/patologia , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , Sarcoma Sinovial/mortalidade , Sarcoma Sinovial/patologia , Índice de Gravidade de Doença , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversosRESUMO
LESSONS LEARNED: The combination of pexidartinib and binimetinib was safe and tolerable and demonstrated encouraging signs of efficacy in two patients with advanced gastrointestinal stromal tumor (GIST) refractory to tyrosine kinase inhibitors (TKIs).Molecular profiling of GISTs at diagnosis and upon progression may provide insight into the mechanisms of response or resistance to targeted therapies.Additional trials are needed to further explore combined KIT and MEK inhibition in treatment-naïve and TKI-refractory patients with advanced GIST. BACKGROUND: Nearly all patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor activity in preclinical GIST models. METHODS: This was an investigator-initiated, phase I, dose escalation study of the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who progressed on imatinib. The primary endpoint was phase II dose determination; secondary endpoints included safety, tolerability, and efficacy. An expansion cohort to further evaluate safety and efficacy was planned. RESULTS: Two patients were treated at dose level one (binimetinib 30 mg b.i.d. and pexidartinib 400 mg every morning and 200 mg every evening), after which the study was terminated by the manufacturer. No dose-limiting toxicities (DLTs) were reported, and treatment was well tolerated. The only grade ≥3 treatment-emergent adverse event (TEAE) was asymptomatic elevated creatine phosphokinase (CPK). Both patients had a best response of stable disease (SD) by RECIST. Progression-free survival (PFS) and overall survival (OS) were 6.1 and 14.6 months, respectively, in one patient with five prior lines of therapy. The second patient with NF1-mutant GIST had a 27% decrease in tumor burden by RECIST and remains on study after 19 months of treatment. CONCLUSION: Pexidartinib combined with binimetinib was tolerable, and meaningful clinical activity was observed in two imatinib-refractory patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Idoso , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Distribuição TecidualRESUMO
Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST. A standard 3 + 3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Two treatment schedules were evaluated incorporating imatinib 400 mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. Results 16 patients enrolled. The median age was 54 years (range: 44-77), 81% were male, and the median number of lines of prior therapy was 4 [range: 2-6, 13 patients had ≥3 prior therapies]. 12 patients received treatment on schedule A [BGJ398 dose range: 25 - 75 mg]: 2 patients experienced dose limiting toxicities (DLT) (n = 1, myocardial infarction & grade (G)4 CPK elevation; n = 1, G3 ALT elevation) on schedule A (BGJ398 75 mg), significant hyperphosphatemia, an on-target effect, was not observed, implying the maximum tolerated dose was below the therapeutic dose. Following protocol amendment, 4 patients enrolled on schedule B [BGJ398 dose range: 75 - 100 mg]: no DLTs were observed. The most common treatment related adverse events occurring in >15% of patients included CPK elevation (50%), lipase elevation (44%), hyperphosphatemia (24%), anemia (19%), and peripheral edema (19%). Among the 12 evaluable patients, stable disease (SD) was the best response observed in 7 patients by RECIST v1.1 and 9 patients by CHOI. Stable disease ≥ 32 weeks was observed in 3 patients (25%). Median progression free survival was 12.1 weeks (95% CI 4.7-19.5 weeks). Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients. Trial Registration: NCT02257541 .
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores Tumorais/metabolismo , Feminino , Seguimentos , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/secundário , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/administração & dosagem , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Fenilureia/administração & dosagem , Prognóstico , Pirimidinas/administração & dosagem , Distribuição TecidualRESUMO
BACKGROUND: Approximately 5% of gastrointestinal stromal tumors (GISTs) originate in the rectum, and historically, radical resection was commonly performed. Little is known about the outcome for rectal GIST in the era of imatinib. METHODS: Using a prospectively maintained database, this study retrospectively analyzed 47 localized primary rectal GISTs treated at our center from 1982 to 2016, stratified by when imatinib became available in 2000. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were analyzed by the Kaplan-Meier method. RESULTS: Rectal GISTs represented 7.1% of 663 primary GISTs. The findings showed 17 patients in the pre-imatinib era and 30 patients in the imatinib era. The two groups had similar follow-up evaluation, age, gender, Miettinen risk, and distance to the anal verge. In the imatinib era, tumors were smaller at diagnosis (median 4 vs. 5 cm; p = 0.029), and 24 of the 30 patients received perioperative imatinib. In the high-risk patients, organ preservation and negative margins were more common among the 13 patients treated with neoadjuvant imatinib than among the 21 patients treated directly with surgery. High-risk patients who received perioperative imatinib (n = 15) had greater (or nearly significantly greater) 5-year OS, DSS, local RFS, and distant RFS than those who did not (n = 19) (91, 100, 100, and 71% vs. 47, 65, 74, and 41%; p = 0.049, 0.052, 0.077, 0.051, respectively). In the imatinib era, no patient has had a local recurrence or death due to GIST. CONCLUSIONS: The use of imatinib is associated with organ preservation and improved oncologic outcome for patients with rectal GIST.
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Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/mortalidade , Mesilato de Imatinib/uso terapêutico , Terapia Neoadjuvante/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Retais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Seguimentos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Oncologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Preservação de Órgãos , Prognóstico , Estudos Prospectivos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
LESSONS LEARNED: Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib.Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations. BACKGROUND: For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS. METHODS: Patients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m(2) gemcitabine on days 1 and 8, 75 mg/m(2) docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response. RESULTS: The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ≥ 90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed. CONCLUSION: GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.
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Desoxicitidina/análogos & derivados , Pirimidinas/administração & dosagem , Sarcoma/tratamento farmacológico , Sulfonamidas/administração & dosagem , Taxoides/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Sarcoma/patologia , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Angiosarcomas (AS) are rare tumors of vascular origin with a variable behavior and overall poor prognosis. We sought to assess the outcomes of patients treated for metastatic disease. METHODS: We performed a retrospective analysis of 119 patients treated for metastatic AS. Outcomes and efficacy measurements of the first and subsequent lines of treatment were analyzed. RESULTS: Median age was 61 years, and the most frequent primary sites were chest wall/breast (31%), viscera (22%) and head/neck (20%). Seventy-three (61%) and 46 (39%) patients received ≥ 2 and ≥ 3 lines of therapy, respectively. The most commonly used agents included taxanes and anthracyclines. Median overall survival was 12.1 months. Median times to tumor progression were 3.5 months for first line, 3.7 months for second line and 2.7 months for third line. Among 48 patients evaluable per RECIST, the overall response rate to first line was 30% and <10% in subsequent lines. Doxorubicin, liposomal doxorubicin and taxanes resulted in similar response rates and survival, and there was no apparent benefit for combination chemotherapy. CONCLUSION: Despite reasonable response rates in the first-line setting, benefit from systemic therapy is short-lived in metastatic AS, and outcomes are poor. Doxorubicin, liposomal doxorubicin and taxanes are reasonable and appropriate choices for monotherapy.
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Antineoplásicos/uso terapêutico , Hemangiossarcoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/uso terapêutico , Progressão da Doença , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Feminino , Hemangiossarcoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Estudos Retrospectivos , Taxoides/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. PATIENTS AND METHODS: We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. RESULTS: Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response. CONCLUSIONS: Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649.
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Aminopiridinas , Lipossarcoma , Humanos , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Lipossarcoma/tratamento farmacológico , Lipossarcoma/patologia , Senescência Celular , Quinase 4 Dependente de Ciclina , Microambiente TumoralRESUMO
PURPOSE: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase II randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS. PATIENTS AND METHODS: Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could cross over to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the two arms was also determined. RESULTS: Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial two treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There were no significant differences in mPFS for the two treatment arms. Clinical benefit (i.e., objective response or stable disease for a minimum of four or six cycles of therapy) on the first-line tyrosine kinase inhibitor (TKI) therapy did not predict benefit on the second-line TKI. Both drugs were well tolerated. As of August 2021, 1 patient (unevaluable for ORR) remains on study. CONCLUSIONS: The study did not meet its endpoints for ORR. Although both TKIs provided clinical benefit, the outcomes may have been attenuated in patients who had progressed ≤6 months before enrollment, potentially accounting for the low response rates. See related commentary by Wilky and Maleddu, p. 1163.
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Sarcoma Alveolar de Partes Moles , Humanos , Sunitinibe/efeitos adversos , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Sarcoma Alveolar de Partes Moles/patologia , Indóis/efeitos adversos , Quinazolinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagemRESUMO
The association between immune-related AEs (irAE) and outcome in patients with sarcoma is not known. We retrospectively reviewed a cohort of patients with advanced sarcoma treated with immune checkpoint blockade (ICB)-based therapy. Association of irAEs with survival was assessed using a Cox regression model that incorporated irAE occurrence as a time-dependent covariate. Tumor samples with available RNA sequencing data were stratified by presence of an irAE to identify patterns of differential gene expression. A total of 131 patients were included. Forty-two (32%) had at least one irAE of any grade and 16 (12%) had at least one grade ≥ 3 irAE. The most common irAEs were hypothyroidism (8.3%), arthralgias (5.3%), pneumonitis (4.6%), allergic reaction (3.8%), and elevated transaminases (3.8%). Median progression-free survival (PFS) and overall survival (OS) from the time of study entry were 11.4 [95% confidence interval (CI), 10.7-15.0) and 74.6 weeks (CI, 44.9-89.7), respectively. On Cox analysis adjusting for clinical covariates that were significant in the univariate setting, the HR for an irAE (HR, 0.662; CI, 0.421-1.041) approached, but did not reach statistical significance for PFS (P = 0.074). Patients had a significantly lower HR for OS (HR, 0.443; CI, 0.246-0.798; P = 0.007) compared with those without or before an irAE. Gene expression profiling on baseline tumor samples found that patients who had an irAE had higher numbers of tumor-infiltrating dendritic cells, CD8+ T cells, and regulatory T cells as well as upregulation of immune and inflammatory pathways. SIGNIFICANCE: irAE after ICB therapy was associated with an improved OS; it also approached statistical significance for improved PFS. Patients who had an irAE were more likely to have an inflamed tumor microenvironment at baseline.
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Nivolumabe , Sarcoma , Humanos , Nivolumabe/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Estudos Retrospectivos , Intervalo Livre de Progressão , Sarcoma/tratamento farmacológico , Microambiente TumoralRESUMO
PURPOSE: Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes. PATIENTS AND METHODS: This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1. RESULTS: Thirty patients were enrolled [60% male; median age 54 years (range, 24-78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%-17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9-26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway-related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline. CONCLUSIONS: Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.
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Leiomiossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Leiomiossarcoma/tratamento farmacológico , Sarcoma/tratamento farmacológico , Sarcoma/genética , Anticorpos Monoclonais Humanizados , Neoplasias de Tecidos Moles/tratamento farmacológico , Microambiente TumoralRESUMO
BACKGROUND: Data regarding the role of anthracyclines and taxanes as first-line treatments of metastatic angiosarcoma are limited. METHODS: Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed. RESULTS: Seventy-five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single-agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression-free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9-6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4-10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS. CONCLUSIONS: First-line single-agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS.
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Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Hemangiossarcoma/tratamento farmacológico , Paclitaxel/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Hemangiossarcoma/mortalidade , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidadeRESUMO
BACKGROUND: The authors tested whether an educational video on the goals of care in advanced cancer (life-prolonging care, basic care, or comfort care) helped patients understand these goals and had an impact on their preferences for resuscitation. METHODS: A survey of 80 patients with advanced cancer was conducted before and after they viewed an educational video. The outcomes of interest included changes in goals of care preference and knowledge and consistency of preferences with code status. RESULTS: Before viewing the video, 10 patients (13%) preferred life-prolonging care, 24 patients (30%) preferred basic care, 29 patients (36%) preferred comfort care, and 17 patients (21%) were unsure. Preferences did not change after the video, when 9 patients (11%) chose life-prolonging care, 28 patients (35%) chose basic care, 29 patients (36%) chose comfort care, and, 14 patients (18%) were unsure (P = .28). Compared with baseline, after the video presentation, more patients did not want cardiopulmonary resuscitation (CPR) (71% vs 62%; P = .03) or ventilation (80% vs 67%; P = .008). Knowledge about goals of care and likelihood of resuscitation increased after the video (P < .001). Of the patients who did not want CPR or ventilation after the video augmentation, only 4 patients (5%) had a documented do-not-resuscitate order in their medical record (kappa statistic, -0.01; 95% confidence interval, -0.06 to 0.04). Acceptability of the video was high. CONCLUSIONS: Patients with advanced cancer did not change care preferences after viewing the video, but fewer wanted CPR or ventilation. Documented code status was inconsistent with patient preferences. Patients were more knowledgeable after the video, reported that the video was acceptable, and said they would recommend it to others. The current results indicated that this type of video may enable patients to visualize "goals of care," enriching patient understanding of worsening health states and better informing decision making.
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Planejamento Antecipado de Cuidados , Técnicas de Apoio para a Decisão , Neoplasias/terapia , Gravação de Videoteipe , Adulto , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , PrognósticoRESUMO
BACKGROUND: Data regarding the management and outcome of patients with metastatic gastrointestinal stromal tumors (GIST) refractory to 1st-line imatinib and 2nd-line sunitinib are limited. METHODS: Medical records of 223 imatinib-resistant and sunitinib-resistant GIST who were treated in 11 major referral centers were reviewed. RESULTS: The three most frequent drugs used in the 3rd-line setting were: nilotinib n = 67 (29.5%), sorafenib n = 55 (24.5%), and imatinib n = 40 (17.5%). There were 18 patients (8%) who received best supportive care (BSC) only. The median progression-free survival (PFS) and overall survival (OS) on 3rd-line treatment were 3.6 months [95% confidence interval (95% CI), 3.1-4.1] and 9.2 months (95% CI, 7.5-10.9), respectively. Multivariate analysis showed that, in the 3rd-line setting, albumin level and KIT/PDGFRA mutational status were significantly associated with PFS, whereas performance status and albumin level were associated with OS. After adjustment for prognostic factors, nilotinib and sorafenib provided the best PFS and OS. Rechallenge with imatinib was also associated with improved OS in comparison with BSC. CONCLUSION: In the 3rd-line setting, rechallenge with imatinib provided limited clinical benefit but was superior to BSC. Sorafenib and nilotinib have significant clinical activity in imatinib-resistant and sunitinib-resistant GIST and may represent an alternative for rechallenge with imatinib.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Intervalo Livre de Doença , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/secundário , Humanos , Mesilato de Imatinib , Indóis/administração & dosagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piperazinas/administração & dosagem , Prognóstico , Proteínas Proto-Oncogênicas c-kit/genética , Pirróis/administração & dosagem , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/metabolismo , Sorafenibe , Sunitinibe , Taxa de Sobrevida , Adulto JovemRESUMO
PURPOSE: To evaluate the feasibility, efficacy, and safety of doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) as an alternative local treatment for extra-abdominal desmoid tumors (DTs). METHODS: Eleven adult female patients (mean age = 40.1 years) with symptomatic, progressively enlarging extra-abdominal DTs were determined ineligible for cryoablation after failing observation or systemic therapy and treated with a single session doxorubicin DEB-TACE. Six rectus sheath, one chest wall, three axilla, and one upper extremity DTs were included. The median follow-up was 155.0 ± 52.3 days. Treatment response was assessed by MRIs and maximum visual analog scale (VAS). RESULTS: All procedures were technically successful without immediate complications. The average size of treated DT was 161.8 ml (range: 28.3-420.0 ml). The mean doxorubicin dose was 13.3 mg/m2. All patients experienced skin changes which improved over time without treatments. No higher-grade adverse events were observed. Initial one-month follow-up MRI demonstrated partial to near-complete tumor necrosis, ranging from 1.4 to 97.6% (mean: 36.4%). Additional follow-up revealed a further reduction of overall tumor volume (mean: - 38.1%, p < 0.0001) and maximum VAS (mean: - 2.6, p = 0.0026) in 10 out of 11 patients (90.9%). After the first month, the residual tumors exhibited continued volume reduction in 10 out of 11 patients (mean: - 16.5%, p = 0.0230). There was also a significant decrease of T2 signal intensity within residual tumor on the latest follow-up (mean: - 29.6%, p = 0.0217), suggesting a reduction in tumor cellularity. CONCLUSION: DEB-TACE may be a safe and effective local treatment alternative in DT patients.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Fibromatose Agressiva , Neoplasias Hepáticas , Adulto , Antibióticos Antineoplásicos , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Doxorrubicina , Feminino , Fibromatose Agressiva/diagnóstico por imagem , Fibromatose Agressiva/terapia , Humanos , Neoplasias Hepáticas/terapia , Resultado do TratamentoRESUMO
PURPOSE: Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors. EXPERIMENTAL DESIGN: We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies. Our primary endpoint was the incidence of HPD; secondary endpoints were clinical or genomic correlates of response or HPD. RESULTS: We treated 134 patients with advanced sarcoma from 2015 to 2019. Twenty-one patients (16%) had a complete or partial response (CR/PR), and 30% of responses were durable for over 2 years. Forty-eight (36%) patients had stable disease (SD), 45 (34%) had progressive disease without HPD (PD), and 15 (11%) had HPD. Five patients (4%) were not evaluable for HPD. The sarcoma subtypes, sites of metastasis, clinical course, and genomic alterations in patients with PD and HPD were similar, except HPD tumors were smaller at baseline. CONCLUSIONS: In patients with advanced sarcoma, PD-1 blockade can mediate durable responses. HPD occurs in sarcoma at an incidence that is similar to what has been reported in other solid tumors, but patients with HPD were clinically and biologically similar to those who had PD. Further research is required to establish whether HPD is a biologically distinct phenomenon and whether a theoretical risk of HPD should influence patient management.
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Melanoma , Terapia Viral Oncolítica , Sarcoma , Progressão da Doença , Seguimentos , Humanos , Receptor de Morte Celular Programada 1 , Sarcoma/tratamento farmacológico , Sarcoma/genéticaRESUMO
BACKGROUND: Angiosarcoma is a histologically and molecularly heterogeneous vascular neoplasm with aggressive clinical behavior. Emerging data suggests that immune checkpoint blockade (ICB) is efficacious against some angiosarcomas, particularly cutaneous angiosarcoma of the head and neck (CHN). METHODS: Patients with histologically confirmed angiosarcoma treated with ICB-based therapy at a comprehensive cancer center were retrospectively identified. Clinical characteristics and the results of targeted exome sequencing, transcriptome sequencing, and immunohistochemistry analyses were examined for correlation with clinical benefit. Durable clinical benefit was defined as a progression-free survival (PFS) of ≥16 weeks. RESULTS: For the 35 patients included in the analyses, median PFS and median overall survival (OS) from the time of first ICB-based treatment were 11.9 (95% CI 7.4 to 31.9) and 42.5 (95% CI 19.6 to 114.2) weeks, respectively. Thirteen patients (37%) had PFS ≥16 weeks. Clinical factors associated with longer PFS and longer OS in multivariate analyses were ICB plus other therapy regimens, CHN disease, and white race. Three of 10 patients with CHN angiosarcoma evaluable for tumor mutational burden (TMB) had a TMB ≥10. Five of six patients with CHN angiosarcoma evaluable for mutational signature analysis had a dominant mutational signature associated with ultraviolet (UV) light. No individual gene or genomic pathway was significantly associated with PFS or OS; neither were TMB or UV signature status. Analyses of whole transcriptomes from nine patient tumor samples found upregulation of angiogenesis, inflammatory response, and KRAS signaling pathways, among others, in patients with PFS ≥16 weeks, as well as higher levels of cytotoxic T cells, dendritic cells, and natural killer cells. Patients with PFS <16 weeks had higher numbers of cancer-associated fibroblasts. Immunohistochemistry findings for 12 patients with baseline samples available suggest that neither PD-L1 expression nor presence of tumor-infiltrating lymphocytes at baseline appears necessary for a response to ICB-based therapy. CONCLUSIONS: ICB-based therapy benefits only a subset of angiosarcoma patients. Patients with CHN angiosarcoma are more likely to have PFS ≥16 weeks, a dominant UV mutational signature, and higher TMB than angiosarcomas arising from other primary sites. However, clinical benefit was seen in other angiosarcomas also and was not restricted to tumors with a high TMB, a dominant UV signature, PD-L1 expression, or presence of tumor infiltrating lymphocytes at baseline.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Hemangiossarcoma , Neoplasias Pulmonares , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Genômica , Hemangiossarcoma/tratamento farmacológico , Hemangiossarcoma/genética , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , TranscriptomaRESUMO
PURPOSE: Because the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma. PATIENTS AND METHODS: In this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib. RESULTS: Nine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch. CONCLUSIONS: The combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling.
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Proteínas Hedgehog , Sarcoma , Secretases da Proteína Precursora do Amiloide , Anilidas/efeitos adversos , Benzazepinas , Fluorocarbonos , Humanos , PiridinasRESUMO
PURPOSE: Dual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST. METHODS: In this trial (NCT01991379), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity. RESULTS: Between September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%). CONCLUSION: The study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.
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Protocolos de Quimioterapia Combinada Antineoplásica , Tumores do Estroma Gastrointestinal , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/uso terapêutico , Resultado do TratamentoRESUMO
PD-1 blockade (nivolumab) efficacy remains modest for metastatic sarcoma. In this paper, we present an open-label, non-randomized, non-comparative pilot study of bempegaldesleukin, a CD122-preferential interleukin-2 pathway agonist, with nivolumab in refractory sarcoma at Memorial Sloan Kettering/MD Anderson Cancer Centers (NCT03282344). We report on the primary outcome of objective response rate (ORR) and secondary endpoints of toxicity, clinical benefit, progression-free survival, overall survival, and durations of response/treatment. In 84 patients in 9 histotype cohorts, all patients experienced ≥1 adverse event and treatment-related adverse event; 1 death was possibly treatment-related. ORR was highest in angiosarcoma (3/8) and undifferentiated pleomorphic sarcoma (2/10), meeting predefined endpoints. Results of our exploratory investigation of predictive biomarkers show: CD8 + T cell infiltrates and PD-1 expression correlate with improved ORR; upregulation of immune-related pathways correlate with improved efficacy; Hedgehog pathway expression correlate with resistance. Exploration of this combination in selected sarcomas, and of Hedgehog signaling as a predictive biomarker, warrants further study in larger cohorts.