RESUMO
PURPOSE: Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte-associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy. PATIENTS AND METHODS: Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival. RESULTS: In total, 155 women (median age, 50 years [range, 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab; 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1-positive and programmed death ligand-1-negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events. CONCLUSION: Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte-associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
OBJECTIVE: This phase II clinical trial evaluated the safety and antitumor activity of balstilimab, an anti-PD-1 antibody, in patients with previously-treated, recurrent/metastatic cervical cancer. METHODS: Eligible patients were 18 years or older with recurrent and/or metastatic cervical cancer and who had relapsed after a prior platinum-based treatment regimen for advanced disease. Balstilimab was administered intravenously at 3 mg/kg once every two weeks, for up to 24 months. The primary endpoint was objective response rate (ORR, RECIST v1.1) as assessed by an independent review committee. RESULTS: At data cutoff, 161 women (median age, 53 years [range 25-81]) were enrolled and treated with balstilimab. Of these, 140 had measurable disease at baseline and one prior line of platinum-based therapy in the metastatic, persistent, or recurrent setting; these patients were included in the efficacy analyses. The ORR was 15% (95% CI, 10.0%-21.8%) and included 5 patients with a complete response and 16 with a partial response. The median duration of response was 15.4 months. In patients with PD-L1-positive tumors the ORR was 20%, however patients with PD-L1-negative tumors also responded to balstilimab (ORR, 7.9%). Responses were not restricted to tumors of squamous cell histology, and an ORR of 12.5% was seen in the subset of patients with cervical adenocarcinoma. The disease control rate was 49.3% (95% CI, 41.1%-57.5%). Immune-mediated enterocolitis (3.1%) and diarrhea (1.9%) were the most common grade 3 or higher treatment-related adverse events. CONCLUSION: Balstilimab demonstrated meaningful and durable clinical activity, with manageable safety, in patients with previously-treated, recurrent/metastatic cervical cancer.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Inibidores de Checkpoint Imunológico/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Diarreia/imunologia , Esquema de Medicação , Enterocolite/induzido quimicamente , Enterocolite/epidemiologia , Enterocolite/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Infusões Intravenosas , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologiaRESUMO
Balstilimab (anti-programmed death 1) and zalifrelimab (anti-CTLA-4) are two new checkpoint inhibitors that have emerged as promising investigational agents for the treatment of cervical cancer, particularly in the setting of previously-treated, recurrent/metastatic disease. Here we describe the rationale and design of RaPiDS (NCT03894215), a two-arm Phase II study evaluating the safety, tolerability and efficacy of balstilimab administered alone or in combination with zalifrelimab in patients with advanced cervical cancer who progressed after first-line, platinum-based chemotherapy. Patients will be randomized in a 1:1 ratio. The primary end point is objective response rate, and key secondary objectives include safety, duration of response, progression-free survival, overall survival and quality of life outcomes.
Lay abstract Current treatment options for women with recurrent/metastatic cervical cancer are limited. Immunotherapy is altering the therapeutic landscape in this setting yet opportunities remain to improve on current outcomes. Dual blockade of different immune checkpoints is an approach shown to be highly effective in other cancers. Balstilimab (anti-programmed death 1) and zalifrelimab (anti-CTLA-4) are two new checkpoint inhibitors showing promise in patients with advanced cervical cancer. The RaPiDS trial is designed to characterize the safety and activity of balstilimab, alone and in combination with zalifrelimab, in patients with recurrent/metastatic cervical cancer who progressed after prior platinum-based chemotherapy. Clinical trial registration: NCT03894215 (ClinicalTrials.gov).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase II como Assunto/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Neoplasias do Colo do Útero/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
Background: Improving surgical outcomes in hepatocellular carcinoma (HCC) patients would greatly benefit from biomarkers. Angiogenesis and inflammation are hallmarks of HCC progression and therapeutic targets. Methods: We retrospectively evaluated preoperative clinical variables and circulating (plasma) biomarkers of angiogenesis and inflammation in a cohort of HCC patients who underwent liver resection (LR) or transplantation (LT). Biomarker correlation with outcomes-freedom of liver recurrence (FLR), disease-free survival (DFS) and overall survival (OS)-was tested using univariate and multivariate Cox regression analyses. Results: Survival outcomes associated with sVEGFR1, VEGF and VEGF-C in LT patients and with IL-10 in LR patients. Moreover, in LT patients within Milan criteria, higher plasma VEGF and sVEGFR1 were associated with worse outcomes, while in those outside Milan criteria lower plasma VEGF-C associated with better outcomes. Multivariate analysis indicated that adding plasma VEGF or VEGF-C to a predictive model including Milan criteria and AFP improved prediction of DFS and OS (all p < 0.05). Conclusion: Survival outcomes after LR or LT differentially associated with angiogenic and inflammatory biomarkers. High plasma VEGF correlated with poorer prognosis within Milan criteria while low plasma VEGF-C associated with better prognosis outside Milan criteria. These candidate biomarkers should be further validated to improve patient stratification.
RESUMO
Anti-vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy's lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment. Mouse models revealed that obesity impairs the effects of anti-VEGF on angiogenesis, tumor growth, and metastasis. In one murine BC model, obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors. IL-6 blockade abrogated the obesity-induced resistance to anti-VEGF therapy in primary and metastatic sites by directly affecting tumor cell proliferation, normalizing tumor vasculature, alleviating hypoxia, and reducing immunosuppression. Similarly, in a second mouse model, where obesity was associated with increased FGF-2, normalization of FGF-2 expression by metformin or specific FGF receptor inhibition decreased vessel density and restored tumor sensitivity to anti-VEGF therapy in obese mice. Collectively, our data indicate that obesity fuels BC resistance to anti-VEGF therapy via the production of inflammatory and angiogenic factors.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Fator 2 de Crescimento de Fibroblastos/metabolismo , Interleucina-6/metabolismo , Obesidade/complicações , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Antineoplásicos/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Metformina/uso terapêutico , Camundongos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Definitive treatment for prostate cancer includes radical prostatectomy (RP), external beam radiation therapy (EBRT), and brachytherapy (BT). The different side effect profiles of these options are crucial factors for patients and clinicians when deciding between treatments. This study reports long-term health-related quality of life (HRQOL) for patients in their second decade after treatment for prostate cancer. We used a validated survey to assess urinary, bowel, and sexual function and HRQOL in a prospective cohort of patients diagnosed with localized prostate cancer 14-18 years previously. We report and compare the outcomes of patients who were initially treated with RP, EBRT, or BT. Of 230 eligible patients, the response rate was 92% (n = 211) and median follow-up was 14.6 years. Compared to baseline, RP patients had significantly worse urinary incontinence and sexual function, EBRT patients had worse scores in all domains, and BT patients had worse urinary incontinence, urinary irritation/obstruction, and sexual function. When comparing treatment groups, RP patients underwent larger declines in urinary continence than did BT patients, and EBRT and BT patients experienced larger changes in urinary irritation/obstruction. Baseline functional status was significantly associated with long-term function for urinary obstruction and bowel function domains. This is one of the few prospective reports on quality of life for prostate cancer patients beyond 10 years, and adds information about the late consequences of treatment choices. These data may help patients make informed decisions regarding treatment choice based on symptoms they may experience in the decades ahead.
Assuntos
Neoplasias da Próstata/epidemiologia , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: We sought to evaluate the effectiveness and safety of utilizing radiotherapy (RT) with standard fractionation, with or without intraoperative RT (IORT), to treat locally recurrent rectal cancer (LRRC). METHODS: Retrospective review of 25 patients with LRRC treated with standard fractionation RT from 2005 to 2011. 15 patients (60%) had prior pelvic RT and 10 (40%) had synchronous metastases. The median equivalent dose in 2-Gy fractions was 30 and 49.6 Gy in patients with and without prior RT, respectively. 23 patients (92%) received concurrent chemotherapy and 16 (64%) underwent surgical resection. Eight patients (33.3%, four with and four without prior RT) received IORT. A competing risks model was developed to estimate the cumulative incidence of local failure with death treated as a competing event. RESULTS: Median follow-up was 36.9 months after the date of local recurrence. 3-year rates of overall survival (OS), local control (LC) and death with LC were 51.6%, 73.3% and 69.2%, respectively. On multivariable analysis, surgical resection was significantly predictive of improved OS (p < 0.05). If surgical resection were removed from the multivariable model, given the collinearity between IORT delivery and surgical resection, then IORT also became a significant predictor of OS (p < 0.05). Systemic disease at the time of local recurrence was not associated with either LC or OS. No patient had grade ≥3 acute or late toxicity. CONCLUSION: RT with standard fractionation is safe and effective in the treatment of patients with LRRC, even in patients with significant risk of systemic disease and/or history of prior RT. Advances in knowledge: The utility of RT with standard fractionation, generally with chemotherapy, in the treatment of LRRC is demonstrated. In this high-risk cohort of patients with a 40% incidence of synchronous metastatic disease, surgical resection of the recurrence was the major predictor of OS, though a benefit to IORT was also suggested. No patients had grade ≥3 acute or late toxicity, though 40% had undergone prior RT, underscoring the tolerability of standard fractionation RT in this setting.
Assuntos
Fracionamento da Dose de Radiação , Cuidados Intraoperatórios/métodos , Recidiva Local de Neoplasia/radioterapia , Neoplasias Retais/radioterapia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. EXPERIMENTAL DESIGN: We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. RESULTS: We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity. CONCLUSIONS: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993-3004. ©2016 AACR.
Assuntos
Neoplasias da Mama/patologia , Macrófagos/metabolismo , Obesidade/patologia , Neoplasias Pancreáticas/patologia , Fator de Crescimento Placentário/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Neoplasias da Mama/imunologia , Dieta Hiperlipídica , Feminino , Glucose/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Macrófagos/imunologia , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Neovascularização Patológica/genética , Obesidade/imunologia , Neoplasias Pancreáticas/imunologia , Fator de Crescimento Placentário/genética , Prognóstico , Transdução de Sinais , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Adulto , Idoso , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologiaRESUMO
PURPOSE: Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). EXPERIMENTAL DESIGN: We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis. RESULTS: The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0-22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9-20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75). CONCLUSIONS: The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study.
Assuntos
Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Piperidinas/administração & dosagem , Quinazolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Intervalo Livre de Doença , Feminino , Glioblastoma/sangue , Glioblastoma/patologia , Humanos , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Quinazolinas/efeitos adversos , Temozolomida , Resultado do TratamentoRESUMO
Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non-small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment-while reducing blood flow, volume, and permeability in the overall population-may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Albuminas/administração & dosagem , Bevacizumab , Biomarcadores Tumorais/sangue , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Feminino , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagemRESUMO
BACKGROUND: Thoracic and cardiac irradiation increases the risk of pulmonary and cardiovascular disease. In addition, radiation, often in combination with chemotherapy, can cause treatment-related pneumonitis. Previously, we showed that the common marker for cardiac damage, troponin T, was not elevated by chemoradiation [Lung Cancer 62:351-355, 2008]. In this study, we explore whether dose-volume metrics and biomarkers for cardiac damage, inflammation or angiogenesis could identify patients receiving thoracic radiation who would later have cardiac or pulmonary complications. FINDINGS: To this end, we quantified cardiac biomarkers including c-reactive protein (cRP) as well as a panel of angiogenic and inflammatory molecules in thirty patients who received radiation therapy to the thorax with or without concurrent chemotherapy between May 2006 and May 2007. Serum was collected at baseline, 2 weeks into radiation treatment and at the completion of radiation therapy. Heart and lung dosimetric parameters and clinical risk factors were also examined, along with the monitoring of adverse pulmonary and cardiac events during follow-up. Contrary to our hypothesis, there was no correlation between serum biomarker levels and cardiac radiation dose. Similarly there was little association between lung dose-volume metrics and inflammatory or angiogenic biomarkers. Furthermore, there was no correlation with serum biomarkers and adverse pulmonary or cardiovascular events. CONCLUSION: Based on these data, acute elevations in serum biomarkers of cardiac damage, inflammation or angiogenesis should not be attributed to thoracic (chemo)radiation and elevations in such biomarkers of tissue damage should be further evaluated.
Assuntos
Biomarcadores/análise , Quimiorradioterapia , Neoplasias Cardíacas/terapia , Mediadores da Inflamação/metabolismo , Neoplasias Pulmonares/terapia , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Cardíacas/metabolismo , Neoplasias Cardíacas/patologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , PrognósticoRESUMO
PURPOSE: We sought to evaluate the incidence of vaginal stenosis (VS) and identify clinical and treatment factors that predict for VS in female patients with anal cancer treated with definitive chemoradiation. METHODS AND MATERIALS: The cohort included 95 consecutive women receiving definitive chemoradiation between 2003 and 2012. All but 1 received intensity modulated radiation therapy; median primary tumor dose 50.4 Gy (range, 41.4-60). A modified National Cancer Institute Common Terminology Criteria for Adverse Events version 4 was used to score VS based on the medical record description of dyspareunia, pain with dilator use, vaginal dryness, or difficult pelvic examination. Ordered logistic regression was performed to assess VS predictors. RESULTS: Median age was 60.4 years (range, 19-97). With median follow-up of 2.5 years, 70 women (74%) had adequate information to assess VS. Of these, VS grade distribution was 21.4% grade 0, 14.3% grade 1, 27.1% grade 2, and 37.1% grade 3. By multivariable ordered logistic regression, younger age (P = .02), higher tumor dose (P = .06), and earlier treatment year (P = .04) were associated with higher grade of VS. CONCLUSIONS: VS is a common late complication in women treated definitively with chemoradiation for anal canal cancer. Younger age, higher tumor dose, and earlier year of treatment were associated with a higher grade of stenosis. Prospective investigation into patient reported outcomes is warranted, including sexual function and VS prevention strategies to better understand its effect on long-term survivorship.
Assuntos
Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/radioterapia , Quimiorradioterapia/efeitos adversos , Constrição Patológica/etiologia , Vagina/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/patologia , Estudos de Coortes , Constrição Patológica/induzido quimicamente , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Adulto JovemAssuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Células Estromais/patologia , Microambiente Tumoral , Feminino , Humanos , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
PURPOSE: To present long-term outcomes of a prospective feasibility trial using either protons or 3-dimensional conformal photon-based (accelerated partial-breast irradiation [APBI]) techniques. METHODS AND MATERIALS: From October 2003 to April 2006, 98 evaluable patients with stage I breast cancer were treated with APBI (32 Gy in 8 fractions given twice daily) on a prospective clinical trial: 19 with proton beam therapy (PBT) and 79 with photons or mixed photons/electrons. Median follow-up was 82.5 months (range, 2-104 months). Toxicity and patient satisfaction evaluations were performed at each visit. RESULTS: At 7 years, the physician rating of overall cosmesis was good or excellent for 62% of PBT patients, compared with 94% for photon patients (P=.03). Skin toxicities were more common for the PBT group: telangiectasia, 69% and 16% (P=.0013); pigmentation changes, 54% and 22% (P=.02); and other late skin toxicities, 62% and 18% (P=.029) for PBT and photons, respectively. There were no significant differences between the groups in the incidences of breast pain, edema, fibrosis, fat necrosis, skin desquamation, and rib pain or fracture. Patient-reported cosmetic outcomes at 7 years were good or excellent for 92% and 96% of PBT and photon patients, respectively (P=.95). Overall patient satisfaction was 93% for the entire cohort. The 7-year local failure rate for all patients was 6%, with 3 local recurrences in the PBT group (7-year rate, 11%) and 2 in photon-treated patients (4%) (P=.22). CONCLUSIONS: Local failure rates of 3-dimensional APBI and PBT were similar in this study. However, PBT, as delivered in this study, led to higher rates of long-term telangiectasia, skin color changes, and skin toxicities. We recommend the use of multiple fields and treatment of all fields per treatment session or the use of scanning techniques to minimize skin toxicity.
Assuntos
Neoplasias da Mama/radioterapia , Fótons/uso terapêutico , Terapia com Prótons/métodos , Radioterapia Conformacional/métodos , Pele/efeitos da radiação , Neoplasias da Mama/patologia , Necrose Gordurosa/etiologia , Necrose Gordurosa/patologia , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Satisfação do Paciente , Fótons/efeitos adversos , Estudos Prospectivos , Terapia com Prótons/efeitos adversos , Radiodermite/patologia , Radiodermite/prevenção & controle , Radioterapia Conformacional/efeitos adversos , Pigmentação da Pele/efeitos da radiação , Telangiectasia/etiologia , Resultado do Tratamento , Carga TumoralRESUMO
PURPOSE: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS AND MATERIALS: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. RESULTS: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). CONCLUSIONS: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Quimiorradioterapia Adjuvante/métodos , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Neoplasias Pancreáticas/terapia , Terapia com Prótons/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Antígeno CA-19-9/sangue , Capecitabina , Antígeno Carcinoembrionário/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Quimiorradioterapia Adjuvante/mortalidade , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Genes ras/genética , Fator de Crescimento de Hepatócito/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas/análise , Proteínas Proto-Oncogênicas p21(ras) , Receptores CXCR/análise , Proteínas ras/análiseRESUMO
OBJECTIVES: For patients with oropharyngeal squamous cell carcinoma (OPSCC), especially for those with HPV-positive tumors, locoregional control is excellent. Distant metastasis, however, remains a substantial problem. The purpose of our study was to evaluate outcomes and predictors of survival after distant metastasis in OPSCC. MATERIALS AND METHODS: Between June 2002 and January 2011, 25 OPSCC patients treated with curative intent subsequently developed distant metastasis. The primary end-points evaluated were time-to-distant metastasis and overall survival after development of distant metastasis. Predictors of outcome were evaluated with median regression analysis or Cox regression. Best subset models were chosen to minimize the Bayesian Information Criterion (BIC). A prognostic index for survival after distant failure was created based on the selected model. RESULTS: Median time-to-distant metastasis after completion of radiation was 7.9 months (range, 1.6-25.4). Median overall survival from distant metastasis was 18.3 months (95% CI, 14.3-39.8). The overall survival rates at 1- and 2-year after development of distant metastasis were 72.0% (95% confidence interval [CI], 53.4-89.6) and 40.8% (95% CI, 20.6-61.0), respectively. In multivariate analysis, Karnofsky Performance Status score (KPS) > or = 80 (p=0.01, hazard ratio [HR] 0.15, 95% CI, 0.04-0.52) and limited, single-organ disease (p=0.003, HR 0.13, 95% CI 0.03-0.61) predicted for increased survival from distant metastasis. Patients with both limited disease and good KPS formed the most favorable risk group with a 2-year survival of 100%. Two patients with human papilloma virus (HPV)-positive tumors were alive without any evidence of disease at 64.6 and 60.4 months, respectively, after aggressive local treatment of solitary metastasis. CONCLUSION: For OPSCC patients with limited, single-organ disease and good KPS, long-term survival can be achieved.
Assuntos
Carcinoma de Células Escamosas/secundário , Metástase Neoplásica , Neoplasias Orofaríngeas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/terapia , Prognóstico , Análise de Regressão , Análise de Sobrevida , Fatores de TempoRESUMO
PURPOSE: Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in intrahepatic cholangiocarcinoma. EXPERIMENTAL DESIGN: We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort. Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status, tumor burden, and a number of clinical variables. RESULTS: Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1/2-mutant (median, 478 ng/mL) versus IDH1/2-wild-type (median, 118 ng/mL) tumors (P < 0.001). This significance was maintained in the validation cohort (343 ng/mL vs. 55 ng/mL, P < 0.0001) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases (P < 0.05). Serum 2HG levels ≥170 ng/mL could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG. CONCLUSIONS: This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden. Clin Cancer Res; 20(7); 1884-90. ©2014 AACR.
Assuntos
Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/sangue , Colangiocarcinoma/genética , Glutaratos/sangue , Isocitrato Desidrogenase/genética , Adulto , Idoso , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/sangue , Colangiocarcinoma/patologia , Feminino , Humanos , Isocitrato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
BACKGROUND: Randomized trials have demonstrated that radiation improves survival in patients with glioblastoma. The purpose of this study was to characterize the risk factors and impact of omission of radiation therapy in such patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) program was used to identify 22,777 patients diagnosed with glioblastoma between 1988 and 2007. Multivariable logistic regression was employed to identify predictors associated with omission of radiation. Cox regression was used to characterize the impact of omitting radiation on all-cause mortality. RESULTS: Among the entire cohort, 16,863 of 22,777 patients (74%) received radiation, whereas 5914 of 22,777 patients (26%) did not. Factors associated with omission of radiation included older age (OR=1.048 per year increase, 95% CI=1.046-1.051, P<.001), lower annual income (OR=0.93 per $10,000 increase, 95% CI=0.90-0.96, P<.001), African American race (reference=white, OR=1.19, 95% CI=1.03-1.37, P=.02), Hispanic race (OR=1.34, 95% CI=1.19-1.50, P< .001), Asian American race (OR=1.24, 95% CI=1.04-1.48, P<.001), unmarried status (OR=1.71, 95% CI=1.60-1.83, P< .001), and subtotal resection/biopsy (OR=1.82, 95% CI=1.69-1.96, P<.001). The use of radiation was significantly associated with improved overall survival (2-year survival: 14.6% versus 4.2%, P<.001; adjusted HR=2.09, 95% CI=2.02-2.16, P<.001). When the population was restricted to patients <50 years old, these findings remained largely unchanged. CONCLUSIONS: Radiation therapy is associated with survival benefit in patients with glioblastoma, and sociodemographic factors play a significant role in the underutilization of radiation. The underlying causes for these disparities in care require further research.
Assuntos
Neoplasias do Sistema Nervoso Central/radioterapia , Glioblastoma/mortalidade , Glioblastoma/radioterapia , Radioterapia/estatística & dados numéricos , Negro ou Afro-Americano , Idoso , Asiático , Neoplasias do Sistema Nervoso Central/mortalidade , Feminino , Hispânico ou Latino , Humanos , Renda , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Programa de SEER , Fatores Socioeconômicos , Análise de SobrevidaRESUMO
PURPOSE: In this phase I study, we sought to determine the feasibility and tolerability of neoadjuvant short course radiotherapy (SC-CRT) delivered with photon RT with concurrent capecitabine for resectable pancreatic adenocarcinoma. MATERIALS AND METHODS: Ten patients with localized, resectable pancreatic adenocarcinoma were enrolled from December 2009 to August 2011. In dose level I, patients received 3 Gy × 10. In dose level 2, patients received 5 Gy × 5 (every other day). In dose level 3, patients received 5 Gy × 5 (consecutive days). Capecitabine was given during weeks 1 and 2. Surgery was performed 1-3 weeks after completion of chemotherapy. RESULTS: With an intended accrual of 12 patients, the study was closed early due to unexpected intraoperative complications. Compared to the companion phase I proton study, patients treated with photons had increased intraoperative RT fibrosis reported by surgeons (27% vs. 63%). Among those undergoing a Whipple resection, increased RT fibrosis translated to an increased mean OR time of 69 min. Dosimetric comparison revealed significantly increased low dose exposure to organs at risk for patients treated with photon RT. CONCLUSIONS: This phase I experience evaluating the tolerability of neoadjuvant SC-CRT with photon RT closed early due to unexpected intraoperative complications.