RESUMEN
BACKGROUND: No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III ß-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported. METHODS: We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival. RESULTS: Patients with TUBB3 protein levels >750 and <750 amol/µg were 21.9% and 78.1%, respectively, and were well-balanced between treatment arms. TUBB3 protein levels were not prognostic. Whereas no survival differences according to the 2 arms were observed in the subgroup with low TUBB3 expression (5-year OS 47% vs 40%; p = 0.44), patients with high TUBB3 had a clinically meaningful poorer OS when receiving docetaxel-based versus 5-FU/LV chemotherapy (5-year OS 31% vs 54%; p = 0.09), with a statistically significant interaction between TUBB3 and treatment (p = 0.049). CONCLUSIONS: The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Tubulina (Proteína)/metabolismo , Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Quimioterapia Adyuvante/métodos , Cisplatino/administración & dosificación , Docetaxel/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Pronóstico , Neoplasias Gástricas/metabolismo , Investigación Biomédica Traslacional/métodosRESUMEN
BACKGROUND: Patients with high microsatellite instability (MSI) gastric cancer (GC) show improved survival and no benefit or harm from adjuvant and/or perioperative chemotherapy. The role of immune microenvironment in GC is largely unknown. MATERIALS AND METHODS: In the present study, 256 tumor tissue blocks were centrally collected from patients enrolled in ITACA-S, a randomized adjuvant trial of 5-FU/LV versus sequential FOLFIRI and cisplatin-docetaxel. MSI status was assessed by multiplex PCR, inflammatory reaction by H&E morphological assessment, and programmed death-ligand 1 (PD-L1) expression by immunohistochemistry. RESULTS: Overall, 9% patients had MSI-high tumors, 23% had high inflammatory reaction, 11% had tumor PD-L1 ≥ 1%, and 11% had stromal PD-L1 ≥ 1%. A significant association with disease-free survival (DFS) and overall survival (OS) was found for MSI-high (hazard ratio [HR], 0.43; p = .02; HR, 0.40; p = .02) and high inflammatory reaction (HR, 0.55; p = .010; HR, 0.53; p = .008) but not for PD-L1. At multivariable analysis, only MSI showed an independent association with both DFS (p = .02) and OS (p = .01), whereas inflammatory reaction showed an independent association only with OS (p = .04). Patients with tumor PD-L1 ≥ 1% had a significantly longer DFS in sequential chemotherapy than in than 5-FU/LV arm (interaction p = .04) and a trend for OS (interaction p = .12). CONCLUSION: Our data suggest that MSI status could be a useful prognostic biomarker in patients with radically resected stage II-III GC and should be used as stratification factor in future trials. Tumor PD-L1 ≥ 1% should be further investigated as a potential predictor of benefit from intensive chemotherapy. IMPLICATIONS FOR PRACTICE: In this post hoc analysis of patients with radically resected gastric cancer randomized to an intensive sequential chemotherapy regimen versus 5-FU/LV monotherapy as adjuvant treatment in the ITACA-S trial, MSI-high status was independently associated with better disease-free survival and overall survival (OS) and inflammatory reaction was independently associated with better OS. Moreover, tumor PD-L1 expression ≥1% was associated with greater benefit from intensive sequential chemotherapy compared with 5-fluorouracil plus leucovorin (5-FU/LV), whereas PD-L1 expression <1% was not, conditioning a statistically significant interaction between such biomarker and treatment arms. The meta-analysis of individual patients' data from available studies could yield data on the role of MSI status that could inform clinical decisions.
Asunto(s)
Inestabilidad de Microsatélites , Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/genética , Quimioterapia Adyuvante , Cisplatino/uso terapéutico , Docetaxel/uso terapéutico , Fluorouracilo/uso terapéutico , Humanos , Pronóstico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Microambiente TumoralRESUMEN
BACKGROUND: In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy. OBJECTIVE: To assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radical metastasectomy in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400â¯mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves. RESULTS AND LIMITATIONS: At a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20-not available [NA]) in the observation arm versus 21 mo (95% CI 11-NA) in the sorafenib arm (log-rank test pâ¯=â¯0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3â¯AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm. CONCLUSIONS: This prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy. PATIENT SUMMARY: This article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/cirugía , Metastasectomía/métodos , Sorafenib/uso terapéutico , Adulto , Anciano , Antineoplásicos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sorafenib/farmacologíaRESUMEN
BACKGROUND: The differential diagnosis between diffuse malignant peritoneal mesothelioma (DMPM) and other peritoneal surface malignancies (PSM) is still challenging. Serum mesothelin and osteopontin are increasingly used as markers of pleural mesothelioma, but their role in DMPM is unclear. We assessed the diagnostic and prognostic values of mesothelin, osteopontin, CEA, CA19.9, CA125, and CA15.3 in DMPM patients. METHODS: Markers were dosed before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) by enzyme-linked immunosorbent assay (ELISA) in 30 DMPM patients and 14 controls with other PSMs. Receiver-operating characteristics (ROC) curve were plotted. The performance of each marker was assessed by the area under the ROC curve (AUC-ROC). RESULTS: Mean mesothelin levels were 7.84 ng/dl (SD = 5.14) in DMPM group and 3.00 ng/dl (SD = 1.25) in controls (P = 0.001). Mean CEA levels were 5.3 ng/dl (SD = 4.7), and 61.96 ng/dl (SD = 112.5) in the two groups (P = 0.008). No statistical difference was seen for osteopontin (P = 0.738), CA19.9 (P = 0.081), CA125 (P = 0.600), and CA15.3 (P = 0.365). AUC-ROC was 0.836 for CA19.9, 0.812 for mesothelin, 0.793 for CEA, and lower for CA125 (0.652), osteopontin (0.531), and CA15.3 (0.481). Using diagnostic cut-offs selected by ROC methodology, sensitivity, specificity, positive and negative predictive values were 70.0%, 100.0%, 100.0%, and 60.9% for mesothelin >5.21 ng/dl, and 90.0%, 85.7%, 93.1%, and 80.0% for CA19.9 < 8.8 U/dl. At multivariate analysis, osteopontin correlated with survival (hazard rate 6.46; 95%CI 1.81-23.05; P = 0.004). CONCLUSION: When assessing PSMs of unknown origin, elevated mesothelin with low CA19.9 may increase the suspicion index for DMPM. Ospeopontin warrants further investigations as a prognostic marker for DMPM.
Asunto(s)
Proteínas Ligadas a GPI/sangre , Mesotelioma/sangre , Osteopontina/sangre , Neoplasias Peritoneales/sangre , Adulto , Anciano , Antígenos de Neoplasias , Antineoplásicos/administración & dosificación , Biomarcadores de Tumor/sangre , Procedimientos Quirúrgicos de Citorreducción/métodos , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Humanos , Hipertermia Inducida/métodos , Inmunohistoquímica , Masculino , Mesotelina , Mesotelioma/diagnóstico , Mesotelioma/terapia , Persona de Mediana Edad , Neoplasias Peritoneales/diagnóstico , Neoplasias Peritoneales/terapia , Pronóstico , Curva ROC , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Encouraging results have been recently reported in selected patients affected by pseudomyxoma peritonei (PMP) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The selection factors predicting clinical outcome are still a matter of clinical investigation. We assessed the prognostic reliability of serum tumor markers in a large series of patients with PMP undergoing CRS and HIPEC. METHODS: Sixty-two patients with PMP were operated on at a single institution with the intent of performing adequate CRS (residual tumor nodules =2.5mm) and HIPEC. Baseline and serial marker measurements were prospectively collected and tested by multivariate analysis with respect to adequate cytoreduction, overall (OS) and progression-free (PFS) survival, along with the following variables: age, sex, performance status, prior surgical score, histological subtype, prior systemic chemotherapy, disease extent, completeness of cytoreduction. RESULTS: Baseline diagnostic sensitivity was 72.6% for CEA, 58.1% for CA19.9, 58.7% for CA125, 36.1% for CA15.3. Fifty-three patients underwent adequate CRS and HIPEC; gross residual tumor was left after surgery in nine. Adequate CRS was performed in 19/27 patients with elevated and in 19/19 with normal baseline CA125 (P = .0140). The other markers were unable to predict the completeness of CRS by univariate analysis. Baseline elevated CA19.9 was an independent predictor of reduced PFS; inadequate CRS and aggressive histology were independent prognostic factors for both reduced OS and PFS. CONCLUSION: Normal CA125 correlated to the likelihood to achieve adequate CRS, which is a significant prognostic factor for PMP. Increased baseline CA19.9 was an independent predictor of worse PFS after CRS and HIPEC.
Asunto(s)
Biomarcadores de Tumor/sangre , Hipertermia Inducida , Neoplasias Peritoneales/sangre , Neoplasias Peritoneales/terapia , Seudomixoma Peritoneal/sangre , Seudomixoma Peritoneal/terapia , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antineoplásicos/administración & dosificación , Antígeno Ca-125/sangre , Antígeno CA-19-9/sangre , Quimioterapia del Cáncer por Perfusión Regional/métodos , Cisplatino/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Mucina-1/sangre , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/cirugía , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Seudomixoma Peritoneal/mortalidad , Seudomixoma Peritoneal/cirugía , Radiografía Abdominal , Radiografía Torácica , Receptores de Superficie Celular/sangre , Sensibilidad y Especificidad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The aim of our study was to evaluate the efficacy and safety in unresectable or advanced renal carcinoma treated with sorafenib, in a situation closely similar to the everyday medical practice. PATIENTS AND METHODS: One hundred and thirty-six patients have been treated with 400 mg b.i.d. of sorafenib administered orally until disease progression or unacceptable toxicity. They were either previously untreated or relapsed after one or more previous treatments with systemic therapy. Most of them had clear cell renal carcinoma (RCC), but other histological types such as papillary, chromophobe, Bellini ducts, sarcomatoid and mixed forms were also represented. RESULTS: Overall disease control of 70.6% was achieved with 7.9% of partial remissions. Response was observed in the majority of patients with RCC, but also in some patients with non-clear cell RCC. Safety was acceptable, with the most common adverse events consisting of hand-foot skin reaction, cutaneous rash, diarrhoea, fatigue and hypertension. CONCLUSIONS: The results confirm previous ones reported in the literature concerning the efficacy and the safety of sorafenib as second-line treatment in patients with RCC. In addition, they disclose the hypothesis that sorafenib could be effective also in patients who underwent multiple previous treatments and in those with histology different from clear cells.