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BACKGROUND: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab has shown clinical benefit for metastatic colorectal cancer (mCRC) refractory to standard therapy. However, few data have been available for patients with pretreated mCRC who are intolerant of intensive therapy (vulnerable). METHODS: We performed a multicenter retrospective study (WJOG14520G; TWILIGHT) of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC. Eligibility criteria included previous chemotherapy (although patients treated with all key cytotoxic agents, a fluoropyrimidine, oxaliplatin, and irinotecan, were excluded) and intolerance of full-dose combination therapy with oxaliplatin or irinotecan at the start of FTD/TPI plus bevacizumab. RESULTS: The median age of 93 evaluable patients was 79 years (range, 21-90). Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and a poor performance status in 19 (20%) patients. FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as third- or fourth-line treatment in 19 (20%) patients. The objective response rate was 4.9% (95% confidence interval [CI], 1.4%-12.2%), and the disease control rate was 67.9% (95% CI, 56.6%-77.8%). With a median follow-up time of 21.6 months, median overall survival and progression-free survival were 18.6 months (95% CI, 12.1-23.2) and 6.3 months (95% CI, 5.0-8.3), respectively. Neutropenia of grade ≥3 developed in 50 (54%) patients, whereas 2 (2%) patients experienced febrile neutropenia, and no treatment-related death was observed. CONCLUSION: Our data show the potential efficacy and acceptable safety profile of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC.
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Neoplasias del Colon , Neoplasias Colorrectales , Demencia Frontotemporal , Pirrolidinas , Neoplasias del Recto , Timina , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Bevacizumab/efectos adversos , Neoplasias Colorrectales/patología , Estudios Retrospectivos , Uracilo , Oxaliplatino/uso terapéutico , Trifluridina/efectos adversos , Irinotecán/uso terapéutico , Demencia Frontotemporal/inducido químicamente , Demencia Frontotemporal/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Combinación de MedicamentosRESUMEN
BACKGROUND: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). METHODS: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. RESULTS: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). CONCLUSIONS: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.
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Nivolumab , Neoplasias Gástricas , Humanos , Nivolumab/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Estudios Retrospectivos , Japón , Ascitis , Pronóstico , Progresión de la EnfermedadRESUMEN
This study compared the bioavailability of two pimitespib formulations (Formulations A and B), evaluated the food effect on Formulation A, and evaluated the safety and efficacy of multiple pimitespib doses in patients with solid tumors. This clinical, pharmacological multicenter study had two cohorts and periods. A single dose of Formulation A or B was administered in a crossover design to compare the pharmacokinetics in Cohort 1. In Cohort 2, the effects of fed vs fasting conditions were evaluated among those receiving Formulation A. Subsequently, multiple Formulation A doses were administered to all patients for safety and efficacy assessments. In Cohorts 1 and 2, 12 and 16 patients, respectively, were analyzed for pharmacokinetics. Thirty patients were analyzed for safety and efficacy. Maximum concentration (Cmax), area under the curve (AUC)last, and AUCinf geometric mean ratios for Formulations A and B (90% confidence interval [CI]) were 0.8078 (0.6569-0.9933), 0.7973 (0.6672-0.9529), and 0.8094 (0.6697-0.9782), respectively; 90% CIs were not within the bioequivalence range (0.80-1.25). In Cohort 2, mean Cmax, AUClast, and AUCinf were higher in fed vs fasting conditions. No safety concerns emerged with single or multiple administration. Overall response rate, disease control rate, and median progression-free survival were 0%, 33%, and 1.5 months, respectively. Four patients had stable disease ≥ 5 months. Bioequivalence of the two formulations was unconfirmed. Systemic exposure of Formulation A was approximately 20% less than Formulation B. A high-fat/calorie meal increased the relative pharmacokinetics and bioavailability of a single 160-mg dose. Trial Registration: JapicCTI-184191 (Japan Pharmaceutical Information Center) registered on November 5, 2018.
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Antineoplásicos , Neoplasias , Administración Oral , Antineoplásicos/efectos adversos , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Humanos , Neoplasias/tratamiento farmacológico , Comprimidos , Equivalencia TerapéuticaRESUMEN
BACKGROUND: Gastric cancer with extensive lymph node metastasis(ELM)is commonly considered unresectable and has a poor prognosis. We conducted a phase â ¡ study to evaluate the safety and efficacy of capecitabine and cisplatin(XP)as preoperative chemotherapy for gastric cancer with ELM. METHODS: The patients received 2 21-day cycles of XP therapy(ca- pecitabine at 2,000mg/m2 twice daily for 2 weeks and cisplatin at 80 mg/m2 on day 1)followed by gastrectomy with D2 plus para-aortic nodal dissection. After R0 resection, S-1 chemotherapy was administered for 1 year. The primary end point was response rate(RR). The planned sample size was 30. RESULTS: Between April 2015 and November 2016, 4 patients were enrolled, but the enrollment was terminated because of poor patient recruitment. The clinical RR was 50%, and R0 resection was achieved in 75% of the patients. The common Grade 3 adverse events during XP therapy were leukocytopenia(25%), anemia(25%), and hyperlipidemia(25%). The common Grade 3 surgical morbidity was abdominal abscess(33%)and pancreatic fistula(33%). The pathological RR was 25%. CONCLUSIONS: Preoperative XP therapy was feasible, but its efficacy was difficult to evaluate because of the small sample size.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas , Capecitabina , Quimioterapia Adyuvante , Cisplatino , Humanos , Ganglios Linfáticos , Metástasis Linfática , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugíaRESUMEN
BACKGROUND: Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival. RESULTS: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. CONCLUSIONS: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Bevacizumab/efectos adversos , Cetuximab/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Camptotecina/efectos adversos , Fluorouracilo/efectos adversos , Neoplasias del Colon/etiología , Neoplasias del Recto/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucovorina/efectos adversosRESUMEN
BACKGROUND: Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has showed clinical benefits in patients with metastatic colorectal cancer. Periodontitis has been observed infrequently in bevacizumab-containing chemotherapy in clinical practice. The purpose of this study was to retrospectively investigate bevacizumab-related periodontitis in metastatic colorectal cancer patients. METHODS: From January 2008 to March 2010, 274 patients received bevacizumab-containing chemotherapy at the National Cancer Center Hospital in Tokyo. Patients who had consulted the dentist for periodontitis were included in the study. We examined the interval between the initiation of the first bevacizumab administration and the day of the consultation with the dentist. Periodontitis was evaluated before and after conservative therapy. RESULTS: Twenty-six patients (9.5 % of the 274 metastatic colorectal cancer patients) were included in this study. The median age was 60 years (range 30-79 years). Nineteen (73 %) patients had a good performance status of 0. The combination regimens used with bevacizumab were infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX, 53 %); infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI, 27 %); capecitabine + oxaliplatin (CapeOX, 8 %); S-1 + oxaliplatin (8 %); and S-1 + irinotecan (4 %). The median time from bevacizumab administration to the consultation with a dentist for periodontitis was 69 days (range 12-390 days), and the median number of bevacizumab administrations was 3.5 (range 1-25). After conservative therapy, 22 (85 %) patients with periodontitis showed an improvement. CONCLUSIONS: Periodontitis occurred frequently in patients receiving bevacizumab. The conservative therapy for periodontitis was very effective, and the prophylaxitic treatment was important.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Periodontitis/patología , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab , Camptotecina/análogos & derivados , Neoplasias Colorrectales/patología , Ciclofosfamida , Supervivencia sin Enfermedad , Doxorrubicina , Femenino , Fluorouracilo , Humanos , Leucovorina , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos , Periodontitis/inducido químicamente , Periodontitis/terapia , Prednisona , Estudios Retrospectivos , Resultado del Tratamiento , VindesinaRESUMEN
Bevacizumab (BV) is an antivascular endothelial growth factor antibody. When administered with other chemotherapeutic drugs, BV-combined regimens prolong survival of colorectal cancer patients. We conducted a phase II trial to confirm the pharmacokinetic parameters from 3-Tesla dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as surrogate biomarkers of BV + FOLFIRI regimen efficacy in colorectal cancer with liver metastases. DCE-MRI was performed before treatment, on the seventh day after first treatment and every 8 weeks thereafter using a 3-Tesla MRI system. DCE-MRI parameters-area under the contrast concentration versus time curve at 90 and 180 s (AUC90 and AUC180, respectively) after contrast injection, and volume transfer constant of contrast agents (K(trans) and K(ep) ) were calculated from liver metastases. Fifty-eight liver metastases were analyzed. Univariate analysis revealed that a decrease in K(trans) ratios (ΔK(trans) ), K(ep) ratios (ΔK(ep) ), AUC90 ratios (ΔAUC90) and AUC180 ratios (ΔAUC180) correlated with higher response (all p < 0.0001) and longer time to progression (TTP) (ΔK(trans) : p = 0.001; ΔK(ep) : p = 0.004; ΔAUC90: p = 0.006; ΔAUC180: p < 0.0001). Multivariate analysis showed that ΔAUC180 was correlated with higher response (p = 0.009), and ΔK(trans) and ΔAUC180 were correlated with longer TTP (ΔK(trans) : p = 0.001; ΔAUC180: p = 0.024). ΔK(trans) and ΔAUC180 are pharmacodynamic biomarkers of the blood perfusion of BV + FOLFIRI. Our data suggest that ΔK(trans) and ΔK(ep) can predict response to chemotherapy at 1 week. Changes in 3-Tesla DCE-MRI parameters confirmed the potential of these biomarkers of blood perfusion as surrogate predictors of response and TTP.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Hepáticas/secundario , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Bevacizumab , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/patología , Medios de Contraste , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
PURPOSE: We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone. PATIENTS AND METHODS: Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate). RESULTS: Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% (P < .001) and 0.3% versus 3.6% (P < .001), respectively. CONCLUSION: FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.
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Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Isoquinolinas/uso terapéutico , Morfolinas/uso terapéutico , Náusea/prevención & control , Antagonistas del Receptor de Neuroquinina-1/uso terapéutico , Piridinas/uso terapéutico , Quinuclidinas/uso terapéutico , Vómitos/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Antieméticos/efectos adversos , Dexametasona/uso terapéutico , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Isoquinolinas/efectos adversos , Japón , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Náusea/inducido químicamente , Náusea/diagnóstico , Antagonistas del Receptor de Neuroquinina-1/efectos adversos , Piridinas/efectos adversos , Quinuclidinas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Vómitos/inducido químicamente , Vómitos/diagnósticoRESUMEN
Bevacizumab is a humanized monoclonal antibody that contains <10% murine protein. To prevent infusion-related hypersensitivity reactions (HSRs), the initial bevacizumab infusion is delivered for 90 min, the second for 60 min and subsequent doses for 30 min. Several previous studies have shown that short bevacizumab infusions are safe and do not result in severe HSRs in patients with colorectal, lung, ovarian and brain cancer. However, the efficacy of short bevacizumab infusions for colorectal cancer management remains unclear. Therefore, to investigate this issue, a prospective multicenter study was conducted using 23 patients enrolled between June 2017 and March 2019. The initial infusion of bevacizumab was for 30 min followed by a second infusion rate of 0.5 mg/kg/min (5 mg/kg over 10 min and 7.5 mg/kg over 15 min. The primary endpoint was progression-free survival (PFS). The overall response and disease control rates were 57 and 87%, respectively. The median PFS time was 306 days (interquartile range, 204-743 days). No HSRs were noted. Adverse events associated with bevacizumab included grade 4 small intestinal perforation and grade 3 stroke in 1 patient each. These results suggest that a short bevacizumab infusion regime comprising an initial infusion for 30 min followed by a second infusion at 0.5 mg/kg/min is safe and efficacious for the management of colorectal cancer.
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INTRODUCTION: We describe the results of an exploratory analysis performed on the first head-to-head study (JapicCTI-194611) comparing two different intravenous (IV) neurokinin 1 (NK1) receptor antagonists, fosnetupitant and fosaprepitant, in combination with palonosetron (PALO) and dexamethasone (DEX) for the prevention of highly emetogenic chemotherapy (HEC)-induced nausea and vomiting (CINV). This analysis was performed to validate the findings of the primary analysis (previously published) utilizing a last observation carried forward (LOCF) approach for missing values for the efficacy endpoint of complete response (no emetic event and no rescue medication), while also evaluating the time periods encompassing the 0-168-hour (h) "extended overall phase" interval. METHODS: Patients scheduled to receive cisplatin-based chemotherapy were randomized 1:1 to fosnetupitant 235 mg or fosaprepitant 150 mg in combination with PALO 0.75 mg and DEX. Complete response rates were calculated and compared (stratified by age category and sex with a Mantel-Haenszel test) during the study's primary overall phase (0-120 h) and during additional time intervals of interest [acute (0-24 h), delayed (24-120 h), extended delayed (> 24-168 h), beyond delayed (120-168 h), and extended overall (0-168 h)]. RESULTS: A total of 785 patients were included (fosnetupitant N = 392, fosaprepitant N = 393). Complete response rates were numerically higher for fosnetupitant versus fosaprepitant for all time intervals and statistically significant for the extended overall phase. Complete response rates for fosnetupitant versus fosaprepitant during the overall, acute, delayed, extended delayed, beyond delayed, and extended overall phases were 75.5% vs. 71.0% (p = 0.1530), 93.9% vs. 92.6% (p = 0.4832), 77.0% vs. 72.8% (p = 0.1682), 74.7% vs. 68.4% (p = 0.0506), 86.7% vs. 81.7% (p = 0.0523), and 73.5% vs. 66.9% (p = 0.0450), respectively. CONCLUSION: In this exploratory analysis, fosnetupitant appeared to be more effective than fosaprepitant in preventing CINV associated with cisplatin-based HEC during the extended 7-day period following chemotherapy. INFOGRAPHIC.
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IMPORTANCE: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. OBJECTIVE: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. INTERVENTIONS: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. MAIN OUTCOMES AND MEASURES: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. RESULTS: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. CONCLUSIONS AND RELEVANCE: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. TRIAL REGISTRATION: UMIN Identifier: UMIN000016794.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Primarias Desconocidas , Afatinib/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/patología , Resultado del TratamientoRESUMEN
PURPOSE: Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. PATIENTS AND METHODS: Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. RESULTS: One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (20%). The 1-year survival rate was 44.0% and 54.9% for site-specific treatment and empirical PC ( P = .264), respectively. Median overall and progression-free survival were 9.8 and 5.1 months, respectively, for site-specific treatment versus 12.5 and 4.8 months for empirical PC ( P = .896 and .550, respectively). Median overall survival (16.7 v 10.6 months; P = .116) and progression-free survival (5.5 v 3.9 months; P = .018) were better for predicted more-responsive than less-responsive tumor types. CONCLUSION: Site-specific treatment that was based on microarray profiling did not result in a significant improvement in 1-year survival compared with empirical PC, although prediction of the original site seemed to be of prognostic value.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Carboplatino/uso terapéutico , Perfilación de la Expresión Génica , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Paclitaxel/uso terapéutico , Medicina de Precisión/métodos , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Carboplatino/efectos adversos , Femenino , Predisposición Genética a la Enfermedad , Humanos , Japón , Masculino , Persona de Mediana Edad , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/patología , Paclitaxel/efectos adversos , Selección de Paciente , Fenotipo , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Estudios Prospectivos , Factores de TiempoRESUMEN
BACKGROUND: In some recently updated clinical guidelines, the fully humanized monoclonal antibody panitumumab, combined with irinotecan, has been recommended as an optional third-line chemotherapy for KRAS wild-type metastatic colorectal cancer (mCRC). The present prospective, multicenter phase II study evaluated the effectiveness and safety of short 15-minute panitumumab infusions. PATIENTS AND METHODS: From January 2011 to December 2011, patients with KRAS wild-type mCRC were enrolled at 8 centers. The key eligibility criteria were age ≥ 20 years and resistance or intolerance to irinotecan, fluoropyrimidine, and oxaliplatin. All patients received 6 mg/kg of panitumumab and 150 mg/m2 or the previous tolerated dose of irinotecan, biweekly, until disease progression or unacceptable toxicity. The initial panitumumab infusion was 60 minutes, followed by a 30-minute infusion and then 15-minute infusions. The primary endpoint was the confirmed response rate using Response Evaluation Criteria In Solid Tumors, version 1.0. The secondary endpoints were progression-free survival, overall survival, and toxicity. The trial is registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN no. 000004647). RESULTS: Of the 43 patients, the median age was 62 years (range, 32-75 years), 58% were male, and the Eastern Cooperative Oncology Group performance status was 0 to 1. The total response rate was 37.2% (95% confidence interval [CI], 23.0-53.3), and the confirmed response rate was 18.6% (95% CI, 8.4-33.4). The median progression-free and overall survival were 5.8 months (95% CI, 3.3-8.4 months) and 13.6 months (95% CI, 10.8-16.5 months), respectively. The most frequent grade 3/4 toxicities were anorexia (12%), leukopenia (9%), and neutropenia (9%). Nine patients did not reach the 15-minute infusion, primarily because of disease progression. No infusion-related reactions were observed. CONCLUSION: The short 15-minute panitumumab infusion regimen was well tolerated, without compromising safety or efficacy in patients with KRAS wild-type, oxaliplatin- and irinotecan-refractory mCRC.
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Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Panitumumab/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias Colorrectales/mortalidad , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Infusiones Intravenosas , Irinotecán/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Oxaliplatino/administración & dosificación , Panitumumab/efectos adversos , Supervivencia sin Progresión , Estudios Prospectivos , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de TiempoRESUMEN
AIM: Cetuximab improves the prognosis for wild-type KRAS metastatic colorectal cancer (MCRC). We evaluated the safety and efficacy of cetuximab in combination with irinotecan in Japanese patients with wild-type KRAS MCRC refractory to irinotecan, oxaliplatin and fluoropyrimidines. METHODS: Cetuximab was administered initially at a dose of 400 mg/m2 , followed by weekly infusions at 250 mg/m2 . Irinotecan was administered every 2 weeks at 150 mg/m2 . Primary endpoint was the incidence of grade 3/4 adverse events; secondary endpoints included overall survival (OS), progression-free survival (PFS), response rate (RR), time to treatment failure (TTF), and TTF for irinotecan. RESULTS: Thirty-four patients were enrolled. Grade 3 or 4 toxicities were leucopenia (11.8%), neutropenia (23.5%), anemia (11.8%), fatigue (2.9%), anorexia (2.9%), diarrhea (14.7%) and hypomagnesemia (5.9%). Skin toxicities were as follows (any grade/grade 3): acne (94.2/8.8%), rash (55.9/0%), nail changes (75.5/8.8%) and hand-foot syndrome (55.9/5.9%). Median PFS was 6.0 months (95%CI; 4.7-7.4). Median OS was 12.9 months (95%CI; 10.0-15.9). RR was 26.4%. Median TTF was 5.1 months and median TTF for irinotecan was 5.0 months (95%CI; 4.3-5.6). CONCLUSION: Cetuximab with irinotecan therapy was well tolerated in Japanese patients with wild-type KRAS colorectal cancer refractory to irinotecan, oxaliplatin and fluoropyrimidine, thus demonstrating the feasibility of their usage.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas ras/efectos de los fármacos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Pueblo Asiatico , Camptotecina/administración & dosificación , Camptotecina/farmacología , Camptotecina/uso terapéutico , Cetuximab/administración & dosificación , Cetuximab/farmacología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Cholangiocarcinoma is an intractable carcinoma originating from the bile duct epithelium. To gain an understanding of the cell biology of cholangiocarcinoma, in vitro cell culture is valuable. However, wellcharacterized cell lines are limited. In the present study, the morphology of the TK cholangiocarcinoma cell line was analyzed by threedimensional culture. Dispersed TK cells were injected into a gelatin mesh scaffold and cultivated for 320 days. The morphology of the TK cells was investigated by phasecontrast microscopy, optical microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). TK cells were observed to proliferate three-dimensionally in the scaffold. The cells exhibited a globoid structure and attached to the scaffold. The SEM observation demonstrated typical microvilli and plicae on the surface of the structure. Light microscopy and TEM confirmed intercellular and celltoscaffold attachment in the threedimensional mesh. The culture also exhibited the formation of a duct-like structure covered by structured microvilli. In conclusion, threedimensional culture of TK cells demonstrated the morphological characteristics of cholangiocarcinoma in vitro. Production of high levels of carbohydrate antigen (CA)199, CA50 and carcinoembryonic antigen was previously confirmed in the TK cell line. As a characteristic morphology was demonstrated in the present study, the TK cholangiocarcinoma cell line may be useful as an experimental model for further study of cholangiocarcinoma.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Forma de la Célula , Colangiocarcinoma/patología , Línea Celular Tumoral , Estructuras de la Membrana Celular/metabolismo , Estructuras de la Membrana Celular/ultraestructura , Colangiocarcinoma/ultraestructura , Humanos , Andamios del TejidoRESUMEN
BACKGROUND: Typically, bevacizumab is initially infused for 90 min, then for 60 min, and subsequently for 30 min. The objective of the present study was to evaluate the safety profile of a short infusion of bevacizumab in Japanese colorectal cancer patients. PATIENTS AND METHODS: The records of 58 patients who received bevacizumab (5 mg/kg) from June 2010 to September 2010 were reviewed. Bevacizumab was administered for 30 min at the first time. If patients had no infusion reaction, the infusion time was shortened to 10 min. RESULTS: None of the 58 patients who received bevacizumab experienced an infusion reaction (95% confidence interval 0-6.2). The only serious adverse event related to bevacizumab infusion was grade 3 proteinuria in 2 patients. CONCLUSION: Short infusion of bevacizumab for 30 min the first time and 10 min is safe and feasible.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/patología , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Estudios RetrospectivosRESUMEN
Cholangiocarcinoma is a disease with a poor prognosis. A human cholangiocarcinoma cell line, TK, was previously established to enable further understanding of the disease. We conducted this investigation to determine whether or not the TK line is useful for pharmacokinetic study of the chemotherapeutic agent gemcitabine (GEM). Along with the BXPC3 human pancreatic adenocarcinoma cell line, the sensitivity to and effects on the TK cell line of GEM were compared. The influence of deoxycytidine kinase (dCK) transduction was also comparatively investigated. The effects of GEM in terms of drug sensitivity of the TK cell line, cell cycle and levels of transcripts of key enzymes were comparable to the BXPC3 cell line. Responses to the drug were similar in both cell lines. In contrast to pancreatic carcinoma, cell lines for research on cholangiocarcinoma have been limited. This study suggests the application of the TK cell line to the pharmacokinetic study of the chemosensitization of therapeutic drugs, such as GEM.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/efectos de los fármacos , Conductos Biliares Intrahepáticos/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colangiocarcinoma/patología , Desoxicitidina/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , GemcitabinaRESUMEN
BACKGROUND: Urocortin is analogous to corticotrophin-releasing factors (CRFs) and a member of the CRF family. We previously demonstrated that urocortin mRNAs were expressed in both human and rat glioma cell lines, and that some of these lines transcribed the receptors. We hypothesize that urocortin might also be expressed in a gastric cancer cell line. The aim of the present study was to clarify the expression of mRNAs of urocortin1 (UCN1), -2 and -3 and of CRF and CRF receptors 1 and 2 in a gastric cancer cell line. MATERIALS AND METHODS: STKM-1 a poorly-differentiated adenocarcinoma cell line was used. Transcripts in the cells were analyzed using cDNA. The fluctuation of mRNA with cellular stress, such as the one caused by a chemotherapeutic agent, serum supplementation and forskolin was examined. RESULTS: Transcripts of UCN1, -2 and CRFR2 were expressed. No changes in transcription of UCN1 and UCN2 were observed with cellular stress. However, expression of CRFR2 mRNA transcripts significantly increased after an initial 24-h exposure to forskolin. CONCLUSION: Expression of the mRNAs of UCN1, 2 and CRFR2 was confirmed in the human gastric cancer cell line, STKM-1. Although the quantity of CRFR2 transcripts varied with forskolin, the overall transcription pattern was not influenced by cellular stimuli.
Asunto(s)
ARN Mensajero/genética , Neoplasias Gástricas/genética , Urocortinas/genética , Secuencia de Bases , Línea Celular Tumoral , Cartilla de ADN , Humanos , Receptores de Hormona Liberadora de Corticotropina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Direct sequencing (DS) has often been used for detection of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. High-resolution melting analysis (HRMA) is another method to detect mutations by using a light scanner, and is more rapid, lower in cost, and more sensitive than DS. We confirmed correspondence between DS and HRMA for KRAS mutation detection in colorectal cancer (CRC). PATIENTS AND METHODS: From 102 patients with CRC, intended to receive cetuximab treatment at the National Cancer Center Hospital between September 2008 and July 2009, formalin-fixed paraffin-embedded tissues were retrospectively analyzed for KRAS status using HRMA and DS. Cetuximab efficacy was evaluated. RESULTS: Success rates of analysis by DS and HRMA were 100 out of the 102 patients (98.0%) and 99 out of the 102 patients (97.1%), respectively. The cases which failed by one method were analyzed by the other. KRAS mutant-type was detected by DS in 47 out of 100 samples (47.0%), and by HRMA in 45 out of 99 samples (45.5%). The concordance between the two methods was 94.8%. Forty-six out of the 53 patients with wild-type KRAS, as detected by DS received cetuximab and the response and disease control rates were 19.6% and 63.0%, respectively. With a median follow-up of 8.8 months, the median progression-free survival was 5.6 months and median overall survival was 11.1 months. The efficacy of two discordant cases which received cetuximab showed that the best responses were stable disease and progressive disease in one each, progression-free survival was 2.9 and 1.1 months and overall survival was 5.3 and 1.2 months, respectively. CONCLUSION: HRMA is a useful optional method for detection of KRAS mutations in CRC in light of accuracy, cost performance and rapidity.