RESUMEN
BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregional anal squamous cell carcinoma (ASCC) in western countries. However, there have been few reports on the clinical outcomes of CCRT in Japan. This study aimed to evaluate the clinical outcomes of CCRT, prognostic factors, and the clinical impact of programmed cell death-ligand 1 (PD-L1) expression of ASCC in Japan. METHODS: Patients with locoregional ASCC were enrolled between 2007 and 2017. All patients received CCRT consisting of ≥ 45 Gy of radiation, 5-fluorouracil, and mitomycin C. Disease-free survival (DFS), overall survival (OS), and adverse events (AEs) were estimated. Expression of p16 and PD-L1 were assessed by immunohistochemical staining (IHC). RESULTS: This study included 36 patients, of whom 30 (83.3%) were female. Among the participants, 32 (88.9%) achieved complete clinical remission, while six (16.7%) experienced recurrence. The five-year DFS and five-year OS were 72.2% and 84.7%, respectively. Grades ≥ 3 serious AEs included neutropenia in 10 (27.7%) and perianal dermatitis in eight (22.2%). In a univariate analysis, male sex, lymph node metastasis, and large tumor size were significantly associated with worse outcome. In a multivariate analysis, tumor size was an independent factor associated with short DFS. Of the 30 patients whose biopsy specimens were available for IHC, 29 (96.7%) were positive for p16, and 13 (43.3%) were positive for PD-L1. However, PD-L1 expression did not show any clinical impact. CONCLUSIONS: The comparative etiology, clinical outcomes, and prognostic factors of CCRT observed in Japanese patients with locoregional ASCC were consistent with western data.
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Neoplasias del Ano , Antígeno B7-H1 , Carcinoma de Células Escamosas , Quimioradioterapia , Humanos , Masculino , Femenino , Neoplasias del Ano/terapia , Neoplasias del Ano/patología , Neoplasias del Ano/mortalidad , Persona de Mediana Edad , Anciano , Japón , Pronóstico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Antígeno B7-H1/metabolismo , Adulto , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Mitomicina/administración & dosificación , Mitomicina/uso terapéutico , Supervivencia sin Enfermedad , Anciano de 80 o más Años , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Estudios Retrospectivos , Recurrencia Local de NeoplasiaRESUMEN
PURPOSE: The association between perioperative and post-adjuvant carcinoembryonic antigen (CEA) levels and recurrence and prognosis remains unclear. We aimed to evaluate whether perioperative CEA levels are an integral component of the assessment of recurrence and prognosis of patients with stage III colon cancer (CC). METHODS: This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 2005 to 2013. We enrolled patients with stage III CC who underwent complete resection of a primary tumor and received adjuvant chemotherapy. We analyzed the association between perioperative and post-adjuvant CEA levels and recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 564 consecutive patients were included in the analysis. The RFS and OS of patients with high postoperative CEA levels were significantly worse than those of patients with normal postoperative CEA levels. In the multivariate analysis, high postoperative CEA levels were associated with shorter RFS and OS. The number of risk factors, postoperative CEA levels, and T/N-stage all had a cumulative effect on RFS and OS. CONCLUSIONS: High postoperative CEA levels and the number of risk factors are associated with recurrence and worse prognosis for patients with stage III CC.
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Antígeno Carcinoembrionario , Neoplasias del Colon , Estadificación de Neoplasias , Humanos , Antígeno Carcinoembrionario/sangre , Neoplasias del Colon/cirugía , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Neoplasias del Colon/sangre , Neoplasias del Colon/tratamiento farmacológico , Quimioterapia Adyuvante , Femenino , Masculino , Estudios Retrospectivos , Anciano , Pronóstico , Persona de Mediana Edad , Factores de Riesgo , Tasa de Supervivencia , Recurrencia Local de Neoplasia , Anciano de 80 o más Años , Adulto , Biomarcadores de Tumor/sangre , Periodo PosoperatorioRESUMEN
INTRODUCTION: This study aimed to extract prognostic factors in patients undergoing neoadjuvant chemotherapy (NAC) for borderline resectable colorectal liver metastasis (BR-CRLM) (tumor size ≥5 cm, number of tumors ≥4, or resectable extrahepatic diseases) and assess validity of this strategy. MATERIALS AND METHODS: Since 2010, patients with BR-CRLM were treated with hepatectomy after six cycles of NAC. Prognostic factors of these patients were evaluated using clinicopathological data. RESULTS: Of 650 patients who underwent initial hepatectomy for CRLM from 2010 to 2018, 246 BR-CRLM cases underwent hepatectomy after NAC (BR-NAC). The 5-year recurrence-free survival rate was 16.7% and the 5-year overall survival rate (5y-OS) was 52.9%. Number of tumors ≥6, carcinoembryonic antigen (CEA) level ≥25 ng/mL, tumor diameter ≥5 cm, and progressive disease (PD) after NAC were identified as independent poor prognostic factors for OS. Patients were divided into four groups according to the number of risk factors, and prognoses of the four groups were well stratified. CONCLUSION: In patients with BR-NAC, number of tumors ≥6, CEA ≥25 ng/mL, tumor diameter ≥5 cm, and PD after NAC were independent poor prognostic factors. Patients with three or four risk factors showed poor prognosis and may need to switch chemotherapy.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Estudios Retrospectivos , Terapia Neoadyuvante/efectos adversos , Antígeno Carcinoembrionario , Neoplasias Colorrectales/patología , Pronóstico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , HepatectomíaRESUMEN
BACKGROUND: This study aimed to investigate whether the addition of induction chemotherapy before chemoradiotherapy (CRT) and total mesorectal excision (TME) with selective lateral lymph node dissection improves disease-free survival for patients with poor-risk, mid-to-low rectal cancer. METHODS: The authors' institutional prospective database was queried for consecutive patients with clinical stage II or III, primary, poor-risk, mid-to-low rectal cancer who received neoadjuvant treatment followed by TME from 2004 to 2019. The outcomes for the patients who received induction chemotherapy before neoadjuvant CRT (induction-CRT group) were compared (via log-rank tests) with those for a propensity score-matched cohort of patients who received neoadjuvant CRT without induction chemotherapy (CRT group). RESULTS: From 715 eligible patients, the study selected two matched cohorts with 130 patients each. The median follow-up duration was 5.4 years for the CRT group and 4.1 years for the induction-CRT group. The induction-CRT group had significantly higher rates of 3-year disease-free survival (83.5 % vs 71.4 %; p = 0.015), distant metastasis-free survival (84.3 % vs 75.2 %; p = 0.049), and local recurrence-free survival (98.4 % vs 94.4 %; p = 0.048) than the CRT group. The pathologically complete response rate also was higher in the induction-CRT group than in the CRT group (26.2 % vs 10.0 %; p < 0.001). Postoperative major complications (Clavien-Dindo classification ≥III) did not differ significantly between the two groups (12.3 % vs 10.8 %; p = 0.698). CONCLUSIONS: The addition of induction chemotherapy to neoadjuvant CRT appeared to improve oncologic outcomes significantly, including disease-free survival, for the patients with poor-risk, mid-to-low rectal cancer who underwent TME using selective lateral lymph node dissection.
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Quimioterapia de Inducción , Escisión del Ganglio Linfático , Neoplasias del Recto , Humanos , Quimioradioterapia , Terapia Neoadyuvante , Estadificación de Neoplasias , Puntaje de Propensión , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Although patients with resectable colorectal liver metastasis (CLM), a population with good prognosis, have been treated with upfront surgery, some patients have had a poor prognosis. This study aimed to investigate biologic prognostic factors in patients with resectable CLMs. METHODS: This single-center retrospective study enrolled consecutive patients who underwent liver resection for initial CLMs at the Cancer Institute Hospital between 2010 and 2020. The study defined CLMs as resectable (tumor size < 5 cm; < 4 tumors; no extrahepatic metastasis) or borderline resectable (BR). Preoperative chemotherapy was administered to patients with BR CLMs. RESULTS: During the study period, 309 CLMs were classified as resectable without preoperative chemotherapy and 345 as BR with preoperative chemotherapy. For the 309 patients with resectable CLMs, the independent poor prognostic factors associated with overall survival in the multivariable analysis were high tumor marker levels (CEA ≥ 25 ng/mL and/or CA19-9 ≥ 50 U/mL; (hazard ratio [HR], 2.45; p = 0.0007), no adjuvant chemotherapy (HR, 1.69; p = 0.043), and age of 75 years or older (HR, 2.09; p = 0.012). The 5-year survival rates for the patients with high tumor marker (TM) levels (CEA ≥25 ng/mL and/or CA19-9 ≥50 U/mL) were significantly worse than for those with low TM levels (CEA < 25 ng/mL and CA19-9 < 50 U/mL) (55.3% vs. 81.1%; p <0.0001) and similar to the rate for those with BR CLMs (52.1%; p = 0.864). Postoperative adjuvant chemotherapy had an impact on prognosis only in the high-TM group (HR, 2.65; p = 0.007). CONCLUSIONS: High TM levels have a prognostic impact on patients with resectable CLMs stratified by tumor number and size. Perioperative chemotherapy improves long-term outcomes for patients with CLM and high TM levels.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Anciano , Pronóstico , Biomarcadores de Tumor , Antígeno CA-19-9 , Neoplasias Colorrectales/patología , Estudios Retrospectivos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patologíaRESUMEN
BACKGROUND: Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. METHODS: This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. RESULTS: Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). CONCLUSION: Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias Pulmonares , Neoplasias del Recto , Humanos , Irinotecán/uso terapéutico , Neoplasias Colorrectales/patología , Factor A de Crecimiento Endotelial Vascular , Camptotecina , Pronóstico , Leucovorina , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fluorouracilo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Neoplasias Pulmonares/etiología , Metástasis de la Neoplasia/tratamiento farmacológicoRESUMEN
BACKGROUND: Regorafenib, a multikinase inhibitor, causes a high frequency of hand-foot skin reactions (HFSRs). The present study evaluated the efficacy of topical aluminum chloride, a perspiration suppressant, in reducing the severity of hand-foot skin reactions (HFSRs) caused by regorafenib. METHODS: The present single-arm study included patients with metastatic colorectal cancer receiving regorafenib. Aluminum chloride ointment was applied topically one week prior to the start of regorafenib treatment, and the observation period was 12 weeks. The primary endpoint was the incidence of regorafenib-related grade 3 HFSR. Secondary endpoints were the incidence of all grades of HFSR, time to any grade of HFSR, time to improvement from grade 2 or higher to grade 1 or lower, treatment discontinuation rate, treatment interruption rate or dosage reduction due to HFSR, and incidence of adverse effects of aluminum chloride. RESULTS: In total 28 patients were enrolled, and 27 patients were analyzed. The incidence of grade 3 HFSR was 7.4%, meeting the primary endpoint. The incidence of all grades of HFSR was 66.7%, and the median time to the occurrence of any grade of HFSR was 15 days. No patients discontinued or reduced the regorafenib dosage because of HFSR. The most common reason for the interruption of regorafenib therapy was liver dysfunction in nine patients (33%) and HFSR in three patients (11%). No serious adverse events related to aluminum chloride were observed. CONCLUSIONS: Aluminum chloride ointment, a drug commonly used in routine practice to treat hyperhidrosis, is safe to use, has no serious side effects, and may be effective in reducing the occurrence of severe, regorafenib-related HFSR. TRAIL REGISTRATION: ClinicalTrials.gov. identifier: jRCTs031180096, Registered on 25/01/2019.
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Compuestos de Fenilurea , Piel , Humanos , Cloruro de Aluminio/farmacología , Pomadas/farmacología , Compuestos de Fenilurea/efectos adversos , Piel/patologíaRESUMEN
BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.
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Carcinoma Adenoescamoso , Neoplasias Colorrectales , Humanos , Cetuximab/efectos adversos , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/cirugíaRESUMEN
BACKGROUND: Alpha-Fetoprotein Producing Gastric Cancer (AFPGC) is an aggressive subgroup of gastric cancer. Recently ramucirumab has shown survival benefits in hepatocellular carcinoma, but only in those with higher Alpha-Fetoprotein (AFP) levels. However, the efficacy of ramucirumab-containing chemotherapy in AFPGC remains unclear. METHODS: We retrospectively assessed 352 patients who received ramucirumab-containing chemotherapy between June 2015 and December 2019. AFPGC was defined when serum AFP levels were elevated at diagnosis and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal at diagnosis. RESULTS: Among the 352 patients, 28 patients were defined as AFPGC and 246 patients were defined as non-AFPGC. AFPGC was characterized by high frequency of liver metastasis and low frequency of peritoneal metastasis compared to non-AFPGC. Ramucirumab containing chemotherapy showed higher response rates in AFPGC (39.1% vs 24.8%, p = 0.198) and disease control rates (86.9% vs 61.5%, p = 0.028) than those of non-AFPGC, respectively. Median progression-free survival (PFS) was 5.5 months (95%CI 3.9-7.1) in AFPGC and 4.0 months (95%CI 3.6-4.6) in non-AFPGC (HR: 0.91, 95% CI 0.61-1.36, p = 0.66), and median overall survival (OS) was 10.7 months (95% CI 7.4-20.8) in AFPGC and 9.2 months (95% CI 8.1-10.4) in non-AFPGC (HR: 0.72, 95% CI 0.48-1.08, p = 0.11), respectively. In multivariate analysis, AFPGC was not a negative prognostic factor both for PFS and OS. CONCLUSION: Ramucirumab containing chemotherapy showed higher response and comparable survival in AFPGC compared to those of non-AFPGC. Considering the generally poor prognosis of AFPGC, ramucirumab-containing chemotherapy might be a promising treatment option in AFPGC.
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Neoplasias Gástricas , alfa-Fetoproteínas , Humanos , alfa-Fetoproteínas/análisis , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , RamucirumabRESUMEN
BACKGROUND: Morphologic response (MR) is a novel chemotherapeutic efficacy predictor of solid tumors, especially those treated with anti-vascular endothelial growth factor antibodies. Nevertheless, the importance of systemic chemotherapy MR for colorectal liver metastases (CLM) remains unclear. We aimed to evaluate the usefulness of MR as a factor associated with the therapeutic effects of chemotherapy plus bevacizumab for initially unresectable CLM cases. METHODS: We retrospectively evaluated the associations between MR and/or Response Evaluation Criteria in Solid Tumors (RECIST), progression-free survival (PFS), and overall survival (OS) in patients who received first-line capecitabine, oxaliplatin, and bevacizumab treatment for initially unresectable CLM using multivariate analysis. Patients who showed a complete or partial response based on the RECIST, or an optimal response based on MR, were defined as "responders." RESULTS: Ninety-two patients were examined, including 31 (33%) patients who responded optimally. PFS and OS estimates were comparable in MR responders and non-responders (13.6 vs. 11.6 months, p = 0.47; 26.6 vs. 24.6 months, p = 0.21, respectively). RECIST responders showed better PFS and OS than non-responders (14.8 vs. 8.6 months, p < 0.01; 30.7 vs. 17.8 months, p < 0.01, respectively). The median PFS and OS estimates of MR and RECIST responders were better than those of single responders or non-responders (p < 0.01). Histological type and RECIST response were independently associated with PFS and OS. CONCLUSION: MR predicts neither PFS nor OS; nevertheless, it may be useful when combined with the RECIST. The Ethics Committee of The Cancer Institute Hospital of JFCR approved this study in 2017 (No. 2017-GA-1123): retrospectively registered.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias Hepáticas , Neoplasias del Recto , Humanos , Bevacizumab/uso terapéutico , Oxaliplatino/uso terapéutico , Capecitabina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Oncogenic mutations in BRAF genes are found in approximately 5-10% of colorectal cancers. The majority of BRAF mutations are located within exons 11-15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation. METHODS: HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis. RESULTS: The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance. CONCLUSIONS: We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.
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Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas c-akt , Humanos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Células HEK293 , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Mutación , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismoRESUMEN
DNA methylation status correlates with clinical outcomes of anti-epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who had previously received anti-EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly methylated colorectal cancer (HMCC) or low-methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor-derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; P = .004), progression-free survival (median: 2.5 vs 6.6 mo, P < .001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 mo, P < .001, HR = 0.23) than did LMCC in patients with RAS wild-type mCRC who were refractory or intolerable to oxaliplatin- and irinotecan-based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti-EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting.
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Neoplasias Colorrectales/genética , Metilación de ADN , Receptores ErbB/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Islas de CpG/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Análisis de Secuencia por Matrices de Oligonucleótidos , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas p21(ras)/genética , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: In the past decade, several successful clinical trials provided new therapeutic agents approved for advanced gastric cancer (AGC). This study evaluated whether these practice-changing results actually altered the clinical practice. PATIENTS AND METHODS: We retrospectively reviewed medical records of treatment-naive AGC patients who received combination chemotherapy of fluoropyrimidine and platinum between 2007 and 2018 and divided them into three groups: Groups A (2007-10), B (2011-14), and C (2015-2018), respectively. We compared the clinicopathological features, treatment details, and clinical outcomes among the three groups. RESULTS: In total, 1004 consecutive patients were enrolled (A; n = 254, B; n = 300, and C; n = 450). The number of patients with poor performance status, older age, esophagogastric junction adenocarcinoma, and primary tumor increased during the study period. All groups had similar median overall survival (OS); ~16 months) without any statistical difference but steady prolongation of survival was observed in the adjusted with imbalance prognostic factors among groups (B/A; hazard ratio, HR 0.82, 95% C.I 0.68-0.98, C/A; HR 0.72, 95% CI 0.60-0.86); OS of HER2-positive AGC patients was clearly improved (HER2-positive vs HER2-negative in Group B, HR 0.80, 95% CI 0.60-1.06; Group C, HR 0.68, 95% CI 0.51-0.90) but that of diffuse-type AGC patients remained dismal. CONCLUSIONS: The increasing availability of chemotherapy options potentially contributed to improved survival of AGC patients, but expanded chemotherapeutic indications made the survival benefit inconspicuous in the whole population. Future therapeutic development for the AGC subset not adequately receiving benefit from previous clinical trials is warranted.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Colorectal cancer with liver metastasis (CLM) has high postoperative recurrence rates; therefore, optimizing perioperative treatment is imperative. Postoperative carcinoembryonic antigen (CEA) can aid in detecting minimal residual disease in colon cancer following curative resection. This study aimed to identify the potential role of serum CEA following liver resection in patients with CLM. METHODS: This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 2004 to 2018 and enrolled patients with CLM who underwent complete resection of primary tumors and CLM. Associations between perioperative CEA levels and characteristics of recurrence were investigated. RESULTS: Recurrence was detected during a median follow-up period of 90.1 months in 343 (54.2%) out of 633 analyzed patients. Patients in the postoperative CEA level > 5 ng/ml group had a significantly higher recurrence rate (75.7% versus 50.0%, p < 0.01) and shorter time until recurrence (4.4 versus 36.9 months, p < 0.01) than those in the postoperative CEA level ≤ 5 ng/ml group. Multivariate analysis revealed that postoperative CEA level > 5 ng/ml was an independent predictor, with hazard ratios of 2.77 (p < 0.01) for recurrence-free survival (RFS) and 3.18 (p < 0.01) for overall survival (OS). Additionally, RFS was significantly shorter among patients in the postoperative CEA level > 5 ng/ml group who did not have normalized CEA levels following adjuvant chemotherapy than among those in the normalized CEA group. CONCLUSIONS: The postoperative and post-adjuvant chemotherapy CEA levels in the CEA level > 5 ng/ml group may be predictors of RFS and OS.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Antígeno Carcinoembrionario , Estudios Retrospectivos , Neoplasias Colorrectales/patología , Pronóstico , Neoplasias Hepáticas/secundario , Recurrencia Local de Neoplasia/cirugía , Recurrencia Local de Neoplasia/diagnósticoRESUMEN
PURPOSE: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors. METHODS: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P < 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS. CONCLUSIONS: Genome-wide DNA methylation status is an independent factor associated with PFS in patients with mCRC treated with first-line EGFR inhibitors.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Neoplasias del Colon/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Islas de CpG , Metilación de ADN/genética , Receptores ErbB/genética , Humanos , Mutación/genética , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias del Recto/genéticaRESUMEN
BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge. METHODS: This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360). DISCUSSION: Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative. TRIAL REGISTRATION: The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Irinotecán/administración & dosificación , Panitumumab/administración & dosificación , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Ensayos Clínicos Fase II como Asunto , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Humanos , Irinotecán/efectos adversos , Japón , Biopsia Líquida , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Estudios Observacionales como Asunto , Panitumumab/efectos adversos , Estudios Prospectivos , Resultado del Tratamiento , Proteínas ras/sangre , Proteínas ras/genéticaRESUMEN
Coronavirus disease 2019 (COVID-19) was declared to be a global pandemic by the World Health Organization on March 11, 2020. On April 7, 2020, a state of emergency was declared in Japan, as had been by other nations worldwide. This unprecedented crisis has profound implications for patients undergoing chemotherapy and for practicing healthcare professionals. Various reports have shown data indicating that cancer patients with COVID-19 have high morbidity and mortality rates. In order to reduce the use of medical resources to avoid the risk of COVID-19 infections in both cancer patients and health care providers, oncologists now have to draw the line for cancer treatments by maintaining their efficacy while avoiding severe adverse events. In this article, we outlined the decisions made regarding the practice of gastrointestinal oncology in our institution during the COVID pandemic.
Asunto(s)
Antineoplásicos/uso terapéutico , COVID-19 , Instituciones Oncológicas/organización & administración , Neoplasias Gastrointestinales/tratamiento farmacológico , Oncología Médica/organización & administración , Oncólogos/psicología , Humanos , Control de Infecciones , Japón , Pandemias , Guías de Práctica Clínica como Asunto , SARS-CoV-2RESUMEN
To assess the efficacy and safety of ramucirumab in combination with FOLFIRI in patients with unresectable metastatic colorectal cancer under clinical practice in Japan, we reviewed manuscripts reporting clinical research, including case reports, of Japanese patients with FOLFIRI plus ramucirumab therapy published starting from 2016, when ramucirumab was approved as a treatment for metastatic colorectal cancer in Japan, to June 2020. We also reviewed an interim report of post-marketing surveillance study. The efficacy of ramucirumab in combination with FOLFIRI including irinotecan 150 mg/m2, which is the recommended dose in Japan and is used as initial dose in Japanese clinical practice, was similar to that of the global, phase 3 RAISE study with irinotecan 180 mg/m2. The desirable effect of FOLFIRI plus ramucirumab was observed in patients with wild-type RAS, primary tumors on the left sides(descending, sigmoid, or rectum colons), or who received anti-epidermal growth factor receptor agents, including panitumumab or cetuximab, as previous treatment. Also, the effectiveness of FOLFIRI plus ramucirumab as a late-line treatment was suggested. Several patients were reported to have nephrosis syndrome after starting ramucirumab, but they recovered with discontinuation of ramucirumab and appropriate treatment. No new safety concerns were observed from the literature or the interim report of post-marketing surveillance study.
Asunto(s)
Camptotecina , Neoplasias Colorrectales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Humanos , Japón , Leucovorina/uso terapéutico , Metástasis de la Neoplasia , RamucirumabRESUMEN
BACKGROUND: Although the prognosis for patients with resected BRAF mutant colorectal liver metastases (CRLM) is poor, the survival impact of the BRAF V600E mutation in such cases remains unclear. METHODS: A multicenter retrospective cohort study was performed to investigate the survival outcomes of patients who underwent initial hepatectomy for histologically confirmed BRAF V600E mutant CRLM between January 2005 and December 2017. RESULTS: Thirty-three patients from 6 institutions were included in this study. During the median duration of the post-hepatectomy follow-up period of 49.2 months, 31 patients (93.9%) developed recurrence after a median period of 5.3 months and the 1-year recurrence-free survival (RFS) rate was 24.2%. Only two patients underwent repeated surgery for recurrence. The other 29 patients had unresectable recurrent lesions, and 27 of them received systemic chemotherapy. The median overall survival (OS) period was 31.1 months and the 5-year OS rate was 18.2%. The factors for a poor RFS prognosis were an elevated serum CA19-9 level (≥ 37 IU/ml) at hepatectomy (HR: 2.139, 95% CI: 1.009-4.534, P = 0.047) and R1 resection (HR: 5.827, 95% CI: 1.585-21.42, P = 0.008), and that for OS was R1 resection only (HR: 4.129, 95% CI: 1.104-15.45, P = 0.035). CONCLUSIONS: Since the early onset unresectable recurrence rate was very high, systemic chemotherapy should be considered for resectable BRAF V600E mutant CRLM. A novel perioperative treatment strategy is needed to improve the survival of such patients.
Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Estudios de Cohortes , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/cirugía , Hepatectomía , Humanos , Japón/epidemiología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Mutación , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: The effect of cetuximab plus mFOLFOX on downsizing of the tumors for curative resection has yet to be assessed for patients with advanced colorectal liver metastases (CRLMs). This study aimed to assess the oncologic benefit of cetuximab plus mFOLFOX for wild-type KRAS patients with advanced CRLMs. METHODS: In this multicenter phase 2 trial, patients with technically unresectable tumor and/or five or more CRLMs harboring wild-type KRAS were treated with mFOLFOX plus cetuximab. The patients were assessed for resectability after 4 treatments, and then every 2 months up to 12 treatments. Patients with resectable disease were offered surgery after a waiting period of 1 month. The primary end point of the study was the R0 resection rate. The secondary end points were safety, progression-free survival (PFS), and overall survival (OS). The study is registered with the University Hospital Medical Information Network-Clinical Trials Registry Clinical Trials Registry (no. C000007923). RESULTS: Between 2012 and 2015, 50 patients from 13 centers were enrolled in this trial. Two patients were excluded because they had not received induction therapy. The 48 patients had a complete response rate of 0% and a partial response rate of 64.6%. For 26 R0 resections (54.2%) and 5 R1 resections (10.4%), no mortality occurred. During a median follow-up period of 31 months, the median OS for all the patients was calculated to be 41 months (95% confidence interval, 28-not reached). The 3-year OS rate was 59%. CONCLUSION: For patients with advanced CRLMs harboring wild-type KRAS, cetuximab administered in combination with mFOLFOX yields high response rates, leading to significantly high R0 resection rates and favorable prognoses.