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1.
Nat Med ; 30(3): 730-739, 2024 Mar.
Article de Anglais | MEDLINE | ID: mdl-38347302

RÉSUMÉ

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .


Sujet(s)
Tumeurs du côlon , Tumeurs colorectales , Tumeurs du rectum , Humains , Panitumumab/usage thérapeutique , Bévacizumab/usage thérapeutique , Anticorps monoclonaux/usage thérapeutique , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/génétique , Tumeurs colorectales/anatomopathologie , Tumeurs du côlon/traitement médicamenteux , Tumeurs du rectum/traitement médicamenteux , Marqueurs biologiques , Récepteurs ErbB/génétique , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protéines proto-oncogènes p21(ras)
2.
J Gastrointest Oncol ; 14(2): 676-691, 2023 Apr 29.
Article de Anglais | MEDLINE | ID: mdl-37201044

RÉSUMÉ

Background: Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment. Methods: Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay. Results: Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months]. Conclusions: Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.

3.
Respir Med Case Rep ; 44: 101865, 2023.
Article de Anglais | MEDLINE | ID: mdl-37214592

RÉSUMÉ

Lung metastasis is an uncommon cause of multiple cavitary lung lesions. Herein, we report a case of multiple cavitary lung lesions of colorectal cancer that responded to chemotherapy. An 81-year-old woman was referred to our hospital for abdominal pain. Computed tomography revealed multiple cavitary lung lesions. The patient was diagnosed with lung metastases from colorectal cancer with a lower gastrointestinal endoscopy and bronchoscopy. Following chemotherapy, the cavitary lung lesions shrank. Lung metastases from colorectal cancer may appear as multiple cavitary lung lesions, which may be misdiagnosed as infections. Clinicians should consider lung metastases when multiple cavitary lung lesions are detected.

4.
JAMA ; 329(15): 1271-1282, 2023 04 18.
Article de Anglais | MEDLINE | ID: mdl-37071094

RÉSUMÉ

Importance: For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined. Objective: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer. Design, Setting, and Participants: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022). Interventions: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. Main Outcomes and Measures: The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate. Results: In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%). Conclusions and Relevance: Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population. Trial Registration: ClinicalTrials.gov Identifier: NCT02394795.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique , Bévacizumab , Tumeurs colorectales , Panitumumab , Sujet âgé , Femelle , Humains , Mâle , Anticorps monoclonaux/administration et posologie , Anticorps monoclonaux/effets indésirables , Anticorps monoclonaux/usage thérapeutique , Antinéoplasiques/administration et posologie , Antinéoplasiques/effets indésirables , Antinéoplasiques/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Bévacizumab/administration et posologie , Bévacizumab/effets indésirables , Bévacizumab/usage thérapeutique , Tumeurs du côlon/traitement médicamenteux , Tumeurs du côlon/génétique , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/génétique , Fluorouracil/administration et posologie , Leucovorine/administration et posologie , Panitumumab/administration et posologie , Panitumumab/effets indésirables , Panitumumab/usage thérapeutique , Oxaliplatine/administration et posologie , Récepteurs ErbB/antagonistes et inhibiteurs , Facteurs de croissance endothéliale vasculaire/antagonistes et inhibiteurs
5.
Head Neck ; 45(5): E10-E15, 2023 05.
Article de Anglais | MEDLINE | ID: mdl-36924196

RÉSUMÉ

BACKGROUND: The efficacy of entrectinib, a potent inhibitor of tropomyosin receptor kinases, c-ros oncogene 1, and anaplastic lymphoma kinase has been demonstrated in neurotrophic receptor tyrosine kinase fusion-positive pediatric and adult solid tumors. However, real-world data on entrectinib therapy for salivary gland malignancies are limited. METHODS: We describe a multicenter case series of four consecutive patients with ETV6-NTRK3 fusion-positive metastatic salivary secretory carcinoma (SSC) treated with entrectinib. RESULTS: All patients had a prior history of systemic therapy with cytotoxic chemotherapy or immune checkpoint inhibitors. All patients achieved durable radiographic complete response. Adverse events included weight gain, dizziness, increase in creatine kinase level, and withdrawal pain, but were manageable by the interruption and dose reduction of entrectinib. CONCLUSION: Durable complete response was achieved with entrectinib in patients with ETV6-NTRK3 fusion-positive metastatic SSC. The clinical benefit of entrectinib supports the importance of routine screening for NTRK gene fusion in patients with SSC.


Sujet(s)
Carcinomes , Tropomyosine , Adulte , Humains , Enfant , Protéines de fusion oncogènes/génétique , Carcinomes/anatomopathologie
6.
Anticancer Res ; 42(4): 2009-2015, 2022 04.
Article de Anglais | MEDLINE | ID: mdl-35347022

RÉSUMÉ

BACKGROUND/AIM: This phase II study assessed the efficacy of capecitabine plus cisplatin in patients with advanced gastric cancer refractory to adjuvant S-1. PATIENTS AND METHODS: This single-arm, open-label, multicenter, phase II study was conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE) in Japan. Patients aged ≥20 years with advanced HER2-negative gastric cancer that was refractory to S-1 were enrolled. Patients received 80 mg/m2 cisplatin on day 1 intravenously and 1,000 mg/m2 capecitabine twice daily from day 1 to day 14, in 3-week cycles. The primary endpoint was progression-free survival (PFS). The threshold overall response rate (ORR) was estimated to be 15%. The secondary endpoints were overall survival (OS), time to treatment failure, ORR, and toxicities. RESULTS: In total, 21 patients were enrolled from seven hospitals. The median patient age was 63 years. Nineteen patients received the protocol treatment. Median PFS was 3.7 months [90% confidence interval (CI)=2.7-5.6 months], which did not reach the predefined threshold of 4.0 months. ORR was 5.9% (95%CI=0.0-17.1%). Median OS was 11.9 months (95% CI 6.3-19.4 months). Febrile neutropenia was observed in 5.3% of patients. The most frequently observed grade 3 non-hematologic toxicities were nausea (15.8%) and hyponatremia (15.8%). CONCLUSION: The addition of a fluoropyrimidine to a platinum agent after adjuvant therapy is not suitable for gastric cancer.


Sujet(s)
Tumeurs spléniques , Tumeurs de l'estomac , Adulte , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Capécitabine , Cisplatine , Humains , Adulte d'âge moyen , Tumeurs spléniques/traitement médicamenteux , Tumeurs de l'estomac/anatomopathologie , Jeune adulte
7.
Cancer Sci ; 113(3): 1057-1068, 2022 Mar.
Article de Anglais | MEDLINE | ID: mdl-34962023

RÉSUMÉ

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.


Sujet(s)
Tumeurs colorectales/génétique , Méthylation de l'ADN , Récepteurs ErbB/antagonistes et inhibiteurs , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antinéoplasiques/usage thérapeutique , Marqueurs biologiques tumoraux/génétique , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/mortalité , Tumeurs colorectales/anatomopathologie , Ilots CpG/génétique , Femelle , Humains , Mâle , Adulte d'âge moyen , Métastase tumorale , Séquençage par oligonucléotides en batterie , Survie sans progression , Protéines proto-oncogènes p21(ras)/génétique , Taux de survie , Résultat thérapeutique
8.
Eur J Cancer ; 154: 296-306, 2021 09.
Article de Anglais | MEDLINE | ID: mdl-34304054

RÉSUMÉ

AIM: The TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis. METHODS: In total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017. RESULTS: With a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72-1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71-1.04, P < 0.0001 for non-inferiority). In patients with left-sided RAS wild-type tumours, median PFS durations were 11.4 and 16.9 months in the control and experimental groups, respectively (HR: 0.68, 95% CI: 0.48-0.96, P = 0.028). CONCLUSION: S-1 and irinotecan plus bevacizumab resulted in comparable OS and non-inferior PFS with that of mFOLFOX6/CapeOX plus bevacizumab treatment as first-line chemotherapy for patients with mCRC. We recommend the use of S-1 and irinotecan plus bevacizumab as a standard first-line regimen independent of tumour sidedness or RAS status in mCRC. TRIAL REGISTRATION: UMIN-CTR: 000007834.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Tumeurs colorectales/traitement médicamenteux , Gènes ras , Mutation , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Bévacizumab/administration et posologie , Tumeurs colorectales/génétique , Tumeurs colorectales/mortalité , Tumeurs colorectales/anatomopathologie , Association médicamenteuse , Femelle , Fluorouracil/usage thérapeutique , Humains , Irinotécan/administration et posologie , Leucovorine/usage thérapeutique , Mâle , Adulte d'âge moyen , Métastase tumorale , Composés organiques du platine/usage thérapeutique , Acide oxonique/administration et posologie , Protéines proto-oncogènes B-raf/génétique , Qualité de vie , Tégafur/administration et posologie
9.
Tohoku J Exp Med ; 254(1): 49-55, 2021 05.
Article de Anglais | MEDLINE | ID: mdl-34053967

RÉSUMÉ

Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patients with unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to be elucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm, open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer and were refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6 mg/kg trastuzumab and 60 mg/m2 docetaxel every 3 weeks. The primary endpoint was the overall response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patients were enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patients among the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%-21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, and the median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The most frequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was not achieved. The results support a current consensus that the continuation of trastuzumab in second-line therapy for gastric cancer is not a recommended option.


Sujet(s)
Tumeurs du sein , Tumeurs de l'estomac , Sujet âgé , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Docetaxel/usage thérapeutique , Femelle , Humains , Survie sans progression , Tumeurs de l'estomac/traitement médicamenteux , Trastuzumab/usage thérapeutique
10.
Cancer Chemother Pharmacol ; 88(3): 393-402, 2021 09.
Article de Anglais | MEDLINE | ID: mdl-34028598

RÉSUMÉ

PURPOSE: The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer. METHODS: This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1-5 and 8-12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations. RESULTS: A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9-4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7-8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036). DISCUSSION: The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug. TRIAL REGISTRATION NUMBER: UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network).


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Tumeurs colorectales/traitement médicamenteux , Évaluation gériatrique/méthodes , Pyrrolidines/administration et posologie , Thymine/administration et posologie , Trifluorothymidine/administration et posologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/pharmacocinétique , Marqueurs biologiques tumoraux/métabolisme , Association médicamenteuse , Surveillance des médicaments/méthodes , Femelle , Humains , Mâle , Neutropénie/induit chimiquement , Survie sans progression , Pyrrolidines/effets indésirables , Pyrrolidines/pharmacocinétique , Taux de survie , Thymine/effets indésirables , Thymine/pharmacocinétique , Trifluorothymidine/effets indésirables , Trifluorothymidine/pharmacocinétique
11.
Cancer Sci ; 112(4): 1567-1578, 2021 Apr.
Article de Anglais | MEDLINE | ID: mdl-33548159

RÉSUMÉ

Oxaliplatin (OX) and irinotecan (IRI) are used as key drugs for the first-line treatment of metastatic colorectal cancer (mCRC). However, no biomarkers have been identified to decide which of the drugs is initially used. In this translational research (TR) of the TRICOLORE trial, the advanced colorectal cancer subtype (aCRCS) was analyzed as a potential biomarker for the selection of OX or IRI. We collected 335 (68.8%) formalin-fixed, paraffin-embedded (FFPE) primary tumor specimens from 487 patients registered in the TRICOLORE trial and performed direct sequencing and immunohistochemical staining of CRC-related genes, comprehensive gene-expression analysis, and genome-wide methylation analysis. The progression-free survival (PFS) of the IRI group was significantly better compared with the OX group in BRAF wild-type (WT), PTEN-positive, and aCRCS A1 patients. Among the molecular factors, aCRCS were only associated with the PFS of OX and IRI groups. The PFS of the IRI group was significantly better compared with the OX group in aCRCS A1 + B1 (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.41-0.82; P = .0023). In contrast, the OX group had better PFS compared with the IRI group in aCRCS B2, although this was not statistically significant (HR = 1.66; 95% CI = 0.94-2.96; P = .083). Nearly half of patients with mCRC (46.8%, aCRCS A1 + B1) respond well to IRI, while only about 18.5% (aCRCS B2) of patients with mCRC responded well to OX. In conclusion, the aCRCS might be a predictive factor for the clinical outcomes of OX-based and IRI-based therapies.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Tumeurs colorectales/traitement médicamenteux , Irinotécan/usage thérapeutique , Oxaliplatine/usage thérapeutique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Marqueurs biologiques tumoraux/métabolisme , Tumeurs colorectales/métabolisme , Survie sans rechute , Femelle , Humains , Mâle , Adulte d'âge moyen , Survie sans progression , Jeune adulte
12.
JCO Precis Oncol ; 4: 898-911, 2020 Nov.
Article de Anglais | MEDLINE | ID: mdl-35050760

RÉSUMÉ

PURPOSE: Several trials have evaluated the efficacy of rechallenge treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with metastatic colorectal cancer (mCRC). A recent trial indicated that RAS status in circulating tumor DNA (ctDNA) may potentially predict patients with RAS wild-type mCRC resistant to anti-EGFR mAb who would benefit from rechallenge treatment, and the findings should be further investigated. MATERIAL AND METHODS: We enrolled patients whose plasma samples were collected in prospective phase II trials, the JACCRO CC-08 (n = 36) and CC-09 (n = 25), which evaluated rechallenge chemotherapy with anti-EGFR mAb for KRAS wild-type mCRC. RAS in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC kit. RESULTS: Sixteen patients were enrolled in this study, with a response rate of 0% and a disease control rate (DCR) of 62.5%. RAS mutations were found at baseline in six patients. The DCR was 33% in patients with RAS mutations in ctDNA, whereas it was 80% in patients without RAS mutation at baseline. Patients with RAS mutation at baseline had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without RAS mutation (median PFS, 2.3 v 4.7 months; hazard ratio [HR], 6.2; P = .013; median OS, 3.8 v 16.0 months; HR, 12.4; P = .0028). Six of 10 patients without RAS mutation at baseline acquired RAS mutations at progression. Postprogression survival after rechallenge treatment was numerically shorter in patients with RAS mutation at progression. CONCLUSION: RAS status in ctDNA was significantly associated with clinical outcomes in patients with mCRC receiving rechallenge treatment with anti-EGFR mAb. These findings could support the clinical utility of OncoBEAM RAS CRC kits for anti-EGFR mAb rechallenge in RAS wild-type mCRC.

13.
Support Care Cancer ; 28(8): 3649-3657, 2020 Aug.
Article de Anglais | MEDLINE | ID: mdl-31811480

RÉSUMÉ

PURPOSE: Capecitabine-based adjuvant chemotherapy for colorectal cancer patients often causes adverse events (AEs), such as diarrhea, stomatitis, anorexia, and hand-foot syndrome (HFS). Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and hence are also expected to attenuate capecitabine-induced AEs. Therefore, we aimed to investigate the safety and efficacy of cystine/theanine treatment in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery. METHODS: A total of 100 colorectal cancer patients treated with capecitabine as an adjuvant chemotherapy after surgery were randomly allocated into the cystine/theanine group (n = 52) or the placebo group (n = 48). The primary endpoint was incidence rate of diarrhea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints included incidence rates of other AEs (CTCAE v.4.0-JCOG), as well as the incidence rate of HFS according to the HFS grading scale. RESULTS: There were no significant differences in capecitabine-induced AEs between the two groups. However, the incidence rate of diarrhea of grade 1 or higher tended to be lower in the cystine/theanine group than the placebo group (18.4% vs. 28.9%, p = 0.169) as well as the incidence rate of HFS of grade 1 or higher (CTCAE v.4.0-JCOG or HFS grading scale) (67.4% vs. 77.8%, p = 0.185, 67.3% vs. 80.0%, p = 0.124, respectively). CONCLUSION: This trial demonstrated that cystine/theanine treatment of colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery is safe and has the tendency to reduce the incidence rate of diarrhea or HFS. TRIAL REGISTRATION: UMIN000024784.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Tumeurs colorectales/traitement médicamenteux , Cystine/usage thérapeutique , Glutamates/usage thérapeutique , Administration par voie orale , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Anorexie/induit chimiquement , Anorexie/traitement médicamenteux , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Capécitabine/administration et posologie , Capécitabine/effets indésirables , Traitement médicamenteux adjuvant , Tumeurs colorectales/chirurgie , Cystine/effets indésirables , Diarrhée/induit chimiquement , Diarrhée/traitement médicamenteux , Méthode en double aveugle , Effets secondaires indésirables des médicaments/traitement médicamenteux , Femelle , Glutamates/effets indésirables , Syndrome mains-pieds/traitement médicamenteux , Syndrome mains-pieds/étiologie , Humains , Mâle , Adulte d'âge moyen , Stomatite/induit chimiquement , Stomatite/traitement médicamenteux
14.
Tohoku J Exp Med ; 245(2): 123-129, 2018 06.
Article de Anglais | MEDLINE | ID: mdl-29937450

RÉSUMÉ

The combinations of oral fluoropyrimidines and cisplatin such as capecitabine and cisplatin (XP) or S-1 and cisplatin (SP) are regarded as a standard therapy against unresectable, recurrent, or advanced gastric cancer (AGC). Especially, SP is the most common regimen against AGC in Japan. For patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC, trastuzumab, a monoclonal antibody targeting HER2 antibody, is additionally used in combination. Although trastuzumab in combination with XP (trastuzumab-XP) have been widely accepted, the efficacy of trastuzumab in combination with SP (trastuzumab-SP) lacks sufficient verification. The aim of the present study is to validate the comparability of trastuzumab-SP to trastuzumab-XP. Patients with HER2-positive AGC were assigned to the trastuzumab-XP or trastuzumab-SP group. We then retrospectively compared the efficacy and safety between both groups. As a first-line chemotherapy, trastuzumab in combination with XP or SP was administered to 58 patients: 28 with trastuzumab-XP and 30 with trastuzumab-SP. In the trastuzumab-XP group, response rate (RR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) were 39.3%, 89.3%, 7.9 months, and 20.0 months, respectively. In the trastuzumab-SP group, RR, DCR, mPFS and mOS were 50.0%, 86.7%, 6.9 months, and 16.7 months, respectively. No significant difference in efficacy was observed between both groups. Severe hand-foot syndrome was observed more frequently in the trastuzumab-XP group than in the trastuzumab-SP group (14.3% vs. 0%, p = 0.05). Trastuzumab in combination with SP is a potential first-line therapeutic option for patients with HER2-positive AGC.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Asiatiques , Cisplatine/usage thérapeutique , Récepteur ErbB-2/métabolisme , Tumeurs de l'estomac/traitement médicamenteux , Tumeurs de l'estomac/anatomopathologie , Trastuzumab/effets indésirables , Trastuzumab/usage thérapeutique , Sujet âgé , Survie sans rechute , Relation dose-effet des médicaments , Femelle , Humains , Estimation de Kaplan-Meier , Mâle , Adulte d'âge moyen , Stadification tumorale , Études rétrospectives , Résultat thérapeutique
15.
Tohoku J Exp Med ; 245(1): 21-28, 2018 05.
Article de Anglais | MEDLINE | ID: mdl-29743448

RÉSUMÉ

Oxaliplatin-based chemotherapy is a well-established regimen for patients with inoperable and metastatic colorectal cancer. However, one of the major limitations of oxaliplatin-based chemotherapy is sensory neuropathy. It was previously reported that introduction of intermittent oxaliplatin treatment to an oxaliplatin-based regimen has a significant benefit on efficacy or safety. Here, we prospectively assessed whether efficacy and safety of first-line chemotherapy for advanced colorectal cancer are achieved by introduction of withdrawal of oxaliplatin treatment for a certain period (intermittent oxaliplatin treatment). The primary endpoint of the present study is to assess the progression free survival time on patients treated with chemotherapy (mFOLFOX6 (levofolinate, 5-fluorouracil and oxaliplatin combination therapy) plus bevacizumab or CapeOX (oxaliplatin and capecitabine combination therapy) plus bevacizumab) with intermittent oxaliplatin treatment. Bevacizumab is a humanized anti-vascular endothelial growth factor antibody. Median progression-free survival by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or the CapeOX plus bevacizumab with intermittent oxaliplatin treatment were 10.6 months (95% confidential interval [CI], 8.3-13.4 months) or 8.0 months (95% CI, 4.2-16.8 months), respectively. Overall response rate by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment was 55.1% or 42.1%, respectively. Grade 3 or 4 neuropathy was observed in 4.1% or 10.5% of patients treated with mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment, respectively. Introduction of intermittent oxaliplatin treatment has improved severe neuropathy in mFOLFOX6 plus bevacizumab regimen without reducing treatment efficacy.


Sujet(s)
Asiatiques , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/chirurgie , Composés organiques du platine/effets indésirables , Composés organiques du platine/usage thérapeutique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs colorectales/anatomopathologie , Survie sans rechute , Femelle , Humains , Estimation de Kaplan-Meier , Mâle , Adulte d'âge moyen , Métastase tumorale , Oxaliplatine , Résultat thérapeutique
16.
PLoS One ; 12(5): e0176972, 2017.
Article de Anglais | MEDLINE | ID: mdl-28489919

RÉSUMÉ

BACKGROUND: Combination therapy with gemcitabine and docetaxel has been reported to be a good therapeutic strategy for patients with soft tissue sarcoma. The aim of the present study was to analyze the efficacy and toxicity of gemcitabine with docetaxel in Japanese patients with advanced bone and soft tissue sarcoma. PATIENTS AND METHODS: We retrospectively analyzed the effect of gemcitabine and docetaxel therapy on overall response, progression-free survival, overall survival, and toxicity in 42 patients with bone or soft tissue sarcoma who had received the therapy between October 2006 and September 2015, at Tohoku University Hospital. RESULTS: The median age was 55 years; 23 patients were men, and 19 were women. Eight had bone sarcoma and 34 had soft tissue sarcoma. Forty patients (95%) had previously been treated with one or more chemotherapeutic regimens. The overall response rate was 6.9% and the disease control rate was 55%. The median progression-free survival was 2.3 months and the median overall survival was 14.3 months. Grade 3 or more neutropenia and febrile neutropenia were observed in 74% and 4.8% of all patients, respectively. CONCLUSION: The response rate was lower and myelosuppression was more frequently observed than in other previous reports. On the other hand, most of toxicities were enough manageable. In addition, some patients had long survival with a good response. Our study supports the notion that gemcitabine and docetaxel therapy is a good therapeutic option for treating patients with advanced soft tissue sarcoma as well as bone sarcoma, also in Asian populations.


Sujet(s)
Antinéoplasiques/usage thérapeutique , Tumeurs osseuses/traitement médicamenteux , Désoxycytidine/analogues et dérivés , Récidive tumorale locale/traitement médicamenteux , Sarcomes/traitement médicamenteux , Tumeurs des tissus mous/traitement médicamenteux , Taxoïdes/usage thérapeutique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antimétabolites antinéoplasiques/effets indésirables , Antimétabolites antinéoplasiques/usage thérapeutique , Antinéoplasiques/effets indésirables , Tumeurs osseuses/mortalité , Tumeurs osseuses/anatomopathologie , Désoxycytidine/effets indésirables , Désoxycytidine/usage thérapeutique , Survie sans rechute , Docetaxel , Calendrier d'administration des médicaments , Association de médicaments , Femelle , Humains , Japon , Mâle , Adulte d'âge moyen , Récidive tumorale locale/mortalité , Récidive tumorale locale/anatomopathologie , Neutropénie/induit chimiquement , Études rétrospectives , Sarcomes/mortalité , Sarcomes/anatomopathologie , Tumeurs des tissus mous/mortalité , Tumeurs des tissus mous/anatomopathologie , Taux de survie , Taxoïdes/effets indésirables , Résultat thérapeutique , Jeune adulte ,
18.
Gan To Kagaku Ryoho ; 42(1): 101-4, 2015 Jan.
Article de Japonais | MEDLINE | ID: mdl-25596689

RÉSUMÉ

We describe a case of liver metastasis of colorectal cancer that became resectable after bevacizumab (Bmab), CPT-11, and S-1 ie Bmab+IRIS combination chemotherapy. A 65-year-old man experienced repeated constipation and diarrhea in August of 2013. Colonoscopy was conducted by a local doctor, and a tumor(diagnosed as adenocarcinoma tub1 by biopsy)was found in the upper rectum. Computed tomography performed at our institution detected synchronous liver metastasis. On September 9, laparoscopic rectal anterior resection was performed to prevent metastasis to the ileus, and on October 9, the patient began receiving Bmab+IRIS combination chemotherapy. Before chemotherapy, 3 metastases with a maximum diameter of 7 cm diameter)were observed in the right lobe of the liver. After 4 courses of chemotherapy, their maximum diameter was 3 cm, which allowed resection. Ultimately, the metastases were completely resected. Conversion of non optimal resection cases of liver metastases to optimal cases by using Bmab+IRIS chemotherapy is extremely rare. We suggest that Bmab+IRIS chemotherapy could be an option for conversion of non optimal liver resection cases to optimal cases. We report this rare case and discuss the implications of adjuvant chemotherapy for this patient.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Tumeurs du foie/traitement médicamenteux , Tumeurs du sigmoïde/anatomopathologie , Adénocarcinome/traitement médicamenteux , Sujet âgé , Anticorps monoclonaux humanisés/administration et posologie , Bévacizumab , Camptothécine/administration et posologie , Camptothécine/analogues et dérivés , Association thérapeutique , Association médicamenteuse , Humains , Irinotécan , Tumeurs du foie/secondaire , Tumeurs du foie/chirurgie , Mâle , Acide oxonique/administration et posologie , Tumeurs du sigmoïde/traitement médicamenteux , Tumeurs du sigmoïde/chirurgie , Tégafur/administration et posologie
19.
Oncology ; 83(2): 101-7, 2012.
Article de Anglais | MEDLINE | ID: mdl-22777333

RÉSUMÉ

OBJECTIVE: S-1 is effective in sequential combination with irinotecan (IRIS) in treating metastatic colorectal cancer. We conducted a randomized phase II trial of modified leucovorin, fluorouracil and irinotecan (mFOLFIRI) + bevacizumab and sequential IRIS + bevacizumab as first- or second-line therapies. METHODS: Sixty metastatic colorectal cancer patients were randomly assigned to receive mFOLFIRI + bevacizumab or sequential IRIS + bevacizumab (7.5 mg/kg of bevacizumab and 150 mg/m(2) of irinitecan, and 80 mg/m(2)/day of S-1 orally from day 3 until day 16 as a 3-week course). The primary endpoint was the safety of each method until week 12, with the secondary endpoint being the comparison of the safety and efficacy of the two methods. RESULTS: The safety of the two treatments was comparable, except that G3 anorexia and diarrhoea were less frequent with sequential IRIS + bevacizumab. The overall response rate was 62% [95% confidence interval (CI) 40.1-79.8] versus 72% (95% CI 50.6-86.2), and progression-free survival was 324 days (95% CI 247-475) versus 345 days (95% CI 312-594) with mFOLFIRI + bevacizumab versus IRIS + bevacizumab, respectively. CONCLUSION: Sequential IRIS + bevacizumab is a safe and effective method of systemic chemotherapy against metastatic colorectal cancer and is compatible with mFOLFIRI + bevacizumab.


Sujet(s)
Anticorps monoclonaux humanisés/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Camptothécine/analogues et dérivés , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/anatomopathologie , Adulte , Sujet âgé , Anticorps monoclonaux humanisés/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Asiatiques , Bévacizumab , Camptothécine/effets indésirables , Camptothécine/usage thérapeutique , Tumeurs colorectales/mortalité , Survie sans rechute , Calendrier d'administration des médicaments , Femelle , Fluorouracil/administration et posologie , Fluorouracil/effets indésirables , Fluorouracil/usage thérapeutique , Humains , Irinotécan , Leucovorine/administration et posologie , Leucovorine/effets indésirables , Leucovorine/usage thérapeutique , Mâle , Adulte d'âge moyen
20.
Anticancer Res ; 31(11): 3719-26, 2011 Nov.
Article de Anglais | MEDLINE | ID: mdl-22110192

RÉSUMÉ

BACKGROUND: Multiple myeloma remains an incurable malignancy despite of the recent approval of new molecular-targeted agents. The complex molecular mechanism, composed of various signal networks, including nuclear factor-κB (NF-κB), phosphoinositide 3-kinase (PI3K)/AKT, Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), and interferon regulatory factor 4 (IRF4) pathways, is a major reason for treatment failure. Curcumin can regulate these molecules, but its low bioavailability prevents its clinical application. MATERIALS AND METHODS: Growth-suppressive abilities of newly synthesized analogs, GO-Y030 and GO-Y078 were analyzed. Molecular-targeted abilities of the analogs for NF-κB, PI3K/AKT, JAK/STAT3, IRF4 pathways, as well as inhibition of interleukin-6 (IL-6) production, were also examined. RESULTS: GO-Y030 and GO-Y078 were 7 to 12-fold more potent growth suppressors for myeloma cells, and 6- to 15-fold stronger inhibitors of NF-κB, PI3K/AKT, JAK/STAT3, and IRF4 pathways than curcumin. GO-Y78 also 14-fold more potently inhibited IL-6 production. CONCLUSION: GO-Y030 and GO-Y078 are potential therapeutic candidates with enhanced abilities for multiple myeloma.


Sujet(s)
Dérivés du benzène/pharmacologie , Curcumine/analogues et dérivés , Interleukine-6/métabolisme , Cétones/pharmacologie , Myélome multiple/traitement médicamenteux , Myélome multiple/anatomopathologie , Transduction du signal/effets des médicaments et des substances chimiques , Apoptose , Technique de Western , Cycle cellulaire , Prolifération cellulaire , Curcumine/pharmacologie , Cytométrie en flux , Humains , Facteurs de régulation d'interféron/génétique , Facteurs de régulation d'interféron/métabolisme , Janus kinase 1/génétique , Janus kinase 1/métabolisme , Myélome multiple/métabolisme , Facteur de transcription NF-kappa B/génétique , Facteur de transcription NF-kappa B/métabolisme , Phosphatidylinositol 3-kinases/génétique , Phosphatidylinositol 3-kinases/métabolisme , Protéines proto-oncogènes c-akt/génétique , Protéines proto-oncogènes c-akt/métabolisme , ARN messager/génétique , RT-PCR , Facteur de transcription STAT-3/génétique , Facteur de transcription STAT-3/métabolisme , Cellules cancéreuses en culture
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