ABSTRACT
BACKGROUND: The efficacy of irinotecan plus continuous trastuzumab beyond progression in patients with gastric cancer previously treated with trastuzumab plus standard first-line chemotherapy has not been reported. METHODS: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer who were previously treated with trastuzumab received trastuzumab every 3 weeks and irinotecan every 2 weeks. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), 6-month survival rates, safety, and subgroup analysis by HER2 status. RESULTS: Sixteen patients were enrolled in a 3-year pre-planned registration period. This study was prematurely closed due to poor patient accrual. The ORR and disease control rate were 6.7% (95% CI, 0.2-32.0) and 53.3% (95% CI, 26.6-78.7). The median PFS and overall survival (OS) were 2.4 months (95% CI, 0.0-5.2) and 9.7 months (95% CI, 8.2-11.2), respectively. The most frequently reported grades 3-4 adverse events were neutropenia (40%), anemia (27%), anorexia (33%), and fatigue (33%). CONCLUSION: With only 16 patients enrolled, the present study has very low power to detect any clinical benefit of trastuzumab plus irinotecan beyond disease progression in patients with HER2-positive advanced gastric cancer who previously received trastuzumab.Trial Identifier: UMIN000007636.
Subject(s)
Breast Neoplasms , Stomach Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Female , Humans , Irinotecan/therapeutic use , Receptor, ErbB-2/metabolism , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Survival Rate , TrastuzumabABSTRACT
BACKGROUND: Ramucirumab is a human IgG1 monoclonal vascular endothelial growth factor receptor-2 antibody that inhibits tumor cell growth and affects the tumor cell microenvironment. We assessed the efficacy and safety of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with previously treated advanced gastric cancer. MATERIALS AND METHODS: Patients with advanced gastric cancer refractory or intolerant to primary chemotherapy were included. Ramucirumab 8 mg/kg plus irinotecan 150 mg/m2 combination therapy was administered every 2 weeks. The primary endpoint was progression-free survival rate at 6 months and secondary endpoints were overall survival, progression-free survival, response rate, safety, and dose intensity for each drug. RESULTS: Thirty-five patients were enrolled between January 2018 and September 2019. The progression-free survival rate at 6 months was 26.5% [95%CI, 13.2%-41.8%, P = .1353)]. Median progression-free and overall survivals were 4.2 months (95%CI, 2.5-5.4 months) and 9.6 months (95%CI, 6.4-16.6 months), respectively. The overall response rate was 25.9% (95%CI, 11.1-36.3%) and disease control rate was 85.2% (95%CI, 66.3-95.8%). Grade ≥3 adverse events that occurred in >10% of patients included neutropenia, leucopenia, anemia, anorexia, and febrile neutropenia. No death or new safety signals with a causal relation to the study treatment were observed. CONCLUSION: Although the primary endpoint was not achieved statistically, combination therapy of ramucirumab plus irinotecan showed anticancer activity and a manageable safety profile for second-line treatment of patients with advanced gastric cancer.
Subject(s)
Stomach Neoplasms , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Humans , Irinotecan/therapeutic use , Stomach Neoplasms/pathology , Tumor Microenvironment , Vascular Endothelial Growth Factor A , RamucirumabABSTRACT
BACKGROUND: The ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab. METHODS: The subjects of this study were mCRC patients who experienced disease progression < 100 days from commencement of first-line chemotherapy containing BEV initiated between Apr 2007 and Dec 2016. Second-line chemotherapy regimens were classified into two groups with and without BEV/other anti-angiogenic agents (BBP and non-BBP) and efficacy and safety were compared using univariate and multivariate analysis. RESULTS: Sixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0-1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46-1.34], p = 0.373, adjusted HR: 0.87 [0.41-1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38-1.12], p = 0.125, adjusted HR 0.53 [0.27-1.07], p = 0.078). CONCLUSION: In mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Analysis of Variance , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Disease Progression , Drug Administration Schedule , Female , Fluorouracil/therapeutic use , Humans , Irinotecan/therapeutic use , Japan , Leucovorin/therapeutic use , Male , Middle Aged , Organoplatinum Compounds/therapeutic use , Oxaliplatin/therapeutic use , Progression-Free Survival , Pyrimidines/therapeutic use , Retrospective Studies , Time FactorsABSTRACT
BACKGROUND: Five-weekly S-1 plus cisplatin (SP) therapy is the standard care for advanced gastric or esophagogastric junction cancer (GC/EGJC) in East Asia. However, its efficacy and safety when combined with trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive advanced GC/EGJC remains unclear. METHODS: Patients received 5-weekly SP therapy (S-1 at 40-60 mg twice daily for 21 days plus cisplatin at 60 mg/m2 on day 8, every 5 weeks) plus trastuzumab therapy (first dose of 8 mg/kg, then 6 mg/kg every 3 weeks). The primary end point was the response rate, and the secondary end points included progression-free survival, overall survival, safety, and serum biomarker levels. RESULTS: Forty-four patients were enrolled. The response rate, progression-free survival, and overall survival were 61% (95% confidence interval 46-76%), 5.9 months, and 16.5 months respectively. The commonest grade 3 or grade 4 adverse events were neutropenia (30%) and anorexia (25%). A significantly higher response rate (92% vs 43%; P = 0.008) and longer progression-free survival (median 14.5 months vs 4.2 months; P = 0.028) were observed in patients with high (n = 14) compared with low (n = 17) pretreatment serum neuregulin 1 levels. CONCLUSIONS: Five-weekly SP therapy combined with trastuzumab therapy showed a good antitumor response and acceptable toxicity in HER2-positive advanced GC/EGJC. Serum neuregulin 1 might be associated with the efficacy of this treatment regimen.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Stomach Neoplasms/drug therapy , Adult , Aged , Cisplatin/administration & dosage , Cisplatin/adverse effects , Disease-Free Survival , Drug Combinations , Female , Humans , Male , Middle Aged , Oxonic Acid/administration & dosage , Oxonic Acid/adverse effects , Receptor, ErbB-2/analysis , Receptor, ErbB-2/biosynthesis , Tegafur/administration & dosage , Tegafur/adverse effects , Trastuzumab/administration & dosage , Trastuzumab/adverse effectsABSTRACT
BACKGROUND: Fluoropyrimidine and platinum combination is the standard treatment for advanced or recurrent gastric cancer (AGC). However, fluoropyrimidine monotherapy is commonly used for elderly patients with AGC because of its good tolerability. METHODS: In this multicenter retrospective study, we collected clinical data of AGC patients aged 70 years or older, treated with S-1 alone or S-1 plus cisplatin (SP) as the first-line treatment between January 2009 and December 2011. Propensity score matched cohorts (PSMC) were used for reducing the confounding effects to compare efficacy and safety between the two treatment groups. Cox regression analysis was performed to clarify the prognostic factors. RESULTS: PSMC (n = 109 in each group) were selected from among 444 eligible patients (S-1 group, 210; SP group, 234); the S-1 group included more patients deemed unfit for intensive chemotherapy than the SP group (e.g., higher age, poorer PS, poor renal function). In the PSMC, patients' characteristics were comparable between groups, except the male ratio (S-1 group, 64.2%; SP group, 77.1%; p = 0.04). No significant differences were observed in either overall survival [hazard ratio (HR) 0.93, p = 0.63] or progression-free survival (HR 1.09, p = 0.61). Severe adverse events (AEs) and hospitalization due to AEs were more frequent in the SP group than in the S-1 group (p < 0.001 each). CONCLUSION: Our findings do not support the survival benefit of SP over S-1 in elderly patients with AGC. We are now conducting a prospective comparative study to optimize treatment strategy and explore applicability of the geriatric assessment for these patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/mortality , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Disease-Free Survival , Drug Combinations , Female , Humans , Male , Multivariate Analysis , Oxonic Acid/administration & dosage , Oxonic Acid/therapeutic use , Propensity Score , Stomach Neoplasms/pathology , Tegafur/administration & dosage , Tegafur/therapeutic use , Treatment OutcomeABSTRACT
This randomized phase II trial compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab plus FOLFIRI as second-line chemotherapy for wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) and to explore the values of oncogenes in circulating tumor DNA (ctDNA) and serum proteins as predictive biomarkers. Patients with WT KRAS exon 2 mCRC refractory to first-line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI. Of 121 randomly assigned patients, 117 were eligible. Median overall survival (OS) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [hazard ratio (HR), 1.16; 95% CI, 0.76-1.77], respectively. Progression-free survival (PFS) was also similar (HR, 1.14; 95% CI, 0.78-1.66). KRAS, NRAS, and BRAF status using ctDNA was successfully examined in 109 patients, and mutations were identified in 19 patients (17.4%). Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations (P for interaction = 0.026 in OS and 0.054 in PFS). OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor-A (VEGF-A) levels and worse in those with low levels (P for interaction = 0.016). Second-line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , ras Proteins/genetics , Adult , Aged , Aged, 80 and over , Alleles , Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/administration & dosage , Biomarkers, Tumor , Camptothecin/adverse effects , Camptothecin/therapeutic use , Female , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Humans , Kaplan-Meier Estimate , Leucovorin/adverse effects , Leucovorin/therapeutic use , Male , Middle Aged , Mutation , Neoplasm Metastasis , Panitumumab , Proto-Oncogene Proteins B-raf , Retreatment , Treatment OutcomeABSTRACT
BACKGROUND: Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity of gastric cancer can be an obstacle to accurate HER2 assessment. Serum HER2, concentrations of the HER2 extracellular domain shed into the bloodstream, has a potential to compensate HER2 immunohistochemistry (IHC) but has not been scrutinized in gastric cancer. This study sought to explore the clinical utility of serum HER2 in gastric cancer. METHODS: We performed a prospective multicenter trial (SHERLOCK trial) involving patients with all-stage gastric or gastro-esophageal junction cancer. Serum HER2 was measured using direct chemiluminescence while tissue HER2 status was determined using IHC and fluorescent in situ hybridization. For stage IV cases, concordance between local and central laboratories in tissue HER2 assessment was also evaluated. RESULTS: Of 224 patients enrolled, both tissue HER2 status and serum HER2 levels were successfully determined in 212 patients and 21% (45/212) were tissue HER2-positive. Serum HER2 levels, ranged from 4.5 to 148.0 ng/ml (median 10.3), correlated with tissue HER2 status (p = 0.003). At a cut-off level of 28.0 ng/ml determined by receiver operating characteristics analysis, sensitivity, specificity, positive and negative predictive values of serum HER2 were 22.6%, 100%, 100% and 82.3%, respectively. All nine cases with elevated serum HER2 were tissue HER2-positive stage IV cases. Among 61 stage IV cases, the agreement rate for IHC scoring between the local and the central laboratories was 82% and tissue HER2 judgment was conflicting in five (8.2%) cases. Of these five cases, four were confirmed as false-negative and two of these four patients demonstrated elevated serum HER2. CONCLUSIONS: Serum HER2 levels correlated with tissue HER2 status in gastric cancer. Although the low sensitivity is a drawback, serum HER2 might be a useful adjunct tool to detect tissue HER2 false-negative gastric cancer.
Subject(s)
Biomarkers/analysis , Receptor, ErbB-2/metabolism , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Gene Amplification , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Prospective Studies , ROC Curve , Receptor, ErbB-2/genetics , Stomach Neoplasms/geneticsABSTRACT
BACKGROUND: Gene mutations in the pathway downstream of epidermal growth factor receptor (EGFR) are considered to induce resistance to anti-EGFR therapy in colorectal cancer (CRC). We recently reported that microRNA-31 (miR-31)-5p may regulate BRAF activation and play a role in the signaling pathway downstream of EGFR in CRC. Therefore, we hypothesized that miR-31-5p can be a useful biomarker for anti-EGFR therapy in CRC. METHODS: We evaluated miR-31-5p expression and gene mutations [KRAS (codon 61 or 146), NRAS (codon 12, 13, or 61), and BRAF (V600E)] in the EGFR downstream pathway in 102 CRC patients harboring KRAS (codon 12 or 13) wild-type who were treated with anti-EGFR therapeutics. Progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: KRAS (codon 61 or 146), NRAS, and BRAF mutations were detected in 6.9, 6.9, and 5.9 % patients, respectively. Compared with CRCs with at least one mutation (n = 20), significantly better PFS (P = 0.0003) but insignificantly better OS were observed in CRCs harboring all wild-type genes (KRAS, NRAS, and BRAF). High miR-31-5p expression was identified in 11 % (n = 11) patients and was significantly associated with shorter PFS (P = 0.003). In CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS (P = 0.027). CONCLUSIONS: High miR-31-5p expression was associated with shorter PFS in patients with CRC treated with anti-EGFR therapeutics. Moreover, in CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS, suggesting that it may be a useful and additional prognostic biomarker for anti-EGFR therapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapy , ErbB Receptors/antagonists & inhibitors , MicroRNAs/genetics , Aged , Antibodies, Monoclonal/therapeutic use , Biomarkers, Tumor/genetics , Cell Line, Tumor , Cetuximab/therapeutic use , Colorectal Neoplasms/pathology , DNA Mutational Analysis , Disease-Free Survival , Female , GTP Phosphohydrolases/genetics , Gene Expression , Humans , Male , Membrane Proteins/genetics , Middle Aged , Neoplasm Metastasis , Panitumumab , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Response Evaluation Criteria in Solid Tumors , Survival RateABSTRACT
AIM: We planned a randomized, open-label trial to evaluate differences between pre-emptive and reactive skin treatment for panitumumab (Pmab)-associated skin toxicities in Japanese patients with metastatic colorectal cancer. PATIENTS & METHODS: Patients receiving third-line Pmab-containing regimens were randomized to pre-emptive or reactive treatment. The primary end point was the cumulative incidence of ≥grade 2 skin toxicities during 6 weeks. Retrospectively, a dermatologist reviewed skin toxicities, in a blinded manner. RESULTS: A total of 95 patients were enrolled (pre-emptive: 47, reactive: 48). The primary end point was achieved (21.3 and 62.5% [risk ratio: 0.34; p < 0.001], for pre-emptive and reactive treatment, respectively). A similar trend was observed in central review. CONCLUSION: Pre-emptive skin treatment could reduce the severity of Pmab-associated skin toxicities in Japanese metastatic colorectal cancer patients.
Subject(s)
Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Colorectal Neoplasms/complications , Colorectal Neoplasms/drug therapy , Skin Diseases/etiology , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , ErbB Receptors/antagonists & inhibitors , Female , Humans , Japan , Male , Middle Aged , Neoplasm Metastasis , Panitumumab , Skin Diseases/pathology , Time Factors , Treatment OutcomeABSTRACT
BRAF is an important gene in colorectal cancers (CRCs) that is associated with molecular characterization and resistance to targeted therapy. Although microRNAs (miRNAs) are useful biomarkers of various cancers, the association between miRNA and BRAF in CRCs is undefined. Therefore, this study was conducted to identify a relationship between specific miRNA molecules and BRAF mutation in CRCs and serrated lesions. miRNA array was used for the measurement of 760 miRNAs in 29 CRCs. To assess the identified miRNAs, quantitative reverse transcription-PCR was performed on 721 CRCs, 381 serrated lesions and 251 non-serrated adenomas. Moreover, proliferation and invasion assays were conducted using cell lines. miRNA array analysis revealed that microRNA-31 (miR-31)-5p was the most up-regulated miRNA in CRCs with mutated BRAF (V600E) compared with CRCs possessing wild-type BRAF (including cases with KRAS mutation). High miR-31 expression was associated with BRAF and KRAS mutations and proximal location (P < 0.0001). High miR-31 expression was related to cancer-specific mortality [multivariate hazard ratio = 2.06, 95% confidence interval: 1.36-3.09, P = 0.0008]. Functional analysis demonstrated that miR-31 inhibitor decreased cell invasion and proliferation. With regard to serrated lesions, high miR-31 expression was less frequently detected in hyperplastic polyps compared with other serrated lesions. In conclusion, associations were identified between miR-31, BRAF and prognosis in CRC. Transfection of miR-31 inhibitor had an antitumour effect. Thus, miR-31 may be a promising diagnostic biomarker and therapeutic target in colon cancers. Moreover, high miR-31 expression in serrated lesions suggested that miR-31 may be a key molecule in serrated pathway.
Subject(s)
Colorectal Neoplasms/genetics , MicroRNAs/genetics , Mutation , Proto-Oncogene Proteins B-raf/genetics , Aged , Colorectal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction , Survival AnalysisABSTRACT
BACKGROUND & AIMS: More information is needed on the long-term outcomes of patients who undergo endoscopic resection of colorectal tumors. We evaluated recurrence of colorectal cancer (CRC) after endoscopic resection or a combination of endoscopic research and surgery for T1 colorectal tumors. METHODS: We conducted a retrospective study of 389 patients with T1 CRC treated by endoscopic resection from January 1989 to December 2008 in Sapporo, Japan. We compared outcomes between patients who underwent subsequent surgery (ER + SURG, n = 205) and those who did not (ER only, n = 184) and statistically adjusted baseline differences between the groups according to the propensity scores. RESULTS: There was almost no risk of cancer recurrence among patients without indications for surgery recommended by the Japanese Society for Cancer of the Colon and Rectum (these indications include tumors with vertical margins, deep submucosal invasion, lymphatic or venous invasion, poor differentiation, or high-grade budding). Among patients with indications for surgery, the cumulative risks of recurrence (CRRs) were 3.7% in the ER + SURG group and 20.1% in the ER only group (P = .001). However, the patients with only deep submucosal invasion had a low CRR, even without surgery (2.3% in the ER + SURG group and 3.4% in the ER only groups, P = .867). In contrast, patients with indications for surgery other than deep submucosal invasion (high-risk patients) had much better outcomes when they also underwent surgery (CRRs: 5.8% in the ER + SURG group vs 58.0% in the ER only group, P < .001). CONCLUSIONS: On the basis of a retrospective study of patients who underwent endoscopic resection for T1 CRC, those with tumors with only submucosal invasion are at low risk for cancer recurrence. However, patients with other high-risk tumor features have greater risks for cancer recurrence and benefit from subsequent surgery.
Subject(s)
Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/pathology , Neoplasm Recurrence, Local/epidemiology , Adenocarcinoma/epidemiology , Adenocarcinoma/pathology , Aged , Colorectal Neoplasms/surgery , Endoscopy, Gastrointestinal , Female , Humans , Intestinal Mucosa/pathology , Male , Middle Aged , Neoplasm Invasiveness , Prognosis , Retrospective Studies , Risk Factors , Treatment OutcomeABSTRACT
The usefulness of comprehensive genomic profiling (CGP) in the Japanese healthcare insurance system remains underexplored. Therefore, this large-scale study aimed to determine the usefulness of CGP in diagnosing digestive cancers. Patients with various cancer types recruited between March 2020 and October 2022 underwent the FoundationOne® CDx assay at the Keio PleSSision Group (19 hospitals in Japan). A scoring system was developed to identify potentially actionable genomic alterations of biological significance and actionable genomic alterations. The detection rates for potentially actionable genomic alterations, actionable genomic alterations, and alterations equivalent to companion diagnosis (CDx), as well as the signaling pathways associated with these alterations in each digestive cancer, were analyzed. Among the 1587 patients, 547 had digestive cancer. The detection rates of potentially actionable genomic alterations, actionable genomic alterations, and alterations equivalent to CDx were 99.5%, 62.5%, and 11.5%, respectively. APC, KRAS, and CDKN2A alterations were frequently observed in colorectal, pancreatic, and biliary cancers, respectively. Most digestive cancers, except esophageal cancer, were adenocarcinomas. Thus, the classification flowchart for digestive adenocarcinomas proposed in this study may facilitate precise diagnosis. CGP has clinical and diagnostic utility in digestive cancers.
ABSTRACT
BACKGROUND: S-1, an oral fluoropyrimidine, is one of the standard chemotherapeutic agents for the treatment of metastatic gastric cancer(MGC). However, the most effective second-line regimen after failure of treatment with first-line agents such as S-1 is yet to be determined. The aim of this study was to investigate the various second-line chemotherapy regimens in MGC patients. METHODS: We retrospectively studied patients with MGC who received second-line treatment after failure of the first-line S-1 or S-1/cisplatin treatment. The overall survival times with each second-line regimen were determined using the Kaplan-Meier method, and the effect on overall survival was analyzed using Cox regression analysis. RESULTS: The median survival time for all patients was 14. 2 months(95% confidence interval(CI): 12. 88-15. 43 months)with a 1-year survival rate of 60. 4%. Kaplan-Meier analysis revealed that the second-line regimens containing irinotecan significantly improved the median survival time as compared to regimens without irinotecan(median survival time: 16. 5 and 13. 8 months, respectively). Cox regression analysis showed that irinotecan-containing regimens were associated with improved overall survival(hazard ratio: 0. 165; 95% CI: 0. 041-0. 665). CONCLUSION: The use of irinotecan-containing regimens as second-line chemotherapy after failure of first-line S-1 therapy may be beneficial for MGC patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Drug Resistance, Neoplasm , Salvage Therapy , Stomach Neoplasms/drug therapy , Aged , Camptothecin/administration & dosage , Camptothecin/therapeutic use , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Drug Combinations , Female , Humans , Irinotecan , Male , Neoplasm Metastasis , Oxonic Acid/administration & dosage , Oxonic Acid/therapeutic use , Retrospective Studies , Stomach Neoplasms/pathology , Tegafur/administration & dosage , Tegafur/therapeutic useABSTRACT
A hierarchical hybrid control system is proposed to cope with highly automated driving in highway environments with multiple lanes and surrounding vehicles. In the high-level layer, the discrete driving decisions are coordinated by the finite-state machine (FSM) based on the relative position identification and predictive longitudinal distance of the surrounding vehicles. The low-level layer is responsible for the vehicle motion control, where the model predictive control (MPC) approach is utilized to integrate the longitudinal and lateral control mainly including car-following control and lane changing control. The proposed control system focuses on two issues regarding safe driving on highways. On one hand, the subject vehicle must always keep a safe distance with its leading vehicle to avoid the rear-end collision. On the other hand, the subject vehicle should also overtake the preceding vehicle by safe lane changes if the desired speed is not achieved. The effectiveness of the hybrid control is tested in the simulation, whose results verify that the driving decisions are made reasonably and the vehicle motion control obeys stability and comfort requirements. Moreover, it is also indicated by the simulations in random scenarios that the control strategy is able to deal with most of ordinary situations on highways although some emergency situations or critical driving maneuvers of other vehicles are not considered.
ABSTRACT
OBJECTIVES: In recent years, CapeOX therapy for patients with colorectal cancer is widely used. We previously reported that a multidisciplinary approach decreases the worsening of adverse events and increases patient satisfaction. In this study, we conducted a multicenter, prospective, observational study to evaluate the incidence of adverse events, health-related quality of life (HRQOL) of the patient, and efficacy of a management (intervention) according to the support system (SMILE study). METHODS: As the interventional method, the following more than one method was carried out in each institute, 1: support with telephone, 2: dosing instruction by a pharmacist, 3: skin care instruction by a nurse, and 4: patient instruction by a doctor. The primary endpoint was the incidence of hand-foot syndrome (HFS) of more than grade 2. The secondary endpoint was the HRQOL evaluation and efficacy. The questionnaire (HADS) was administered before the start of the chemotherapy and in 1, 2, 4, 5, and 8 courses to evaluate quality of life (QOL). RESULTS: From April 2011 to September 2012, 80 patients were enrolled from 14 sites, and all patients were the subjects of analysis. The demographic background was as follows: man/woman: 46/34, age median: 63 (36-75), and management interventional method 1/2/3/4: 36/68/73/78. The overall percentage of HFS that exceeded grade 2 within 6 months was 16.3%. It was 11.1% with the telephone support group and 20.5% without the telephone support group (p = 0.26). CONCLUSIONS: A multi-professional telephone support may reduce the deterioration of HFS. Further study which includes larger cohort is needed in the future.
ABSTRACT
BACKGROUND: Regorafenib demonstrated survival benefits as salvage therapy for patients with metastatic colorectal cancer. However, severe toxicities frequently occurred early in the treatment with the standard dose (160 mg/day), resulting in a dose reduction or interruption. To improve the tolerability and maintain sufficient efficacy, we conducted a phase II study of regorafenib with a lower starting dose (120 mg/day). PATIENTS AND METHODS: Regorafenib was initiated at 120 mg/day, and the dosage was increased to 160 mg/day on day 15 of the first cycle for patients who had met the dose escalation criteria. The primary endpoint was the disease control rate (DCR). The pharmacokinetics of the total and unbound regorafenib and its active metabolites (M2, M5) were assessed. RESULTS: A total of 70 patients were enrolled from September 2016 to December 2017. Only 6 patients achieved dose escalation to 160 mg on day 15 as planned. For the 68 evaluable patients, the DCR was 32.4% (95% confidence interval, 21.5%-44.8%), which was less than the threshold (30%) of our statistical hypothesis. The serum concentrations of total regorafenib for patients whose dose was escalated to 160 mg/day were significantly lower than those of the patients whose dose was not escalated (median, 3978 vs. 7244 nM; P = .027). The serum unbound concentrations of the sum of regorafenib and the active metabolites correlated significantly with the maximum grade of regorafenib-related symptomatic adverse events in the first cycle (11,138 vs. 19,096 pM; P = .035). CONCLUSION: Regorafenib with a low starting dose of 120 mg/day did not achieve the expected DCR. A relationship of unbound exposure with toxicity was found.
Subject(s)
Adenocarcinoma/drug therapy , Colorectal Neoplasms/drug therapy , Phenylurea Compounds/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Pyridines/administration & dosage , Adenocarcinoma/blood , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/blood , Colorectal Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Japan , Male , Middle Aged , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/toxicity , Prospective Studies , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/toxicity , Pyridines/pharmacokinetics , Pyridines/toxicityABSTRACT
BACKGROUND: Predictive markers for the clinical outcomes of second-line treatment in patients with metastatic colorectal cancer (mCRC) remain unclear. OBJECTIVE: This retrospective biomarker study was conducted to explore predictive markers for patients with KRAS exon 2 wild-type mCRC who were treated with FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev) in the WJOG6210G trial. PATIENTS AND METHODS: The associations of early tumor shrinkage (ETS), tumor location, and VEGF-D with progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox proportional hazards model. Spearman's correlation coefficient was used to analyze the association of depth of response (DpR) with PFS and OS. Serum VEGF-D levels were measured in samples collected before treatment using magnetic bead panel Milliplex xMAP kits. RESULTS: In total, 101 patients (Pani, n = 49; Bev, n = 52) were enrolled in this study. Patients with ETS had longer PFS (Pani: hazard ratio (HR) 0.40, P = 0.009; Bev: HR 0.078, P = 0.0002) and OS (Pani: HR 0.49, P = 0.044; Bev: HR 0.35, P = 0.048) than patients without ETS. The DpR was moderately correlated with PFS and OS in Pani (rs = 0.75, P < 0.001; rs = 0.60, P < 0.001) and Bev groups (rs = 0.68, P < 0.001; rs = 0.44, P = 0.002). No significant differences were observed in PFS and OS between the two treatment groups even if in left-sided tumors. No significant interaction between VEGF-D levels and treatment was observed in PFS and OS. CONCLUSIONS: ETS and DpR serve as surrogate markers of PFS and OS in the second-line treatment with FOLFIRI plus targeted agent for mCRC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Biomarkers, Tumor/metabolism , Camptothecin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Panitumumab/therapeutic use , Proto-Oncogene Proteins p21(ras)/metabolism , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bevacizumab/pharmacology , Camptothecin/pharmacology , Camptothecin/therapeutic use , Colorectal Neoplasms/pathology , Female , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Humans , Leucovorin/pharmacology , Leucovorin/therapeutic use , Male , Middle Aged , Panitumumab/pharmacology , Retrospective StudiesABSTRACT
BACKGROUND: Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study. PATIENTS AND METHODS: Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety. RESULTS: From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%). CONCLUSION: Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Cetuximab/administration & dosage , Colorectal Neoplasms/drug therapy , Fluorouracil/administration & dosage , Irinotecan/administration & dosage , Oxaliplatin/administration & dosage , Panitumumab/administration & dosage , Proto-Oncogene Proteins p21(ras)/genetics , Adenocarcinoma/genetics , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cetuximab/adverse effects , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm , Female , Fluorouracil/adverse effects , Humans , Irinotecan/adverse effects , Male , Middle Aged , Mutation , Oxaliplatin/adverse effects , Panitumumab/adverse effects , Progression-Free Survival , Time FactorsABSTRACT
A 47-year-old woman patient who presented with weakness in the proximal parts of the upper and lower limbs and difficulty in swallowing was given a diagnosis of advanced esophageal cancer complicated with polymyositis. Steroid therapy was initiated for the polymyositis, but the CK level remained high. Chemotherapy was then selected as the preferred treatment option for the esophageal cancer, however, the treatment was ineffective and the patient died of respiratory failure. There is currently no consensus on the safety of therapy for malignant carcinoma complicated with collagen diseases, therefore, the selection of treatment modality for the disease must be made with care.
Subject(s)
Esophageal Neoplasms/complications , Polymyositis/complications , Autopsy , Esophageal Neoplasms/pathology , Female , Humans , Middle AgedABSTRACT
The polycomb group protein enhancer of zeste homolog 2 (EZH2) is a methyltransferase that suppresses microRNA-31 (miR-31) in various human malignancies including colorectal cancer. We recently suggested that miR-31 regulates the signaling pathway downstream of epidermal growth factor receptor (EGFR) in colorectal cancer. Therefore, we conducted this study for assessing the relationship between EZH2 expression and clinical outcomes in patients with colorectal cancer treated with anti-EGFR therapeutics. We immunohistochemically evaluated EZH2 expression and assessed miR-31 and gene mutations [KRAS (codon 61/146), NRAS (codon 12/13/61), and BRAF (codon 600)] in 109 patients with colorectal cancer harboring KRAS (codon 12/13) wild-type. We also evaluated the progression-free survival (PFS) and overall survival (OS). In the result, low EZH2 expression was significantly associated with shorter PFS (log-rank test: P = 0.023) and OS (P = 0.036) in patients with colorectal cancer. In the low-miR-31-expression group and the KRAS (codon 61/146), NRAS, and BRAF wild-type groups, a significantly shorter PFS (P = 0.022, P = 0.039, P = 0.021, and P = 0.036, respectively) was observed in the EZH2 low-expression groups than in the high-expression groups. In the multivariate analysis, low EZH2 expression was associated with a shorter PFS (P = 0.046), independent of the mutational status and miR-31. In conclusion, EZH2 expression was associated with survival in patients with colorectal cancer who were treated with anti-EGFR therapeutics. Moreover, low EZH2 expression was independently associated with shorter PFS in patients with cancer, suggesting that EZH2 expression is a useful additional prognostic biomarker for anti-EGFR therapy.