Isamu Okamoto

Kinki University, Ōsaka, Ōsaka, Japan

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Publications (189)948.46 Total impact

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    ABSTRACT: Hepatocyte growth factor (HGF) expression is a poor prognostic factor in various types of cancer. Expression levels of HGF have been reported to be regulated by shorter poly(dA) sequences in the promoter region. In the present study, the poly(dA) mononucleotide tract in various types of human cancer cell lines was examined and compared with the HGF expression levels in those cells. Short deoxyadenosine repeat sequences were detected in five of the 55 cell lines used in the present study. The H69, IM95, CCK-81, Sui73 and H28 cells exhibited a truncated poly(dA) sequence in which the number of poly(dA) repeats was reduced by ≥5 bp. Two of the cell lines exhibited high HGF expression, determined by reverse transcription quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The CCK-81, Sui73 and H28 cells with shorter poly(dA) sequences exhibited low HGF expression. The cause of the suppression of HGF expression in the CCK-81, Sui73 and H28 cells was clarified by two approaches, suppression by methylation and single nucleotide polymorphisms in the HGF gene. Exposure to 5-Aza-dC, an inhibitor of DNA methyltransferase 1, induced an increased expression of HGF in the CCK-81 cells, but not in the other cells. Single-nucleotide polymorphism (SNP) rs72525097 in intron 1 was detected in the Sui73 and H28 cells. Taken together, it was found that the defect of poly(dA) in the HGF promoter was present in various types of cancer, including lung, stomach, colorectal, pancreas and mesothelioma. The present study proposes the negative regulation mechanisms by methylation and SNP in intron 1 of HGF for HGF expression in cancer cells with short poly(dA).
    Oncology letters 01/2015; 9(1):405-410. · 0.24 Impact Factor
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    ABSTRACT: Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m2. Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m2 and one at 200 mg/m2; the maximum tolerated dose of this study was determined to be 200 mg/m2. Of the 17 patients, 13 patients (76.5 %) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4 %) and pyrexia (23.5 %). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m2. The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).
    Investigational New Drugs 12/2014; · 3.50 Impact Factor
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    ABSTRACT: Background S-1, a novel oral fluoropyrimidine, has potent antitumor activity against non–small-cell lung cancer (NSCLC). Meanwhile, leucovorin enhances the efficacy of 5-fluorouracil by inhibiting thymidylate synthase. Therefore, this phase II clinical trial evaluated the safety and efficacy of S-1 plus leucovorin combination therapy for previously treated patients with NSCLC. Patients and methods Patients with stage IIIB or IV NSCLC were prospectively enrolled if they received 1 or 2 prior chemotherapy regimens. S-1 (40–60 mg) and leucovorin (25 mg) were administered together orally twice per day for 7 consecutive days followed by 7 days of rest. This 2-week cycle was repeated for a maximum of 25 cycles until the onset of disease progression or unacceptable adverse events. Endpoints included objective tumor response, progression-free survival, overall survival, and safety. Results Among 33 patients, 6 (18.2%), 14 (42.4%), and 11 (33.3%) had partial response, stable disease, and progressive disease, respectively. Median progression-free and overall survival times were 3.5 and 11.7 months, respectively. The common grade 3 toxicities included stomatitis (18.2%), anorexia (12.1%), and neutropenia (9.1%). One patient had pneumatosis cystoides intestinalis, and another experienced paralytic ileus. There were no treatment-related deaths. Conclusions S-1 plus leucovorin combination therapy demonstrated promising efficacy and an acceptable toxicity profile in previously treated patients with NSCLC (Clinical Trials Registry No.: UMIN000004568).
    Lung Cancer. 12/2014;
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    ABSTRACT: Crizotinib is the first clinically available tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and is associated with the development of complex renal cysts. We now describe a 39-year-old woman who developed infected complex renal cysts during crizotinib treatment. After 10 months of such treatment, she presented with a high fever and low back pain. Computed tomography findings were consistent with complex renal cysts and perilesional inflammation. Interventions including cyst drainage and antibiotic administration contributed to diagnosis and management of the infected cysts.
    Investigational New Drugs 11/2014; · 3.50 Impact Factor
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    ABSTRACT: We previously showed that tumor-derived heregulin, a ligand for HER3, is associated with both de novo and acquired resistance to cetuximab. We have now examined whether patritumab, a novel neutralizing monoclonal antibody to HER3, is able to overcome such resistance. Human colorectal cancer (DiFi) cells that are highly sensitive to cetuximab were engineered to stably express heregulin by retroviral infection, and the effects of cetuximab and patritumab on the resulting DiFi-HRG cells were examined. DiFi-HRG cells released substantial amounts of heregulin and showed resistance to cetuximab. Cetuximab alone inhibited EGFR and ERK phosphorylation in DiFi-HRG cells, but it had no effect on the phosphorylation of HER2, HER3, or AKT, suggesting that sustained AKT activation by HER2 and HER3 underlies cetuximab resistance in these cells. In contrast, patritumab in combination with cetuximab markedly inhibited the phosphorylation of EGFR, HER2, HER3, ERK, and AKT. The combination therapy also inhibited the growth of DiFi-HRG tumor xenografts in nude mice to a greater extent than did treatment with either drug alone. Activation of HER2-HER3 signaling associated with the operation of a heregulin autocrine loop confers resistance to cetuximab, and patritumab is able to restore cetuximab sensitivity through inhibition of heregulin-induced HER3 activation.
    Oncotarget 11/2014; · 6.64 Impact Factor
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    ABSTRACT: Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, are promising therapies for advanced non-small cell lung cancer (NSCLC). Our study was aimed to determine whether there were conditions under which the addition of bevacizumab would enhance the antitumor activity of erlotinib against NSCLC tumors in vitro and in vivo.
    Cancer Chemotherapy and Pharmacology 10/2014; · 2.80 Impact Factor
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    ABSTRACT: Background: This Phase I, open-label study evaluated the safety/tolerability and maximum tolerated dose (MTD) of second-line nintedanib combined with docetaxel in Japanese patients with advanced non-small-cell lung cancer (NSCLC).Methods: Eligible patients received docetaxel 60 or 75 mg/m (Day 1) plus nintedanib 100, 150, or 200 mg twice daily (bid; Days 2-21) in 21-day cycles. Standard 3+3 dose escalations were performed separately in patient cohorts with a body surface area (BSA) of <1.5 m (BSA<1.5) and BSA≥1.5, respectively.Results: Forty-two patients (17 BSA<1.5, 25 BSA≥1.5) were treated. The MTD of nintedanib was 150 and 200 mg bid in BSA<1.5 and BSA≥1.5 patients, respectively in combination with 75 mg/m of docetaxel. Dose-limiting toxicities (all grade 3 hepatic enzyme elevations) occurred in 12 patients (six per cohort). Drug-related adverse events included neutropenia (95%), leukopenia (83%), fatigue (76%), alopecia (71%), decreased appetite (67%), and elevations in alanine aminotransferase (64%) and aspartate aminotransferase (64%). All hepatic enzyme elevations were reversible and manageable with dose reduction or discontinuation. Among 38 evaluable patients, 10 (26%) had a partial response and 18 (47%) had stable disease.Conclusions: Continuous treatment with second-line nintedanib combined with docetaxel was manageable and showed promising signs of efficacy in Japanese patients with advanced NSCLC.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 10/2014; · 4.55 Impact Factor
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    ABSTRACT: Background With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease. Methods In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390. Findings Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16·0 months (95% CI 13·9–18·1) with erlotinib plus bevacizumab and 9·7 months (5·7–11·1) with erlotinib alone (hazard ratio 0·54, 95% CI 0·36–0·79; log-rank test p=0·0015). The most common grade 3 or worse adverse events were rash (19 [25%] patients in the erlotinib plus bevacizumab group vs 15 [19%] patients in the erlotinib alone group), hypertension (45 [60%] vs eight [10%]), and proteinuria (six [8%] vs none). Serious adverse events occurred at a similar frequency in both groups (18 [24%] patients in the erlotinib plus bevacizumab group and 19 [25%] patients in the erlotinib alone group). Interpretation Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted. Funding Chugai Pharmaceutical Co Ltd.
    The Lancet Oncology 10/2014; · 25.12 Impact Factor
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    ABSTRACT: Recent clinical trials have shown that immune-checkpoint blockade yields a clinical response in a subset of individuals with advanced non-small cell lung cancer (NSCLC). We examined whether the expression of programmed death-ligand 1 (PD-L1) is related to clinicopathologic or prognostic factors in patients with surgically resected NSCLC.
    Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 07/2014;
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    ABSTRACT: The performance of scientifically and ethically valid prospective clinical trials is the only means by which to obtain reliable clinical evidence that can improve clinical practice and thus the outcome of patients with lung cancer. The efficacy of treatment for advanced lung cancer remains limited; many cooperative study groups for lung cancer have been established in Japan since 1990s, and they have completed several landmark investigator-initiated clinical trials. This review highlights eight active Japanese cooperative study groups for lung cancer and summarizes their achievements made through clinical trials. In addition to their benefits, the existence of multiple study groups for a single disease such as lung cancer presents several challenges including the provision of infrastructure to ensure the scientific integrity of trial results, the unnecessary duplication of effort and the wasting of limited resources, and the accrual and completion of large-scale phase III trials in the shortest possible time. Collaboration among Japanese cooperative groups has recently increased in order to overcome these challenges. Although institutional barriers to the performance of such large intergroup trials remain, further harmonization and collaboration among cooperative groups will be vital in allowing Japanese investigators to make further important contributions for the development of new lung cancer therapies.
    Respiratory Investigation. 07/2014;
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    ABSTRACT: Purpose: Irreversible EGFR-tyrosine kinase inhibitors (TKIs) are thought to be one strategy to overcome EGFR-TKI resistance induced by T790M gate-keeper mutations in non-small cell lung cancer (NSCLC), yet they display limited clinical efficacy. We hypothesized that additional resistance mechanisms that cooperate with T790M could be identified by profiling tyrosine phosphorylation in NSCLC cells with acquired resistance to reversible EGFR-TKI and harboring T790M. Experimental Design: We profiled PC9 cells with TKI-sensitive EGFR mutation and paired EGFR-TKI-resistant PC9GR (gefitinib-resistant) cells with T790M using immunoaffinity purification of tyrosine-phosphorylated peptides and mass-spectrometry-based identification/quantification. Profiles of erlotinib perturbations were examined. Results: We observed a large fraction of the tyrosine phosphoproteome was more abundant in PC9- and PC9GR-erlotinib treated cells, including phosphopeptides corresponding to MET, IGF, and AXL signaling. Activation of these receptor tyrosine kinases by growth factors could protect PC9GR cells against the irreversible EGFR-TKI afatinib. We identified a Src-family kinase (SFK) network as EGFR-independent and confirmed that neither erlotinib nor afatinib affected Src phosphorylation at the activation site. The SFK-inhibitor dasatinib plus afatinib abolished Src phosphorylation and completely suppressed downstream phosphorylated Akt and Erk. Dasatinib further enhanced anti-tumor activity of afatinib or T790M-selective EGFR-TKI (WZ4006) in proliferation and apoptosis assays in multiple NSCLC cell lines with T790M mediated resistance. This translated into tumor regression in PC9GR xenograft studies with combined afatinib and dasatinib. Conclusions: Our results identified both co-drivers of resistance along with T790M and support further studies of irreversible or T790M-selective EGFR inhibitors combined with dasatinib in NSCLC patients with acquired T790M.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2014;
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    ABSTRACT: The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC.
    The Journal of clinical investigation. 06/2014;
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    ABSTRACT: The optimal treatment for elderly patients with limited-disease small cell lung cancer has not been defined. We therefore performed a Phase I study for split-dose cisplatin plus etoposide combined with early concurrent accelerated hyperfractionated thoracic radiotherapy in elderly (70 years of age or older) patients with limited-disease small cell lung cancer.
    Japanese Journal of Clinical Oncology 05/2014; · 1.90 Impact Factor
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    ABSTRACT: The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non–small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m2) with (group DZ) or without (group D) zoledronic acid (4 mg) every 21 days. There were 50 patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94 patients (DZ, 48; D, 46), the median progression-free survival was 2.7 months (95% confidence interval [CI], 1.5–3.5 months) for the DZ group and 2.6 months (95% CI, 1.5–3.4 months) for the D group (stratified log-rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0–15.8 months) for the DZ group and 9.7 months (95% CI, 6.1–12.5 months) for the D group (stratified log-rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).This article is protected by copyright. All rights reserved.
    Cancer Science 05/2014; · 3.48 Impact Factor
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    ABSTRACT: Archival formalin-fixed, paraffin-embedded (FFPE) tumor specimens were collected from advanced NSCLC patients enrolled in LETS phase III trial comparing first-line S-1/carboplatin with paclitaxel/carboplatin and subjected to multiplex genotyping for 214 somatic hotspot mutations in 26 genes (LungCarta Panel) and 20 major variants of ALK, RET, and ROS1 fusion genes (LungFusion Panel) with the Sequenom MassARRAY platform. MET amplification was evaluated by fluorescence in situ hybridization. A somatic mutation in at least one gene was identified in 48% of non-squamous cell carcinoma and 45% of squamous cell carcinoma specimens, with EGFR (17%), TP53 (11%), STK11 (9.8%), MET (7.6%), and KRAS (6.2%). Mutations in EGFR or KRAS were associated with a longer or shorter median overall survival, respectively. The LungFusion Panel identified ALK fusions in six cases (2.5%), ROS1 fusions in five cases (2.1%), and a RET fusion in one case (0.4%), with these three types of rearrangement being mutually exclusive. Nine (3.9%) of 229 patients were found to be positive for de novo MET amplification. This first multiplex genotyping of NSCLC associated with a phase III trial shows that MassARRAY-based genetic testing for somatic mutations and fusion genes performs well with nucleic acid derived from FFPE specimens of NSCLC tissue.
    Oncotarget 04/2014; 5(8):2293-304. · 6.64 Impact Factor
  • Journal of Clinical Oncology 02/2014; · 18.04 Impact Factor
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    ABSTRACT: Somatic mutations in the epidermal growth factor receptor gene (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). Clinical indicators of the likely survival benefit of EGFR-TKI treatment in NSCLC patients with EGFR mutations have not been identified, however. We therefore evaluated progression-free survival (PFS) and overall survival (OS) according to tumor response and tumor shrinkage pattern in such patients. Among 145 EGFR mutation-positive NSCLC patients treated with EGFR-TKIs, 68 individuals were selected for analysis. Of the 68 selected patients, 6 achieved a complete response (CR), 42 a partial response (PR), and 14 stable disease (SD). Both PFS and OS were significantly longer in patients who achieved a CR or PR than in those who experienced SD. Multivariate analysis showed that a response (CR or PR) to EGFR-TKIs was significantly associated with both PFS and OS. Among the CR/PR group, the median maximal tumor shrinkage relative to baseline was 56%, and the median time to response (TTR) was 4.2 weeks. The subsets of these patients who experienced rapid tumor regression (TTR of ≤4.2 weeks) or a high degree of tumor shrinkage (≥56%) did not show a more favorable PFS or OS compared with those who experienced slow tumor regression or a low degree of tumor shrinkage. Response (CR or PR) may represent the optimal surrogate for efficacy among EGFR mutation-positive NSCLC patients treated with EGFR-TKIs.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2014; 9(2):200-4. · 4.55 Impact Factor
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    ABSTRACT: Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as "oncogene addiction". A new generation of drugs that selectively target such "driver oncogenes" manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an "oncogenic driver" and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.
    Cancers. 01/2014; 6(3):1540-1552.
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    ABSTRACT: nab-Paclitaxel (nab-P) is approved, in the United States, in combination with carboplatin for the first-line treatment of advanced non-small-cell lung cancer, based on a randomized phase 3 trial of nab-P plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C). This trial revealed a higher overall response rate (33% versus 25%; p = 0.005) and longer, but not statistically significant, overall and progression-free survival for nab-P/C versus sb-P/C. In addition, nab-P/C demonstrated lower rates of grade 3 or higher peripheral neuropathy, myalgia, arthralgia, and neutropenia but higher rates of anemia and thrombocytopenia. This report analyzes patient and physician assessment of symptoms within this trial. Patients completed the taxane subscale of the Functional Assessment of Cancer Therapy questionnaire, which focuses on taxane toxicity, including peripheral neuropathy and neurotoxicity. Mean baseline scores and changes from baseline are reported. Physicians also graded the severity of neuropathy at each patient visit using National Cancer Institute Common Toxicity Criteria. Patients receiving nab-P/C reported significantly less worsening of peripheral neuropathy (p < 0.001), pain (p < 0.001), and hearing loss (p = 0.002). Patient-reported edema was similar between the two treatment arms. In agreement with patient-reported symptoms, the results of a per-treatment cycle physician assessment of peripheral neuropathy also favored nab-P/C over sb-P/C (p < 0.001). In this trial of patients receiving first-line treatment for advanced non-small-cell lung cancer, nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 01/2014; 9(1):83-90. · 4.55 Impact Factor

Publication Stats

4k Citations
948.46 Total Impact Points

Institutions

  • 2006–2014
    • Kinki University
      • Faculty of Medicine
      Ōsaka, Ōsaka, Japan
    • Kyoto University
      Kioto, Kyōto, Japan
  • 2012
    • Kurashiki Central Hospital
      Kurasiki, Okayama, Japan
    • Kishiwada City Hospital
      Kisiwada, Ōsaka, Japan
  • 2011
    • Aichi Medical University
      Japan
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
  • 2009
    • Aichi Cancer Center
      Ōsaka, Ōsaka, Japan
  • 2008–2009
    • National Cancer Center, Japan
      • Center for Cancer Control and Information Services
      Edo, Tōkyō, Japan
    • IIzuka Hospital
      Иидзука, Fukuoka, Japan
  • 2007
    • Nara Hospital
      Ikuma, Nara, Japan
    • Osaka Medical College
      Takatuki, Ōsaka, Japan
  • 1998–2005
    • Kumamoto University
      • • Department of Respiratory Medicine
      • • Graduate School of Medical Sciences
      • • Department of Tumor Genetics and Biology
      Kumamoto, Kumamoto Prefecture, Japan
  • 2002–2003
    • Thomas Jefferson University
      • Department of Microbiology & Immunology
      Philadelphia, PA, United States