Kaname Nosaki

Role of surgical resection for patients with limited disease-small cell lung cancer

OBJECTIVES Although chemotherapy and radiotherapy are recommended for patients with limited disease small cell lung cancer (LD-SCLC), several series have reported favorable survival outcomes even in patients with stages II and III disease who underwent surgical resection. The purpose of this study is to compare the outcomes of the use of surgical resection to the other conventional non-surgical treatments in patients with LD-SCLC with respect to each clinical stage. MATERIALS AND METHODS We retrospectively reviewed 277 patients who received treatment for LD-SCLC and compared the outcomes of the use of surgical resection to the other conventional non-surgical treatments. RESULTS The clinical stage was stage I in 50 cases (18%), stage II in 53 cases (19%) and stage III in 174 cases (63%). Eighty-eight patients received surgical resection and 189 patients were treated with non-surgical treatment. Surgery was performed in 44 patients (88%) with stage I, 27 patients (52%) with stage II and 17 patients (10%) with stage III disease. The five-year survival rates of the patients according to clinical stage were 58% in stage I, 29% in stage II and 18% in stage III. The five-year survival rates of the patients with and without surgical resection according to clinical stage were as follows: 62% and 25% in stage I (p<0.01), 33% and 24% in stage II (p=0.95), 18% and 18% in stage III (p=0.35), respectively. In 44 propensity score-matched pairs with stages II and III disease, including matching for variables such as age, gender and the PS, the five-year survival rates was better in patients with surgical resection than in those without surgery (p=0.04). CONCLUSION Surgical resection is effective for the patients with stage I LD-SCLC and some cases of stage II or III disease.

Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors

Introduction AZD4877 is a potent Eg5 inhibitor that has been shown to have an acceptable tolerability profile in a Phase I study of Western patients with solid tumors. This study was conducted to evaluate the safety, pharmacokinetic (PK) profile, maximum tolerated dose (MTD) and efficacy of AZD4877 in a Japanese population with solid tumors. Methods In this Phase I, open-label, dose-escalation study, AZD4877 (10, 15, 20 or 25 mg) was administered as a 1-hour intravenous infusion on days 1, 8 and 15 of repeated 28-day cycles to Japanese patients with advanced solid tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PK variables were assessed pre- and post dosing. The MTD of AZD4877 was determined by evaluating dose-limiting toxicities (DLTs). Efficacy was evaluated by assessing best response according to Response Evaluation Criteria In Solid Tumors version 1.0. Results Of the 21 patients enrolled, 18 received at least one dose of AZD4877 (N = 3 in both the 10 and 15 mg cohorts, N = 6 in both the 20 and 25 mg cohorts). The most commonly reported AEs were fatigue and nausea (39% of patients each). One patient in each of the 20 and 25 mg cohorts experienced a DLT (neutropenia and febrile neutropenia). Dose escalation was halted at 25 mg and the MTD was not defined in this population. CTCAE grade ≥3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56%) and leukopenia (44%) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877 clearance and elimination half-life appeared independent of dose. The best response to AZD4877 was stable disease in five of 16 evaluable patients. Conclusion AZD4877 up to doses of 25 mg was well tolerated in Japanese patients. There was little evidence of clinical efficacy.

Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor–naïve patients with non–small cell lung cancer harboring EGFR mutations

The T790M secondary mutation of the epidermal growth factor receptor (EGFR) gene accounts for 50% to 60% of cases of resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The prevalence of T790M in EGFR mutation-positive patients who acquire resistance to the irreversible, second-generation EGFR-TKI afatinib has remained unclear, however. We here determined the frequency of T790M acquisition at diagnosis of progressive disease in patients with EGFR-mutated non-small cell lung cancer (NSCLC) treated with afatinib as first-line EGFR-TKI. Among 56 enrolled patients, 37 individuals underwent molecular analysis at rebiopsy. Of these 37 patients, 16 individuals (43.2%) had acquired T790M, including 11/21 patients (52.4%) with an exon 19 deletion of EGFR and 5/13 patients (38.5%) with L858R. None of three patients with an uncommon EGFR mutation harbored T790M. T790M was detected in 14/29 patients (48.3%) with a partial response to afatinib, 1/4 patients (25%) with stable disease, and 1/4 patients (25%) with progressive disease as the best response. Median progression-free survival after initiation of afatinib treatment was significantly (P = 0.043) longer in patients who acquired T790M (11.9 months; 95% confidence interval, 8.7-15.1) than in those who did not (4.5 months; 95% confidence interval, 2.0-7.0). Together, our results show that EGFR-mutated NSCLC patients treated with afatinib as first-line EGFR-TKI acquire T790M at the time of progression at a frequency similar to that for patients treated with gefitinib or erlotinib. They further underline the importance of rebiopsy for detection of T790M in afatinib-treated patients.The T790M secondary mutation of the epidermal growth factor receptor (EGFR) gene accounts for 50% to 60% of cases of resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The prevalence of T790M in EGFR mutation–positive patients who acquire resistance to the irreversible, second-generation EGFR-TKI afatinib has remained unclear, however. We here determined the frequency of T790M acquisition at diagnosis of progressive disease in patients with EGFR-mutated non–small cell lung cancer (NSCLC) treated with afatinib as first-line EGFR-TKI. Among 56 enrolled patients, 37 individuals underwent molecular analysis at rebiopsy. Of these 37 patients, 16 individuals (43.2%) had acquired T790M, including 11/21 patients (52.4%) with an exon 19 deletion of EGFR and 5/13 patients (38.5%) with L858R. None of three patients with an uncommon EGFR mutation harbored T790M. T790M was detected in 14/29 patients (48.3%) with a partial response to afatinib, 1/4 patients (25%) with stable disease, and 1/4 patients (25%) with progressive disease as the best response. Median progression-free survival after initiation of afatinib treatment was significantly (P = 0.043) longer in patients who acquired T790M (11.9 months; 95% confidence interval, 8.7–15.1) than in those who did not (4.5 months; 95% confidence interval, 2.0–7.0). Together, our results show that EGFR-mutated NSCLC patients treated with afatinib as first-line EGFR-TKI acquire T790M at the time of progression at a frequency similar to that for patients treated with gefitinib or erlotinib. They further underline the importance of rebiopsy for detection of T790M in afatinib-treated patients.

The Controlling Nutritional Status Score Is a Significant Independent Predictor of Poor Prognosis in Patients With Malignant Pleural Mesothelioma

Introduction Malignant pleural mesothelioma (MPM) is a devastating neoplasm; however, some patients exhibit a good response to chemotherapy or multidisciplinary therapy, including surgery and chemotherapy. It is therefore important to discover the factors that can be used to select patients who will benefit from such treatment. Although the Controlling Nutritional Status (CONUT) score has been used to predict the prognosis in other types of malignancy, its utility in patients with MPM is unknown. The aim of this study was to clarify the clinical significance of the CONUT in patients with MPM. Methods The data of 83 patients, who were treated with surgery, chemotherapy, or multidisciplinary therapy, were analyzed in the present study. A cut‐off CONUT score of 2 was used to classify all of the patients into low or high CONUT groups. Results Fifty‐two of the 83 patients were classified into the low CONUT group. A high CONUT score was significantly correlated with chemotherapy alone (P = .011). The high CONUT group had significantly poorer overall survival (OS) (P < .001) and disease‐ or progression‐free survival (DFS/PFS) (P < .001). The clinical stage and the CONUT score were found to be independent predictive factors for the OS: clinical stage, I/II and III/IV; P = .001 and CONUT score, ≥ 3 and ≤ 2; P = .011, respectively. The clinical stage and the CONUT score were also independent predictive factors for DFS/PFS: clinical stage, I/II and III/IV; P = .006 and CONUT score, ≥ 3 and ≤ 2; P = .013, respectively. Conclusions The CONUT score was an independent predictor of a poor prognosis in the patients with MPM. This score provides useful information for selecting patients who will benefit from the treatment. Micro‐Abstract The aim of this study was to clarify the clinical significance of the Controlling Nutritional Status (CONUT) in malignant pleural mesothelioma. The data of 83 patients were analyzed. The high CONUT group had significantly poorer overall survival (P < .001) and disease‐ or progression‐free survival (P < .001). The CONUT score provides useful information for selecting patients who will benefit from the treatment.

Monitoring of somatic mutations in circulating cell-free DNA by digital PCR and next-generation sequencing during afatinib treatment in patients with lung adenocarcinoma positive for EGFR activating mutations

Background Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness of such liquid biopsy testing with both the digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) during treatment of patients with the epidermal growth factor receptor (EGFR) inhibitor afatinib. Patients and methods Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations and were treated with afatinib. Plasma samples were collected before and during (4 and 24 weeks) afatinib treatment as well as at disease progression. Tumor and plasma DNA were analyzed by dPCR and NGS. Results Thirty-five patients were enrolled. The objective response rate and median progression-free survival (PFS) were 77.1% and 13.8 months, respectively. Tumor and plasma DNA were available for 32 patients. dPCR and NGS detected EGFR activating mutations in 81.3% and 71.9% of baseline cfDNA samples, respectively. In 19 patients treated with afatinib for ≥24 weeks, the number of EGFR mutant alleles detected in cfDNA by dPCR declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number (<10 copies per milliliter) at 4 weeks. Median PFS was slightly longer for patients with undetectable EGFR mutant alleles in cfDNA at 4 weeks than for those in whom such alleles were detectable (14.3 versus 10.0 months). A total of 45 somatic mutations was identified in baseline tumor DNA, and 30 (66.7%) of these mutations were identified in cfDNA by NGS. Allele frequency for somatic mutations in cfDNA determined by NGS changed concordantly during afatinib treatment with the number of EGFR mutant alleles determined by dPCR. Conclusions Monitoring of cfDNA by dPCR is informative for prediction of afatinib efficacy, whereas that by NGS is reliable and has the potential to identify mechanisms of treatment resistance.

A novel, polymer-coated oncolytic measles virus overcomes immune suppression and induces robust antitumor activity

Although various therapies are available to treat cancers, including surgery, chemotherapy, and radiotherapy, cancer has been the leading cause of death in Japan for the last 30 years, and new therapeutic modalities are urgently needed. As a new modality, there has recently been great interest in oncolytic virotherapy, with measles virus being a candidate virus expected to show strong antitumor effects. The efficacy of virotherapy, however, was strongly limited by the host immune response in previous clinical trials. To enhance and prolong the antitumor activity of virotherapy, we combined the use of two newly developed tools: the genetically engineered measles virus (MV-NPL) and the multilayer virus-coating method of layer-by-layer deposition of ionic polymers. We compared the oncolytic effects of this polymer-coated MV-NPL with the naked MV-NPL, both in vitro and in vivo. In the presence of anti-MV neutralizing antibodies, the polymer-coated virus showed more enhanced oncolytic activity than did the naked MV-NPL in vitro. We also examined antitumor activities in virus-treated mice. Complement-dependent cytotoxicity and antitumor activities were higher in mice treated with polymer-coated MV-NPL than in mice treated with the naked virus. This novel, polymer-coated MV-NPL is promising for clinical cancer therapy in the future.

Signet ring cell adenocarcinoma of the lung with an EML4–ALK fusion gene mimicking mucinous (colloid) adenocarcinoma: A case report

We herein report a case of signet ring cell adenocarcinoma of the lung with an EML4-ALK fusion gene mimicking mucinous (colloid) adenocarcinoma. A 79-year-old female presented with a pulmonary tumor located in the right lower lobe measuring 21 mm in size. A right lower lobectomy was performed. The postoperative pathological examination revealed signet ring cell carcinoma with abundant mucin pools, and a multiplex RT-PCR analysis revealed the variant 2 inversion of the EML4-ALK gene.

How should we manage small focal pure ground-glass opacity nodules on high-resolution computed tomography? A single institute experience.

BACKGROUND Although the detection of pure ground-glass opacity (p-GGO) nodules on high-resolution chest computed tomography (HRCT) often implies a diagnosis of lung adenocarcinoma, the management of p-GGO nodules remains under discussion. OBJECTIVE To assess the correlation between the radiological and pathological diagnoses of small p-GGO on HRCT. PATIENTS AND METHODS This is a single-institution retrospective study. We analyzed 89 consecutive patients, including 33 patients with resected p-GGO nodule(s) equal or less than 20 mm in maximal diameter on axial images of HRCT. RESULTS Thirty-nine patients underwent locoregional treatment (Treatment group), including surgical resection in 33 and stereotactic body radiation therapy in six. The remaining 50 patients were observed (Observation group) using periodic chest HRCT. The median follow-up time was 30.4 (4.9-102.5) months in the Treatment group and 44.8 (0.4-1125.8) months in the Observation group. During the follow-up period, the p-GGO nodules increased in size in eight patients over a median of 20.6 (12.1-50.6) months, with increased attenuation in three patients over a median of 20.6 (12.1-50.6) months, and either decreased in size or disappeared in four patients over a median of 6.9 (2.0-11.2) months. Thirty-three patients with 47 nodules underwent surgical resection, including 41 adenocarcinomas, one neuroendocrine tumor, three cases of atypical adenomatous hyperplasia and two benign lesions. The frequency of invasive adenocarcinoma was higher among the larger p-GGO nodules. CONCLUSIONS Careful observation and decision making with respect to the timing of intervention in cases of p-GGO nodules are warranted.

Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non‐small‐cell lung cancer

Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(–) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v‐positive cancer cells. Chemotherapy‐naïve patients with advanced non‐squamous non‐small‐cell lung cancer were enrolled in a dose‐escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end‐point was the percentage of patients who experience dose‐limiting toxicity. Fifteen patients were enrolled in the study. Dose‐limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression‐free survival was 11.7 months, much longer than that for cisplatin–pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin–pemetrexed, with the addition of SASP tending to prolong progression‐free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854.

Are Anthracycline-Based Regimens Truly Indicated To Be the Standard Chemotherapy Regimen for Thymic Carcinoma?

Introduction Thymic carcinoma (TC) is an exceptionally rare form of tumor that differs from thymoma by virtue of its very poor prognosis. The difficulties associated with conducting prospective trials involving rare diseases such as TC limit the evidence that can be applied to their treatment. To the extent possible, however, all medical treatment should be evidence based. Methods We reviewed the clinical results regarding chemotherapy and thymic epithelial malignancies, which include invasive thymoma and TC. We conducted a search of the PubMed database to extract all the chemotherapeutic clinical trials from January 1990 to December 2014. The search included the terms chemotherapy, thymic malignancy, thymoma, and thymic carcinoma and all English‐language publications. Results From the initial total of 248 articles, we excluded articles that were only in abstract form, review articles, and case reports. In addition, to focus on cytotoxic therapies, we excluded articles on molecular target therapy for TC from our study. After the exclusion criteria were applied, 31 articles remained; they included prospective and retrospective trials. Conclusions This study assessed the reliable and assessable data on the chemotherapy regimens for TC to identify the evidence‐based recommendations. The results indicate that the only recommended anthracycline‐containing regimen would be carboplatin plus amrubicin—not the combination of cisplatin, doxorubicin, vincristine, and cyclophosphamide—and that the recommended regimens without anthracycline would be carboplatin plus paclitaxel and cisplatin plus docetaxel.