Prognostic impact of concomitant pH-regulating drugs in patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitors: the Tokushukai REAl-world Data project 01-S1.

PURPOSE: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs). RESULTS: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively. CONCLUSION: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.

Effectiveness and Safety of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in Pulmonary Sarcomatoid Carcinoma.

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC. Methods: This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan. Results: A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS. Conclusions: ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.

Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01).

OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC.

Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.

HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non-Small Cell Lung Cancer.

PURPOSE: EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non-small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC. EXPERIMENTAL DESIGN: Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells. RESULTS: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd. CONCLUSIONS: Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.

The efficacy of amrubicin on central nervous system metastases originating from small-cell lung cancer: a case series of eight patients.

BACKGROUND: Central nervous system (CNS) metastases caused by small-cell lung cancer (SCLC) are incurable and therefore fatal. Although such metastases are usually treated with chemotherapy or radiotherapy, their sensitivity to these treatment measures is unclear. Amrubicin appears to be a promising agent for relapsed SCLC, but its effectiveness in CNS metastases originating from SCLC is unknown. METHODS: Between April 2002 and December 2009, 110 SCLC patients with CNS metastasis were treated at Shizuoka Cancer Center. Of these, we retrospectively reviewed 8 consecutive cases with CNS metastases originating from relapsed SCLC that were treated with amrubicin as a second-line therapy. RESULTS: We recorded three sensitive relapses and five refractory cases. Amrubicin yielded a CNS response rate of 50 % (2 partial responses and 2 complete response; 95 % CI, 21.5-78.5\ %) and the disease control rate for CNS lesions was 87.5 % (95 % CI, 52.9-97.8 %). All of the sensitive relapse patients achieved a partial response. The median time to progression for CNS metastases was 150.5 days (95 % CI, 9-171 days), and the median survival time from the start of amrubicin administration was 230.5 days (95 % CI, 89-619 days). We also report a dramatic improvement in one patient's radiological result of intramedullary spinal cord metastasis and alleviation of her symptoms following amrubicin monotherapy including this case series. CONCLUSIONS: The results of this study suggest that amrubicin is active in patients with CNS metastases originating from SCLC.

Disease flare after gefitinib discontinuation.

INTRODUCTION: A recent retrospective analysis found that 23% of non-small cell lung cancer patients who acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) demonstrated "disease flare" after discontinuation of EGFR-TKIs. However, limitations of this study present the need for further investigation to elucidate this phenomenon in more detail. METHODS: We reviewed the clinical records of EGFR mutated patients with advanced lung adenocarcinoma who were treated with gefitinib monotherapy in our hospital between January 2007 and December 2010. Disease flare was defined as unexpected interventions (e.g. radiation therapy or pleural drainage), hospitalization, or death attributable to disease progression after gefitinib discontinuation. RESULTS: Among 52 eligible patients, only two experienced disease flare (4%; 95% confidence interval: 1-13%). In both cases, interval time from gefitinib discontinuation to disease flare was 11 days, and the brain was the site of flare. Survival time after gefitinib was significantly shorter in the flare patients (78 and 97 days, respectively) compared with the no-flare patients (median 388 days). CONCLUSIONS: Our analysis demonstrated a lower incidence rate of disease flare after gefitinib discontinuation compared with the previous report, but the prognosis was similarly poor.

Efficacy of rechallenge chemotherapy in patients with sensitive relapsed small cell lung cancer.

OBJECTIVES: To evaluate the efficacy of rechallenge with current induction regimens for sensitive-relapse small cell lung cancer (SCLC) patients. METHODS: We defined sensitive relapse as treatment-free interval (TFI≥90 d). Sensitive-relapse SCLC patients who received second-line chemotherapy were separated into those treated with rechallenge chemotherapy (rechallenge group) and those treated with other regimens (other group). The endpoints were overall survival (OS), progression-free survival, and toxicity. RESULTS: Sixty-five patients (19 rechallenge group and 46 other group) were assessable for efficacy and safety evaluation. No significant differences in age, sex, ECOG performance status at relapse, disease extent at diagnosis, or response to first-line treatment were found between the 2 groups, but TFI was significantly longer in the rechallenge group. Twenty-one patients of the other group received amrubicin. There was no significant difference in OS between the 2 groups (median survival time [MST]: rechallenge group, 14.4 mo; other group, 13.1 mo; P=0.51). In the patients treated with amrubicin, MST was 12.6 months. Comparing the rechallenge group with the patients treated with amrubicin, there was also no significant difference in OS (P=0.38). Both the rechallenge and other group included 11 patients with ex-sensitive relapse (TFI≥180 d). There was no significant difference in OS between the 2 groups (MST 15.7 vs. 26.9 mo, P=0.46). CONCLUSIONS: Rechallenge chemotherapy did not prove superior to other chemotherapies, suggesting that monotherapy, such as amrubicin, might be reasonable as second-line chemotherapy for sensitive-relapse SCLC patients.

A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib.

Epithelioid inflammatory myofibroblastic sarcoma is a variant of inflammatory myofibroblastic tumor with aggressive clinical course associated with RANBP2-ALK fusion. The present report describes a case of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. The feature of the neoplasms, including epithelioid morphology, anaplastic lymphoma kinase staining on the nuclear membrane, and results from the reverse transcriptase-polymerase chain reaction, led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib, an oral anaplastic lymphoma kinase inhibitor, resulted in tumor shrinkage. Distinguishing epithelioid inflammatory myofibroblastic sarcoma from conventional inflammatory myofibroblastic tumor is important, and crizotinib is a promising treatment for this aggressive tumor.

[Evaluation of recurrence rates on change in hormone receptor and human epidermal growth factor receptor 2 status after neo-adjuvant chemotherapy in breast cancer patients].

BACKGROUND: Neo-adjuvant chemotherapy(NAC)may affect hormone receptor(HR)and human epidermal growth factor receptor 2(HER2)status in breast cancer patients. However, the correlation between recurrence rates and this status change remains unclear. METHODS: We evaluated 70 consecutive breast cancer patients receiving NAC with anthracyclines and taxanes, with or without trastuzumab, between January 2005 and May 2012. Pre-treatment core needle biopsy samples and specimens obtained after surgery were tested to determine HR and HER2 status. The relationship between HR and HER2 status changes and recurrence rates was then assessed. RESULTS: Pathological complete response(pCR)was observed in 13 cases and non-pCR was observed in 57 cases. Of the non-pCR cases, HR-positive status changed to HR-negative status in 6.3% of patients, but a change from negativity to positivity was not observed. HER2-positive status changed to HER2-negative status in 48.0% of patients, and a change from negativity to positivity was observed in 12.5% of cases. The recurrence rate among patients with conversion to a HR-negative status was 0%and that among patients with conversion to a HER2-negative status was 25.0%. CONCLUSION: Recurrence rates were not significantly associated with HR and HER2 status conversion after NAC. Future research is warranted to confirm out results.

Comparison of chemotherapeutic efficacy between LCNEC diagnosed using large specimens and possible LCNEC diagnosed using small biopsy specimens.

BACKGROUND: It is often difficult to diagnose large cell neuroendocrine carcinomas (LCNEC) of the lung using small biopsy specimens. Some recent studies attempted to diagnose LCNEC using biopsy specimens; in 2011, the International Association for the Study of Lung Cancer pathological panels suggested possible LCNEC as a diagnosis for LCNEC by using biopsy specimens. Here, we compared the chemotherapeutic efficacy in possible LCNEC and LCNEC diagnosed using surgically resected specimens. METHODS: We retrospectively reviewed patients who received platinum-based chemotherapy as first-line chemotherapy at our institution during September 2002-September 2011. Further, we compared the clinical characteristics, chemotherapeutic responses, and survival outcomes of patients diagnosed as having "LCNEC definite" with those diagnosed as having "possible LCNEC." RESULTS: We selected 34 patients of whom 10 were diagnosed with LCNEC using surgically resected specimens and 24 patients with possible LCNEC were diagnosed using small biopsy specimens. In both groups, almost all patients were men and were smokers. Small-cell carcinoma-based chemotherapy, such as platinum plus irinotecan or platinum plus etoposide, was used for treating 60 % LCNEC patients (6/10) and 67 % possible LCNEC patients. In the LCNEC and possible LCNEC groups, respectively, the response rate was 70 and 54 % (p = 0.39), median progression-free survival was 2.9 and 4.4 months (p = 0.20), and median survival time was 12.8 and 9.1 months (p = 0.50). CONCLUSION: No statistically significant differences were found in chemotherapeutic responses and survival outcomes between the 2 groups, which suggests that chemotherapeutic efficacy is similar in both possible LCNEC and LCNEC.

The impact of clinical outcomes according to EGFR mutation status in patients with locally advanced lung adenocarcinoma who recieved concurrent chemoradiotherapy.

OBJECTIVES: Among patients with locally advanced lung adenocarcinoma, the frequency of epidermal growth factor receptor (EGFR) and KRAS mutations was unknown. In addition, it has not been fully evaluated about the role of these mutations treated with concurrent chemoradiotherapy (CCR). METHODS: The clinical records of locally advanced lung adenocarcinoma patients treated with CCR at Shizuoka Cancer Center between September 2002 and December 2009 were reviewed. RESULTS: Forty-four patients were eligible for this study. EGFR mutation was detected in 13 (29.5%) of 44 patients, and KRAS mutation was detected in 2 (6.5%) of 31 patients. Among EGFR mutation status known patients, overall response rate, median progression-free survival (PFS), and median survival time were 52.3%, 11.5 months, and 35.8 months, respectively. Overall response rate was significantly higher in EGFR mutant group than in EGFR wild-type group (76.9% vs. 41.9%, P=0.02), but this difference did not translate into a significant PFS benefit (9.6 vs. 13.2 mo, P=0.78). Locoregional relapse occured less frequently in patients with EGFR mutation than those with EGFR wild-type, but not significant (15.4% vs. 32.3%, P=0.46). Brain was the most frequent metastatic site of relapse in EGFR mutant group. CONCLUSIONS: Among locally advanced lung adenocarcinoma, EGFR mutation was detected in 29.5% and KRAS mutation was detected in 6.5%. We were not able to detect a difference in PFS or overall survival between EGFR mutant and wild-type patients treated with conventional CCR. Locoregional relapse was approximately half in the EGFR mutant group compared with the EGFR wild-type group; however, this finding did not reach statistical significance.

A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors.

PURPOSE: Nimotuzumab is a humanized IgG1 monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors. METHODS: Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens. RESULTS: Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression. CONCLUSIONS: Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted.

A phase II study of cisplatin /S-1 in patients with carcinomas of unknown primary site.

BACKGROUND: Carcinomas of unknown primary site (CUPs) are heterogeneous tumors associated with a poor prognosis. This phase II trial was designed to evaluate the efficacy and safety of a novel combination chemotherapy of S-1 and cisplatin (CDDP) in patients with CUP. PATIENTS AND METHODS: Patients with previously untreated CUPs were eligible for this trial. The treatment schedule consisted of oral S-1 (40 mg/m(2)) twice a day on days 1-21, and intravenous CDDP (60 mg/m(2)) on day 8. This schedule was repeated every 5 weeks. RESULTS: A total of 46 patients were enrolled. The overall response rate and the disease control rate were 41.3% and 80.4%, respectively. The median overall survival time was 17.4 months. Grade 3/4 neutropenia, thrombocytopenia, and febrile neutropenia occurred in 28.3%, 13.0%, and 2.2% of the patients, respectively. CONCLUSION: CDDP plus S-1 combination chemotherapy is well tolerated and active first-line empiric therapies for patients with CUP.

Size-based isolation of circulating tumor cells in lung cancer patients using a microcavity array system.

BACKGROUND: Epithelial cell adhesion molecule (EpCAM)-based enumeration of circulating tumor cells (CTC) has prognostic value in patients with solid tumors, such as advanced breast, colon, and prostate cancer. However, poor sensitivity has been reported for non-small cell lung cancer (NSCLC). To address this problem, we developed a microcavity array (MCA) system integrated with a miniaturized device for CTC isolation without relying on EpCAM expression. Here, we report the results of a clinical study on CTCs of advanced lung cancer patients in which we compared the MCA system with the CellSearch system, which employs the conventional EpCAM-based method. METHODS: Paired peripheral blood samples were collected from 43 metastatic lung cancer patients to enumerate CTCs using the CellSearch system according to the manufacturer's protocol and the MCA system by immunolabeling and cytomorphological analysis. The presence of CTCs was assessed blindly and independently by both systems. RESULTS: CTCs were detected in 17 of 22 NSCLC patients using the MCA system versus 7 of 22 patients using the CellSearch system. On the other hand, CTCs were detected in 20 of 21 small cell lung cancer (SCLC) patients using the MCA system versus 12 of 21 patients using the CellSearch system. Significantly more CTCs in NSCLC patients were detected by the MCA system (median 13, range 0-291 cells/7.5 mL) than by the CellSearch system (median 0, range 0-37 cells/7.5 ml) demonstrating statistical superiority (p = 0.0015). Statistical significance was not reached in SCLC though the trend favoring the MCA system over the CellSearch system was observed (p = 0.2888). The MCA system also isolated CTC clusters from patients who had been identified as CTC negative using the CellSearch system. CONCLUSIONS: The MCA system has a potential to isolate significantly more CTCs and CTC clusters in advanced lung cancer patients compared to the CellSearch system.

A microarray-based gene expression analysis to identify diagnostic biomarkers for unknown primary cancer.

BACKGROUND: The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. METHODS: Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value<0.001). RESULTS: Among the 44 genes that were up-regulated in the CUP group, 6 genes for ribosomal proteins were identified. Two of these genes (RPS7 and RPL11) are known to be involved in the Mdm2-p53 pathway. We also identified several genes related to metastasis and apoptosis, suggesting a biological attribute of CUP. CONCLUSIONS: The protein products of the up-regulated and down-regulated genes identified in this study may be clinically useful as unique biomarkers for CUP.

A phase I study of S-1 with concurrent radiotherapy in elderly patients with locally advanced non-small cell lung cancer.

BACKGROUND: A phase I study was performed to evaluate dose-limiting toxicity and the recommended dose for the oral fluoropyrimidine S-1 administered concurrently with thoracic radiotherapy (TRT) in elderly (≥ 70 years of age) patients with locally advanced non-small cell lung cancer. METHODS: S-1 was administered on days 1 to 14 and 22 to 35 at oral doses of 65 or 80 mg m(-2) day(-1). TRT was administered in 2-Gy fractions five times weekly for a total dose of 60 Gy. Twelve previously untreated patients were treated with S-1 at 65 (n=6) or 80 (n=6) mg m(-2) day(-1). RESULTS: All patients completed the planned 60 Gy of TRT. Dose-limiting toxicity included pneumonitis (n=2), infection (n=1), and stomatitis (n=1), each of grade 3, but each event was reversible. The recommended dose for S-1 was determined to be 80 mg m(-2) day(-1). No patient experienced toxicity of grade 4. The dose intensity of S-1 was well maintained and the combination of S-1 plus TRT was well tolerated overall. The overall response rate was 83.3 %, with a median survival time of 34.0 months. CONCLUSIONS: Administration of S-1 at 80 mg m(-2) day(-1) on days 1 to 14 and 22 to 35 can be safely combined with concurrent TRT in elderly patients with locally advanced non-small cell lung cancer.

The role of ßIII-tubulin in non-small cell lung cancer patients treated by taxane-based chemotherapy.

BACKGROUND: The aim of this study is to evaluate whether class III ß-tubulin (TUBB3) expression could predict progression-free survival or overall survival in relapsed non-small cell lung cancer (NSCLC) patients treated with taxene-based chemotherapy. METHODS: Immunohistochemistal staining was used to examine the expression of TUBB3 in resected lung tumor specimens obtained from 56 patients treated with platinum-based chemotherapy against recurrent tumors after curative resections. Excision repair cross-complementation group 1, breast cancer susceptibility gene 1, vascular endothelial growth factor, Ki-67, CD34, and p53 were also correlated with clinical features and outcome after treatment. RESULTS: Of the 56 patients enrolled in the study, 29 were treated by carboplatin plus paclitaxel as first-line treatment, and 24 patients received docetaxel monotherapy as second- or third-line treatment. A positive TUBB3 expression is closely associated with a poor response to taxane-based chemotherapy. TUBB3 expression was an independent prognostic factor for predicting poor progression-free survival after docetaxel administration. However, TUBB3 expression could not predict outcome after carboplatin plus paclitaxel treatment. The other biomarkers tested were not independent prognostic factors for predicting outcome after taxane-based chemotherapy. CONCLUSION: TUBB3 expression is associated with resistance to taxane-based chemotherapy and is an independent prognostic factor for predicting poor progression-free survival after docetaxel treatment alone. TUBB3 expression may be a predictive marker for chemoresistance to docetaxel in NSCLC with postoperative recurrent disease.

Feasibility of postoperative adjuvant chemotherapy of cisplatin plus vinorelbine for completely resected non-small-cell lung cancer: a retrospective study in Japan.

BACKGROUND: The efficacy of postoperative adjuvant cisplatin (CDDP)-based chemotherapy, such as the combination of CDDP and vinorelbine (VNR), has been established for surgically resected non-small-cell lung cancer (NSCLC). However, the optimal treatment schedule and dosage for CDDP and VNR are unknown. We evaluated patient compliance with and the safety of adjuvant chemotherapy of CDDP at 80 mg/m(2) administered on day 1 plus VNR at 25 mg/m(2) administered on days 1 and 8, every 3 weeks. METHODS: Medical records of 100 surgically resected NSCLC patients, treated with a combination of CDDP and VNR at the Shizuoka Cancer Center between February 2006 and October 2011, were retrospectively reviewed. RESULTS: Eighty-three (83%) patients completed the planned 4 cycles of CDDP plus VNR and 59 (59%) received the planned doses. Sixty-eight percent of the patients experienced a decreased neutrophil count (grade 3/4 toxicity); 1%, a decreased platelet count; and 4%, febrile neutropenia. No treatment-related deaths were noted in this study. Univariate analysis of the factors influencing patient compliance with this adjuvant chemotherapy showed that neither patient characteristics nor surgical procedure was significantly associated. CONCLUSIONS: Our results indicated that adjuvant chemotherapy with CDDP at 80 mg/m(2) administered on day 1 plus VNR at 25 mg/m(2) administered on days 1 and 8, every 3 weeks, was feasible for surgically resected NSCLC cases.