Irinotecan and Gemcitabine as Second-Line Treatment in Patients with Malignant Pleural Mesothelioma following Platinum plus Pemetrexed Chemotherapy: A Retrospective Study.

BACKGROUND: Cisplatin-pemetrexed combination chemotherapy is the current standard primary treatment for malignant pleural mesothelioma (MPM). It was first approved for untreated and unresectable MPM in the 2003 National Comprehensive Cancer Network (NCCN) guidelines. However, to date, standard treatments for patients with MPM who previously underwent chemotherapy, as recommended by the NCCN Malignant Pleural Mesothelioma guidelines, have been inadequate. To explore treatment options for such patients, we performed this retrospective study of patients who received irinotecan plus gemcitabine as second-line therapy for MPM. METHODS: We investigated 62 patients diagnosed with unresectable MPM between January 2008 and October 2017 who experienced recurrence following cisplatin treatment (or carboplatin) plus pemetrexed or pemetrexed monotherapy as first-line treatment, and who underwent irinotecan plus gemcitabine combination therapy as second-line treatment. Irinotecan (60 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1 and 8 every 3 weeks, including a 1-week washout period. Our endpoints were efficacy, survival period, and toxicity. RESULTS: patients' median age was 65 years (range 50-79), and the histological MPM types were epithelioid (n = 48), sarcomatoid (n = 6), biphasic (n = 6), and desmoplastic (n = 2). One patient experienced a partial response, 40 had stable disease, and 21 had progressive disease. The disease control rate was 66.1% and the response rate 2.1%. Additionally, the median progression-free and overall survival time were 5.7 and 11.3 months, respectively. The most common adverse events were neutropenia (32.2%), loss of appetite (16.1%), nausea/diarrhea (11.3%), and thrombocytopenia/phlebitis (9.7%). Grade 3 adverse events included neutropenia (12.9%) and thrombocytopenia/phlebitis (2.1%); however, all adverse events were managed with symptomatic therapy. CONCLUSIONS: Despite the fact that second-line irinotecan plus gemcitabine combination therapy did not produce marked tumor shrinkage, it achieved a relatively high disease control rate of >65% with an acceptable toxicity profile. Hence, the combination of irinotecan plus gemcitabine may be considered for MPM treatment, with consideration of combination with immune checkpoint inhibitors as a potential next step.

Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin-1 receptor (IL-1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro-inflammatory cytokine IL-1ß and the IL-1R in MPM cells. Stimulation by IL-1ß promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor-associated macrophages (TAMs) as the major source of IL-1ß in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos-activated inflammasome in TAMs induced the production of IL-1ß, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL-1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL-1ß/IL-1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973).

EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest.

Small-cell lung cancer (SCLC) is characterized by one of neuroendocrine tumors, and is a clinically aggressive cancer due to its rapid growth, early dissemination, and rapid acquisition of multidrug resistance to chemotherapy. Moreover, the standard chemotherapeutic regimen in SCLC has not changed for three decades despite of the dramatic therapeutic improvement in non-SCLC. The development of a novel therapeutic strategy for SCLC has become a pressing issue. We found that expression of Eph receptor A2 (EphA2) is upregulated in three of 13 SCLC cell lines and five of 76 SCLC tumor samples. Genetic inhibition using siRNA of EphA2 significantly suppressed the cellular proliferation via induction of cell cycle arrest in SBC-5 cells. Furthermore, small molecule inhibitors of EphA2 (ALW-II-41-27 and dasatinib) also exclusively inhibited proliferation of EphA2-positive SCLC cells by the same mechanism. Collectively, EphA2 could be a promising candidate as a therapeutic target for SCLC.

Analysis of Pleiotropic Effects of Nivolumab in Pretreated Advanced or Recurrent Non-small Cell Lung Cancer Cases.

BACKGROUND/AIM: Nivolumab is an immune checkpoint inhibitor for advanced non-small cell lung cancer (NSCLC). We investigated the safety and efficacy of nivolumab by analyzing the response factor, adverse effects (AE), and the post-treatment condition of pretreated advanced or recurrent NSCLC patients. PATIENTS AND METHODS: Nivolumab (3 mg/kg) was administered to 79 pre-treated NSCLC patients from December 2015 to January 2018. Nivolumab efficacy and AE were assessed using the Response Evaluation Criteria in Solid Tumors and the Common Terminology Criteria, respectively. RESULTS: Progression-free survival (PFS) was significantly prolonged in cases where the therapeutic effect of the pretreatment was a partial response (p=0.0004). Five cases (6.3%) experienced grade 3-4 AEs. PFS was significantly prolonged in the skin rash group versus the non-skin rash group, and in patients where nivolumab treatment was discontinued. CONCLUSIONS: Long-term survival was observed in patients with skin rash. Therapeutic effect of nivolumab immediately following its administration appears to be favorable for survival.

Double cancer comprising malignant pleural mesothelioma and squamous cell carcinoma of the lung treated with radiotherapy: A case report.

Pleurectomy/decortication (P/D) is the surgical treatment of choice for early malignant mesothelioma, but it remains unclear whether radiotherapy along with P/D should be used as multimodal treatment for this disease. We herein present the case of a 76-year-old man with a history of asbestos exposure who was diagnosed with left-sided malignant pleural mesothelioma in February 2010. The patient underwent chemotherapy with a combination of cisplatin and pemetrexed and achieved stable disease, after which time he was kept under observation. A positron emission tomography/computed tomography scan performed in February 2011 revealed nodular shadows with fluorodeoxyglucose uptake in S3 of the left lung; using bronchoscopy, the patient was diagnosed with stage IIB (cT3N0M0) primary squamous cell carcinoma. Chemoradiotherapy with vinorelbine and 60 Gy/20 fr radiotherapy was performed, and a partial response was obtained, suggesting that the radiotherapy used to treat the carcinoma of the lung may have also helped control the disease activity of the pre-existing mesothelioma. The present case indicates the value of radiotherapy in the treatment of malignant mesothelioma. The aim of the present study was to examine the possibility of new multimodal treatments for mesothelioma, along with a discussion of the relevant literature.

Successful Treatment of Pulmonary Pleomorphic Carcinoma with Nivolumab: A Case Report.

Pulmonary pleomorphic carcinoma (PPC) has a poor prognosis due to the poor results of treatment with systemic chemotherapy. We report the case of a 73-year-old woman with PPC who showed a favorable response to nivolumab. As first-line treatment for postoperative recurrence, she received carboplatin and nanoparticle albumin-bound paclitaxel. However, 12 months later, a new metastatic lymph node appeared. Nivolumab was administered as second-line treatment, and the patient showed a favorable prolonged response. The effects of treatment of PPC with nivolumab seem promising. The results of a future prospective study are expected to identify indicators for the treatment of PPC.