Yoshiro Nakahara

High plasma levels of soluble programmed cell death ligand 1 are prognostic for reduced survival in advanced lung cancer

OBJECTIVES Programmed cell death-ligand 1 (PD-L1) expressed in tumor tissues is a key molecule for immune suppression, given its role in immune checkpoints. The significance and implication of soluble PD-L1 (sPD-L1) in the blood of lung cancer patients remain unknown. PATIENTS AND METHODS Blood samples were prospectively collected from patients with advanced lung cancer, and the plasma sPD-L1 concentrations were measured by enzyme-linked immunosorbent assay. The correlations of the plasma sPD-L1 levels with clinico-pathological status, laboratory data, and survival of the patients were analyzed. RESULTS Ninety-six patients with advanced lung cancer were analyzed, including 73 with adenocarcinoma, 12 with squamous cell carcinoma, and seven with small-cell lung cancer. Sixty-five were naïve to chemotherapy, and 20 had received two or more lines of chemotherapy. The mean plasma sPD-L1 concentration of all the patients was 6.95±2.90ng/ml (range 2.30-20.0ng/ml), and this value is significantly increased compared with that previously reported for normal subjects. No correlation of the plasma sPD-L1 level with histological subtypes, adenocarcinoma genetic status, smoking history, clinical stage or laboratory data was found. However, overall survival was significantly reduced in patients with high (≥7.32ng/ml) compared with low (<7.32ng/ml) plasma sPD-L1 levels (13.0 vs. 20.4 months, p=0.037). Multivariate analysis revealed that high sPD-L1 levels were significantly related to poor prognosis (hazard ratio 1.99, p=0.041). CONCLUSION High plasma sPD-L1 levels were associated with poor prognosis in patients with advanced lung cancer, possibly associated with suppression of anti-tumor immunity. Clinical trial register and their clinical registration number: UMIN%000014760.

A Prospective Study of Shortened Vitamin Supplementation Prior to Cisplatin–Pemetrexed Therapy for Non-Small Cell Lung Cancer

BACKGROUND Prior supplementation with folic acid and vitamin B12 is required to reduce pemetrexed therapy toxicity; the recommended lead-in time is at least 7 days. On the basis of previous pharmacokinetic and clinical studies, we hypothesized that the lead-in time could be shortened to 24 hours, enabling earlier commencement of standard chemotherapy; thus, we planned the first prospective trial of this regimen. METHODS Patients with advanced nonsquamous non-small cell lung cancer who had not previously received cytotoxic chemotherapy were enrolled. After measurement of homocysteine concentrations, the patients received 1,000 μg of vitamin B12 by intramuscular injection and began taking 350-500 μg of oral folic acid daily. Starting 24-48 hours after the vitamin B12 injection, the patients received intravenous 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin for 4 cycles at 3 weekly intervals. The primary endpoint was the proportion of patients who developed neutropenia grade ≥3. RESULTS Thirty patients received chemotherapy starting within 48 hours of the vitamin B12 injection. No treatment-related deaths or grade 4 toxicity occurred. Neutropenia grade ≥3, other laboratory toxicities grade ≥3, and nonlaboratory toxicities grade ≥3 occurred in 6.7%, 13%, and 13% of patients, respectively. The baseline homocysteine concentrations were not higher in patients with grade ≥3 toxicities than in the remainder of the cohort (mean values, 8.6 and 10.7 μmol/L, respectively). The response rate to chemotherapy was 43%. CONCLUSION The shortened vitamin supplementation was well tolerated and retained antitumor efficacy. Analysis of baseline homocysteine concentrations confirmed the efficacy of short-term vitamin supplementation.

Eligibility for Bevacizumab as an Independent Prognostic Factor for Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: A Retrospective Cohort Study

Background Bevacizumab requires some unique eligibility criteria, such as absence of hemoptysis and major blood vessel invasion by the tumor. The prognostic impact of these bevacizumab-specific criteria has not been evaluated. Methods Patients with stage IIIB/IV, non-squamous non-small cell lung cancer who started chemotherapy before the approval of bevacizumab were reviewed. Patients with impaired organ function, poor performance status or untreated/symptomatic brain metastasis were excluded before the evaluation of bevacizumab eligibility. We compared overall survival and time to treatment failure among patients who were eligible (Group A) or ineligible (Group B) to receive bevacizumab. Results Among 283 patients with stage IIIB/IV non-squamous non-small cell lung cancer, eligibility for bevacizumab was evaluated in 154 patients. Fifty-seven patients were considered ineligible (Group B) based on one or more of a history of hemoptysis (n = 20), major blood vessel invasion (n = 43) and cardiovascular disease (n = 8). The remaining 97 patients were classified into Group A. Overall survival was significantly better in Group A (median, 14.6 months) than in Group B (median, 7.1 months; p<0.0001). Time to treatment failure was also significantly longer in Group A (median, 6.9 months) than in Group B (median, 3.0 months; p<0.0001). Adjusted hazard ratios of bevacizumab eligibility for overall survival and time to treatment failure were 0.48 and 0.38 (95% confidence intervals, 0.33–0.70 and 0.25–0.58), respectively. Conclusion Eligibility for bevacizumab itself represents a powerful prognostic factor for patients with non-squamous non-small cell lung cancer. The proportion of patients who underwent first-line chemotherapy without disease progression or unacceptable toxicity can also be biased by bevacizumab eligibility. Selection bias can be large in clinical trials of bevacizumab, so findings from such trials should be interpreted with extreme caution.

A prospective, multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911

BACKGROUND Low-dose erlotinib may be as effective as gefitinib or erlotinib at full dose in non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR) gene. METHODS Patients with chemotherapy pretreated NSCLC harbouring EGFR mutations received erlotinib at 50 mg/d until disease progression or unacceptable toxicities. The dose was escalated to 150 mg/d in patients showing no response (i.e. without major tumour shrinkage according to Response Evaluation Criteria in Solid Tumours (RECIST)) to the initial dose during the first 4 weeks. The primary end-point was the objective response rate at the dose of 50 mg/d. RESULTS Thirty-four patients from seven institutes were enrolled. The study was closed early when no response was confirmed in 15 patients, excluding the possibility that the primary end-point would be met. The objective response and disease control rates at the dose of 50 mg/d as determined by an independent review committee were 54.5% and 84.8%, respectively. Four additional patients achieved partial response with increased 150 mg/d dose. Progression-free survival and median survival times during the entire period of the study were 9.5 and 28.5 months, respectively. Treatment-related toxicities were generally mild, the most common being skin disorders and diarrhoea. Only one case experienced grade 3 toxicity, which was transient increase of hepatic enzymes. CONCLUSION The primary end-point was not met; low-dose erlotinib is not recommended for fit patients with NSCLC harbouring EGFR mutations. However, it may merit further evaluation for elderly or frail patients.

Retrospective analysis of unknown primary cancers with malignant pleural effusion at initial diagnosis

Malignant pleural effusion (MPE) can occur during the progression of various cancers. However, factors, such as the incidence of MPE associated with different types of cancers and its potential for diagnosing previously undetected cancers, are unknown. Moreover, MPE may accompany potentially curable cancers or those with a favorable survival prognosis with adequate treatment. The present study determined the types of cancers accompanied by MPE at initial diagnosis and investigated appropriate related methods for diagnosing previously unknown cancers.

Small-cell lung cancer with a rare epidermal growth factor receptor gene mutation showing “wax-and-wane” transformation

BackgroundSmall-cell lung cancer with epidermal growth factor receptor (EGFR) gene mutation typically manifests as a transformation occurring after EGFR tyrosine kinase inhibitor therapy for adenocarcinoma with EGFR mutation, whereas primary small-cell lung cancer showing EGFR mutation is extremely rare. Second biopsy of EGFR-mutated tumor has been broadly recognized as necessary, but is not always performed in daily practice, mainly due to the imbalance between the potential risk of the diagnostic procedure and the therapeutic impact of the biopsy result.Case presentationA 70-year-old woman who had never smoked was referred to our hospital with chief complaints of cough and back pain. Transbronchial lung biopsy from the primary tumor of the left upper lobe revealed combined small-cell lung cancer and adenocarcinoma, a subtype of small-cell lung cancer. EGFR L861Q mutation was detected in both small-cell lung cancer and adenocarcinoma components. Given the staging of cT2aN3M1b (Stage IV) and histological diagnosis, first-line chemotherapy with cisplatin plus irinotecan was initiated, and partial response was achieved. Seven months after initial diagnosis, the primary tumor enlarged again, and a second biopsy from the enlarged lesion detected only adenocarcinoma with the L861Q mutation. Erlotinib was started, but multiple brain metastases and enlarged mediastinal lymph nodes subsequently appeared. Whole-brain radiation therapy was performed, and endobronchial ultrasonography-guided transbronchial biopsy from the lymph node revealed reverse transformation to small-cell lung cancer with the L861Q mutation. Amrubicin therapy achieved partial response after two cycles, with the shrinkage lasting for eight months. Serum sialyl Lewis X antigen level increased when the adenocarcinoma component was dominant, whereas plasma pro-gastrin-releasing peptide level increased when the small-cell lung cancer component became dominant.ConclusionsTransformation of the tumor correlates with the difference between small-cell lung cancer and adenocarcinoma in sensitivity to therapies, so repeated biopsies are beneficial for choosing appropriate treatments. Noninvasively obtainable parameters such as tumor markers can support the need for biopsy.

The role of prophylactic cranial irradiation for patients with small-cell lung cancer

Small-cell lung cancer (SCLC) has a particular propensity to metastasize to the brain, affecting ~10% of SCLC patients at diagnosis, but may occur in more than 50% of 2-year survivors. Most cytotoxic drugs have limited ability to cross the blood-brain barrier, and the effectiveness of chemotherapy for brain metastasis is limited. Therefore, prophylactic cranial irradiation (PCI) has been proposed to treat SCLC. A meta-analysis revealed that PCI significantly decreased the risk of brain metastasis and increased the 3-year survival rate; it has been established as a standard therapy for limited-disease SCLC. However, certain aspects of PCI remain unclarified, including the roles in resected SCLC and extensive-disease SCLC, and its neurotoxicities. In addition, information on PCI has been obtained from old clinical trials without the use of new imaging devices, such as magnetic resonance imaging. Evidence from advanced imaging techniques is needed in this era.

Safety and efficacy of carboplatin plus nab-paclitaxel for treating advanced non-small-cell lung cancer with interstitial lung disease

There are few established treatments for patients with non-small-cell lung cancer (NSCLC) with interstitial lung disease (ILD). The safety and efficacy of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin is uncertain, although the combination of carboplatin and paclitaxel is the most common regimen for treating NSCLC patients with ILD. A total of 9 NSCLC patients with ILD, treated between April 2013 and March 2016, were retrospectively investigated. Carboplatin (AUC 5-6) was administered on day 1 and nab-paclitaxel on days 1, 8 and 15, every 4-6 weeks. The median age of the patients upon initiating chemotherapy was 67 years. The pathological examination revealed 6 patients with squamous cell carcinoma, and 6 patients exhibited the typical pattern of ILD. The response rate was 55.6%, and the median progression-free and overall survival time was 174 and 344 days, respectively. Acute exacerbation of ILD was not observed in any of the patients, and febrile neutropenia developed in 3 patients (3/9, 33.3%). Thus, treatment with carboplatin plus nab-paclitaxel was found to be safe and effective for NSCLC patients with ILD, although management of hematological adverse events, such as febrile neutropenia, was required. However, these encouraging results require confirmation by a large-scale clinical trial.

Impact of EGFR-Tyrosine Kinase Inhibitors on Postoperative Recurrent Non-Small-Cell Lung Cancer Harboring EGFR Mutations.

Background: It is unclear whether there is a difference in the efficacy of treatment by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) between patients with postoperative recurrent non-small-cell lung cancer (NSCLC) and those with stage IV NSCLC harboring EGFR mutations. Patients and Methods: The records of NSCLC patients harboring EGFR mutations who were treated with gefitinib or erlotinib were retrospectively reviewed, and the treatment outcomes were evaluated. Moreover, we performed an immunohistochemical analysis of PD-L1 expression in tumor lesions of the postoperative recurrence group. Results: In 205 patients, both the progression-free survival (PFS) time (9.4 vs. 16.9 months) and the median survival time (24.7 vs. 37.4 months) were significantly longer in the postoperative group than in the stage IV group. Additionally, multivariate analysis identified that postoperative recurrence was an independent predictor of PFS and overall survival, as were performance status and smoking status. The PFS durations were 15.7 and 16.6 months for the high- and low-PD-L1 expression groups, respectively, and no significant difference was observed (P = 0.73). Conclusions: The findings of this study provide a valuable rationale for considering postoperative recurrence as a predictive factor for favorable PFS and overall survival in patients with NSCLC harboring activating EGFR mutations who receive EGFR-TKIs.

Pneumothorax during Pazopanib Treatment in Patients with Soft-Tissue Sarcoma: Two Case Reports and a Review of the Literature

Pazopanib, a multitargeting tyrosine kinase inhibitor, has single-agent activity in patients with advanced soft-tissue sarcoma. Herein, we describe 2 cases of pneumothorax that occurred during pazopanib treatment in patients with soft-tissue sarcoma. These 2 patients had multiple lung metastases. According to previous reports and our past experience, the risk of pneumothorax may be higher in patients with multiple lung metastases. Although a causal relationship is uncertain, the risk of pneumothorax when prescribing pazopanib for these patients should be considered.