Highlights • A phase II trial of gefitinib with inserted cisplatin plus docetaxel therapy. • Patients with advanced non-small cell lung cancer harboring EGFR mutations were enrolled. • The median ...progression free survival (PFS) was 19.5 months and 5-year PFS rate was 22.0%. • The median survival time was 48.0 months and 5-year survival rate was 36.5%. • The insertion of chemotherapy might prevent the acquired resistance to EGFR-TKIs.
Abstract
Lymphocytes play an important role in the cancer immune system. In the present study, we aimed to evaluate the associations of lymphopenia during proton beam therapy (PBT) and concurrent ...chemotherapy with clinical outcomes and to determine whether lung or bone is more influential on lymphopenia during PBT. Data from 41 patients with stage III non-small cell lung cancer (NSCLC) who received PBT of 74 GyE with concurrent chemotherapy between 2007 and 2017 were reviewed retrospectively. The correlation between dosimetry parameters obtained from dose–volume histograms of the bone and lung and lymphopenia during PBT were analyzed. Minimum absolute lymphocyte count (ALCmin) and maximum neutrophil/lymphocyte ratio (NLRmax) were used as indicators of lymphopenia. Bone V5–20 and lung V5–50 were significantly correlated with the ALCmin and NLRmax during PBT. Multivariable analysis showed that the NLRmax, but not the ALCmin, was associated with overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). The 3-year rates of OS, PFS and DMFS of patients with a low (≤ 6.3) versus high (> 6.3) NLRmax were 73.9% vs 44.4% (P = 0.042), 26.1% vs 5.6% (P = 0.022) and 39.1% vs 5.6% (P < 0.001), respectively. Lung V20 was significantly associated with DMFS on multivariable analyses (hazard ratio: 1.094, P = 0.008), whereas bone V5 had no impact on survival outcomes. We concluded that the NLRmax was a better prognostic indicator than the ALCmin, and the lung dose had more influence than the bone dose on the main survival outcomes in stage III NSCLC patients treated with PBT combined with concurrent chemotherapy.
•EGFR-mutated non-ADC patients are more prone to distant metastasis.•EGFR-mutated non-ADC patients are more prone to malignant pleural effusion.•ADC and EGFR del19-positive non-ADC patients can ...benefit from EGFR-TKI treatment.•EGFR L858R-positive non-ADC patients might not benefit from the EGFR-TKI treatment.•EGFR L858R-positive non-ADC patients may require different therapeutic options.
The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-adenocarcinoma (ADC) non-small cell lung cancer patients is not well established. Herein, we investigated key prognostic factors influencing the efficacy of EGFR-TKIs in these patients.
A total of 12,320 lung cancer patients pathologically diagnosed in 2012 at teaching hospitals in Japan were retrospectively selected. The follow-up survey was closed in 2016.
EGFR-mutated non-ADC patients were more prone to malignant pleural effusion (MPE) and distant metastasis than ADC patients (P = 0.071 and 0.022, respectively). EGFR-mutated ADC patients were likely to have a longer median overall survival (OS) than non-ADC patients hazard ratio (HR) 1.3 (95 % CI, 0.97–1.8, P = 0.072)—29.5 months (95 % CI, 27.9–31.1 months) versus 19.5 months (95 % CI, 10.8–28.2 months) (P = 0.068). There was no significant difference in median OS between EGFR-positive ADC and non-ADC patients receiving treatment with first-generation EGFR-TKI. Among EGFR-positive non-ADC patients, the median OS was significantly longer for patients receiving EGFR-TKI treatment than for those who did not HR 4.5 (95 % CI, 2.1–9.8, P < 0.001)—25.5 months (95 % CI, 8.1–42.9 months) versus 7.5 months (95 % CI, 3.4–11.6 months) (P < 0.001). While there was no significant difference in the median OS for ADC patients with either 19 del or L858R mutations, the median OS was significantly longer for EGFR-mutated non-ADC patients with 19 del than for those with L858R mutation (HR 3.2 95 % CI, 1.5–6.9, P = 0.004; it was not reached for 19 del and was 15.5 months for L858R 95 % CI, 6.6–24.4 months, P = 0.002).
EGFR-mutated non-ADC patients were more prone to MPE and distant metastasis. Both ADC and EGFR del19-positive non-ADC patients can benefit from EGFR-TKI treatment, whereas EGFR L858R-positive non-ADC patients might require different therapeutic options.
Background
Left-ventricular (LV) global longitudinal strain (GLS) has been reported to be a robust and sensitive marker of chemotherapy-induced cardiac damage. Image quality is paramount for accurate ...GLS measurements. In real-world cardio-oncology settings, the incidence of suboptimal echocardiography quality and its significance in clinical decision-making have not been well investigated. This prospective study examined the incidence and impact of suboptimal echocardiographic image quality on detecting subtle myocardial damage by chemotherapy.
Methods
Seventy-seven consecutive patients with breast cancer (age, 52 ± 12 years, 76 women, 33 with left-sided breast cancer) were included in this study. Echocardiography was performed at 3-month intervals 1 year before and after chemotherapy initiation. We classified the image quality of each echocardiographic acquisition into three groups: optimal, suboptimal, or inadequate for speckle tracking.
Results
Among the 376 examinations obtained during the cardiac monitoring, the image quality in 194 (52%) was optimal, suboptimal in 159 (42%), and inadequate in 23 (6%). The interobserver reproducibility was 0.91 in the optimal and 0.21 in the suboptimal group. In contrast, the optimal group showed progressive impairment in both GLS (
p
= 0.001) and LV ejection fraction (LVEF) (
p
< 0.001) during follow-up, and the suboptimal group showed a progressive decrease in LVEF (
p
= 0.006), but not in GLS (
p
= 0.13). Left-sided mammotomy and/or reconstruction surgery and high body mass index were significant determinants of suboptimal image quality.
Conclusions
Even in cases of minor image quality impairment, the physician should assess GLS carefully to avoid errors in crucial clinical decision-making.
To compare the incidence and degree of renal toxicity associated with innovator and generic cisplatin formulations, increase in the serum creatinine (CRN) levels (mg/dL) and incidence of grade 2–3 ...CRN elevation during the first and all cycles of chemotherapy were retrospectively evaluated in patients treated with innovator (group 1, n = 296) and generic (group 2, n = 321) cisplatin formulations. There were no differences in the sex, age, performance status or number of chemotherapy cycles between groups 1 and 2. The median increases in CRN levels during the first cycle were 0.20 mg/dL regardless of the sex or group. There was no difference in the incidence of grade 2–3 CRN elevation between groups 1 and 2 among female or male patients. The median increases in CRN levels during all cycles were 0.2 (0–1.0) and 0.3 (0–1.8) in the female patients of groups 1 and 2, respectively (P = 0.68), and 0.3 (0–2.1) and 0.5 (0–3.6) in the male patients of groups 1 and 2, respectively (P < 0.001). Grade 2–3 CRN elevation was observed in 18.1% and 24.7% of the female patients in groups 1 and 2, respectively (P = 0.33), and 9.4% and 20.9% of the male patients in groups 1 and 2, respectively (P < 0.001). Renal toxicity was slightly more severe in patients treated with the generic cisplatin formulation than in those treated with the innovator formulation, especially among the male patients. (Cancer Sci 2011; 102: 162–165)
Pemetrexed (PEM) inhibits DNA and RNA synthesis and is currently one of the first‐line agents for mesothelioma. PEM suppresses the activities of several enzymes involved in purine and pyrimidine ...synthesis, and elevated activity of these enzymes in tumors is often linked with resistance to PEM. The agent also stimulates AMP‐activated protein kinase (AMPK) and consequently influences the mammalian target of rapamycin complex 1 (mTORC1) pathways. Nevertheless, it remains unclear whether PEM resistance is linked to the AMPK or mTORC1 pathways. Here, we established two independent PEM‐resistant mesothelioma cell lines in which expression of the PEM‐target enzymes was not elevated, and found that levels of phosphorylated AMPK and p70S6K and, to a lesser extent, levels of phosphorylated AKT and p53, were increased in these cells as compared with the respective parent cells. PEM stimulation also augmented phosphorylation of AMPK, p70S6K, AKT and p53 in most cases. An AMPK activator increased phosphorylation and PEM resistance in parental cells, and the inhibitor decreased the resistance of PEM‐resistant cells. In contrast, inhibitors for p70S6K and AKT did not influence PEM resistance; furthermore, increased levels of endogenous p53 did not affect PEM sensitivity. These data collectively indicate that constitutive activation of AMPK is associated with PEM resistance, and that this is unconnected with elevated DNA and RNA synthesis.
Pemetrexed (PEM), an anti‐cancer agent, inhibits the activity of enzymes involved in DNA/RNA synthesis and AICART. Suppressed AICART activity increases the substrate, ZMP, an AMP analog, and consequently augments AMPK function, which in turn influences mTORC1 responses. The current study showed that PEM‐resistant mesothelioma exhibited constitutively activated AMPK and that the increased AMPK activity was linked with PEM‐resistance, which was unconnected to DNA/RNA synthetic enzymes.
Background
To evaluate the long‐term outcomes of high‐dose (74 GyE) proton beam therapy (PBT) with concurrent chemotherapy for stage III non‐small cell lung cancer (NSCLC).
Methods
Between July 2007 ...and March 2018, 45 patients with stage III NSCLC were treated with passive‐scattering PBT of 74 GyE and concurrent chemotherapy. Among the 45 patients, the median age was 62 years (range 39–79 years) and 32 patients were men. The clinical stages were stage IIIA in 14 patients and stage IIIB in 31 patients. Thirty‐six patients received chemotherapy consisting of cisplatin and vinorelbine.
Results
The median follow‐up time was 42.1 months (range 6.4–127.0 months) for all patients and 63.5 months (range 9.4–127.0 months) for the 12 survivors. The 3‐ and 5‐year overall survival rates were 63.7% and 38.8%, respectively, and the median overall survival was 49.1 months. Over the follow‐up period, disease recurrence was observed in 32 (71%) patients. The 3‐ and 5‐year progression‐free survival rates were 22.2% and 17.7%, respectively, with a median progression‐free survival of 13.1 months. In‐field control improved survival and the in‐field control rate was better in patients with T0–3 tumors (p = 0.023) and stage IIIA/IIIB‐N3 disease (p = 0.030). Dosimetric parameters of the heart and lung were not associated with survival. No grade 4 or 5 acute or late non‐hematologic toxicities were observed.
Conclusions
Passive‐scattering PBT of 74 GyE with chemotherapy showed favorable survival and a low incidence of severe adverse events in patients with stage III NSCLC.
Forty‐five patients with stage III non‐small cell lung cancer (14 stage IIIA, 31 stage IIIB) who received high‐dose (74 GyE) passive‐scattering proton beam therapy (PBT) with concurrent chemotherapy were retrospectively reviewed to analyze survivals and toxicities. The 3‐ and 5‐year overall survival rates were 63.7% and 38.8%, respectively, and the median overall survival was 49.1 months. Passive‐scattering PBT of 74 GyE with chemotherapy showed favorable survival and a low incidence of severe adverse events in patients with stage III NSCLC.
To identify polymorphisms in DNA repair genes that affect responses to platinum-based doublet chemotherapy in patients with non-small-cell lung cancer (NSCLC).
In total, 640 patients with NSCLC who ...received platinum-based doublet chemotherapy in the National Cancer Center Hospital in Japan from 2000 to 2008 and whose responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) participated in a study of the association between response and genotypes for 30 single nucleotide polymorphisms (SNPs) in 27 DNA repair genes. Candidate SNPs were selected in a discovery set of 201 patients, and their associations were validated in an independent set of 439 patients by prespecified P value criteria.
Homozygotes for the minor allele TP53-72Pro of the Arg72Pro SNP in the TP53 gene showed a better response rate (54.3%) than those for the major allele TP53-72Arg (29.1%; P = 4.4 × 10(-5)) irrespective of therapeutic regimens, and minor allele homozygotes had significantly longer progression-free and overall survivals than major allele homozygotes (hazard ratio HR, 0.85; 95% CI, 0.74 to 0.98; P = .020; and HR, 0.86; 95% CI, 0.74 to 0.99; P = .039). Minor allele carriers for SNP Lys940Arg in the poly (ADP-ribose) polymerase 1 (PARP1) gene showed a better response rate to the paclitaxel regimen (45.8%) than to the gemcitabine regimen (10.5%; P for interaction = .019).
Polymorphisms in the TP53 and PARP1 genes are involved in inter-individual differences in the response to platinum-based doublet chemotherapy in patients with NSCLC.
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