Developing and validating an integrated gross tumor volume (GTV)-TNM stratification system for supplementing unresectable locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy.

PURPOSE: The gross tumor volume (GTV) could be an independent prognostic factor for unresectable locally advanced non-small cell lung cancer (LANSCLC). We aimed to develop and validate a novel integrated GTV-TNM stratification system to supplement LANSCLC sub-staging in patients treated with concurrent chemoradiotherapy (CCRT). METHODS: We performed a retrospective review of 340 patients with unresectable LANSCLC receiving definitive CCRT. All included patients were divided into two randomized cohorts. Then the Kaplan-Meier method and Cox regression were calculated to access the prognostic value of the integrated GTV-TNM stratification system, which was further validated by the area under the receiver operating characteristic curve (AUC) score and F1-score. RESULTS: The optimal outcome-based GTV cut-off values (70 and 180 cm3) of the modeling cohort were used to determine each patient's integrated GTV-TNM stratum in the whole cohort. Our results indicated that a lower integrated GTV-TNM stratum could had better overall survival and progression-free survival (all P < 0.001), which was recognized as an independent prognostic factor. Also, its prognostic value was robust in both the modeling and validation cohorts. Furthermore, the prognostic validity of the integrated GTV-TNM stratification system was validated by significantly improved AUC score (0.636 vs. 0.570, P = 0.027) and F1-score (0.655 vs. 0.615, P < 0.001), compared with TNM stage. CONCLUSIONS: We proposed a novel integrated GTV-TNM stratification system to supplement unresectable LANSCLC sub-staging due to its prognostic value independent of TNM stage and other clinical characteristics, suggesting that it could be considered in individual treatment decision-making process.

Changes and Influential Factors of Chemotherapy Usage for Non-Small Cell Lung Cancer Patients in China: A Multicenter 10-Year (2005-2014) Retrospective Study.

BACKGROUND: Chemotherapy has improved the survival of non-small cell lung cancer (NSCLC) patients over the past few decades. However, there have not been any epidemiological studies on chemotherapy for Chinese NSCLC patients. PATIENTS AND METHODS: The patients diagnosed as primary lung cancer between January 1, 2005, and December 31, 2014, in eight hospitals from eight provinces in China were retrospectively reviewed. Demographic and clinical data were extracted from medical history systems. Chi-square test and logistic regression were used to analyze the changes of chemotherapy usage and influential factors. RESULTS: A total of 7184 lung cancer cases were eligible, among which 6481 NSCLC cases were included in this analysis. Among stage I/II patients, the percentages of receiving adjuvant chemotherapy did not change significantly between the earlier (28.5%) and the latter five years (25.7%) (p = 0.1288). Among stage IIIA patients, the percentages of chemotherapy usage did not change significantly between the earlier and the latter five years in neo-adjuvant (7.5% vs 5.6%, p = 0.1478) and adjuvant (23.1% vs 26.8%, p = 0.1129) treatment. The proportions of first-line platinum-based doublets for stage IIIB/IV patients changed significantly over the 10 years (p < 0.0001). Patients from provinces with inferior gross domestic product, with lower medical reimbursement rates and without smoking history were more likely to use the docetaxel/paclitaxel doublets, comparing with the gemcitabine doublets. CONCLUSION: From 2005 to 2014, there was no significant change in the chemotherapy pattern of early NSCLC. Economic factors mainly contributed to the significant changes in the first-line chemotherapy regimen selection for advanced patients.

What are the clinical symptoms and physical signs for non-small cell lung cancer before diagnosis is made? A nation-wide multicenter 10-year retrospective study in China.

BACKGROUND: Most lung cancer patients are diagnosed after the onset of symptoms. However, whether the symptoms of lung cancer were independently associated with the diagnosis of lung cancer is unknown, especially in the Chinese population. METHODS: We conducted a 10 years (2005-2014) nationwide multicenter retrospective clinical epidemiology study of lung cancer patients diagnosed in China. As such, this study focused on nonsmall cell lung cancer (NSCLC). We calculated the odds ratios (ORs) for variables associated with the symptoms and physical signs using multivariate unconditional logistic regressions. RESULTS: A total of 7184 lung cancer patients were surveyed; finally, 6398 NSCLC patients with available information about their symptoms and physical signs were included in this analysis. The most common initial symptom and physical sign was chronic cough (4156, 65.0%), followed by sputum with blood (2110, 33.0%), chest pain (1146, 17.9%), shortness of breath (1090, 17.0%), neck and supraclavicular lymphadenectasis (629, 9.8%), weight loss (529, 8.3%), metastases pain (378, 5.9%), fatigue (307, 4.8%), fever (272, 4.3%), and dyspnea (270, 4.2%). Patients with squamous carcinoma and stage III disease were more likely to present with chronic cough (P < 0.0001) and sputum with blood (P < 0.0001) than patients with other pathological types and clinical stages, respectively. Metastases pain (P < 0.0001) and neck and supraclavicular lymphadenectasis (P = 0.0006) were more likely to occur in patients with nonsquamous carcinoma than in patients with other carcinomas. Additionally, patients with stage IV disease had a higher percentage of chest pain, shortness of breath, dyspnea, weight loss, and fatigue than patients with other stages of disease. In multivariable logistic analyses, compared with patients with adenocarcinoma, patients with squamous carcinoma were more likely to experience symptoms (OR = 2.885, 95% confidence interval [CI] 2.477-3.359) but were less likely to present physical signs (OR = 0.844, 95% CI 0.721-0.989). The odds of having both symptoms and physical signs were higher in patients with late-stage disease than in those with early-stage disease (P < 0.0001). CONCLUSIONS: The symptoms and physical signs of lung cancer were associated with the stage and pathological diagnosis of NSCLC. Patients with squamous carcinoma were more likely to develop symptoms, but not signs, than patients with adenocarcinoma. The more advanced the stage at diagnosis, the more likely that symptoms or physical signs are to develop. Further prospective cohort studies are needed to explore these results.

Comparison of hyper- and hypofractionated radiation schemes with IMRT technique in small cell lung cancer: Clinical outcomes and the introduction of extended LQ and TCP models.

PURPOSE: To evaluate the outcomes of 45 Gy/15 fractions/once-daily and 45 Gy/30 fractions/twice-daily radiation schemes utilizing intensity-modulated radiation therapy (IMRT) in extensive stage small cell lung cancer (SCLC), and to build up a new radiobiological model for tumor control probability (TCP) considering multiple biological effects. METHODS: Fifty-eight consecutive patients diagnosed with extensive stage SCLC, treated with chemotherapy and chest irradiation, were retrospectively reviewed. Thirty-seven received hyperfractionated IMRT (Hyper-IMRT, 45 Gy/30 fractions/twice-daily) and 21 received hypofractionated IMRT (Hypo-IMRT, 45 Gy/15 fractions/once-daily). Local progression-free survival (LPFS) and overall survival (OS) were calculated and compared. An extended linear-quadratic (LQ) model, LQRG, incorporating cell repair, redistribution, reoxygenation, regrowth and Gompertzian tumor growth was created based on the clinical data. The TCP model was reformulated to predict LPFS. The classical LQ and TCP models were compared with the new models. Akaike information criterion (AIC) was used to assess the quality of the models. RESULTS: The 2-year LPFS (34.1% vs 27.9%, p = 0.44) and OS (76.9% vs 76.9%, p = 0.26) were similar between Hyper- and Hypo-IMRT patients. According to the LQRG model, the α/ß calculated was 9.2 (95% confidence interval: 8.7-9.9) Gy after optimization. The average absolute and relative fitting errors for LPFS were 9.1% and 18.7% for Hyper-IMRT, and 8.8% and 16.2% for Hypo-IMRT of the new TCP model, compared with 29.1% and 62.3% for Hyper-IMRT, and 30.7% and 65.3% for Hypo-IMRT of the classical model. CONCLUSIONS: Hypo- and Hyper-IMRT resulted in comparable local control in the chest irradiation of extensive stage SCLC. The LQRG model has better performance in predicting the TCP (or LPFS) of the two schemes.

Clinical characteristics and medical service utilization of lung cancer in China, 2005-2014: Overall design and results from a multicenter retrospective epidemiologic survey.

OBJECTIVES: This study aimed to explore the clinical profile and its trajectory of lung cancer on clinicopathological characteristics and medical service utilization in China. METHODS: Patients diagnosed with primary lung cancer in tertiary hospitals during 2005-14 were selected from seven geographic regions of China. Data on clinical characteristics and medical service utilization was extracted from medical record, and the ten-year trends were explored. RESULTS: A total of 7184 patients were included, the mean age was 58.3 years and the male-to-female-ratio was 2.7. From 2005 to 2014, the proportion of ≥60 year-old patients increased from 41.2% to 56.2% (p < 0.001). The smoking rate decreased from 62.9% to 51.1% (p < 0.001) and the proportion of females increased from 23.5% to 31.9% (p < 0.001). The proportion of advanced stage increased from 41.9% to 47.4% (p < 0.001). Adenocarcinoma's proportion increased from 36.4% to 53.5% (p < 0.001) while that of squamous carcinoma decreased from 45.4% to 34.4% (p < 0.001). The application of chest X-ray dropped from 50.2% to 31.0% (p < 0.001) but that of chest CT increased from 65.8% to 81.4% (p < 0.001). As two main treatment options, chemotherapy (p = 0.290) and surgery (p = 0.497) remained stable. The medical expenditure per patient increased from 40,508 to 66,020 Chinese Yuan (p < 0.001). CONCLUSIONS: The sustaining high smoking exposure, increasing proportion of female patients, advancing clinical stage, shifting of predominant pathology and increasing medical expenditure demonstrate potential challenges and directions on lung cancer prevention and control in China. Despite substantial changes of clinical characteristics, main treatment options remained unchanged, which needs further investigation.

Clinicopathological parameters predicting recurrence of pT1N0 esophageal squamous cell carcinoma.

AIM: To identify the clinicopathological characteristics of pT1N0 esophageal squamous cell carcinoma (ESCC) that are associated with tumor recurrence. METHODS: We reviewed 216 pT1N0 thoracic ESCC cases who underwent esophagectomy and thoracoabdominal two-field lymphadenectomy without preoperative chemoradiotherapy. After excluding those cases with clinical follow-up recorded fewer than 3 mo and those who died within 3 mo of surgery, we included 199 cases in the current analysis. Overall survival and recurrence-free survival were assessed by the Kaplan-Meier method, and clinicopathological characteristics associated with any recurrence or distant recurrence were evaluated using univariate and multivariate Cox proportional hazards models. Early recurrence (≤ 24 mo) and correlated parameters were assessed using univariate and multivariate logistic regression models. RESULTS: Forty-seven (24%) patients had a recurrence at 3 to 178 (median, 33) mo. The 5-year recurrence-free survival rate was 80.7%. None of 13 asymptomatic cases had a recurrence. Preoperative clinical symptoms, upper thoracic location, ulcerative or intraluminal mass macroscopic tumor type, tumor invasion depth level, basaloid histology, angiolymphatic invasion, tumor thickness, submucosal invasion thickness, diameter of the largest single tongue of invasion, and complete negative aberrant p53 expression were significantly related to tumor recurrence and/or recurrence-free survival. Upper thoracic tumor location, angiolymphatic invasion, and submucosal invasion thickness were independent predictors of tumor recurrence (Hazard ratios = 3.26, 3.42, and 2.06, P < 0.001, P < 0.001, and P = 0.002, respectively), and a nomogram for predicting recurrence-free survival with these three predictors was constructed. Upper thoracic tumor location and angiolymphatic invasion were independent predictors of distant recurrence. Upper thoracic tumor location, angiolymphatic invasion, submucosal invasion thickness, and diameter of the largest single tongue of invasion were independent predictors of early recurrence. CONCLUSION: These results should be useful for designing optimal individual follow-up and therapy for patients with T1N0 ESCC.

Gefitinib for asymptomatic brain metastasis from advanced non-small cell lung cancer: Report of a favourable outcome.

Brain metastasis (BM) is common in patients with non-small cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have now been included as standard treatment options for NSCLC harboring EGFR-activating mutations, only a few prospective reports demonstrate the efficacy of these agents in a BM setting. We report a case of a patient with advanced NSCLC, in which oral gefitinib documented a significant antitumor effect on parallel progression of extracranial lesion and BM occurred during chemotherapy.

Hypofractionated radiotherapy for medically inoperable stage I non-small cell lung cancer.

BACKGROUND: To investigate the clinical outcomes and toxicity of hypofractionated radiotherapy for medically inoperable stage I non-small cell lung cancer (NSCLC). METHODS: Patients treated with radiotherapy at a dose of 4-6 Gy per fraction using fixed-field intensity modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT) at our hospital from June 2005 to December 2013 were analyzed. The total prescription doses ranged from 50-78 Gy with 4-6 Gy per fraction. The median follow-up period was 24 months. RESULTS: A total of 65 patients with stage I NSCLC were analyzed, including 43 primary NSCLC patients and 22 patients with recurrent or second primary NSCLC. An objective response (complete or partial response) was achieved at six months in 84.6% of patients. The three-year local control rate was 90.8%. Kaplan-Meier estimates of local failure-free, progression-free, overall, and cancer-specific survival rates at three years were 90.3%, 64.3%, 68.9%, and 88.8%, respectively. The rate of symptomatic radiation pneumonitis was 16.9%, and no grade 4-5 toxicity was observed. CONCLUSION: Favorable local control and outcome was achieved with hypofractionated radiotherapy in patients with inoperable stage I NSCLC with acceptable toxicity. The most common schedule of 6 Gy × 12 fractions may be a promising regimen, and a prospective study is in process.

MicroRNA-related polymorphisms in apoptosis pathway genes are predictive of clinical outcome in patients with limited disease small cell lung cancer.

We examined the impact of single nucleotide polymorphisms (SNPs) at miRNA binding sites in the 3'-UTRs of genes in the apoptosis pathway on the prognosis of patients with limited disease-small cell lung cancer (LD-SCLC). Twelve tagSNPs in seven genes were genotyped using blood samples from 146 LD-SCLC patients treated with chemoradiotherapy. Cox proportional hazard regression models and recursive partitioning analysis were performed to identify SNPs significantly associated with overall survival. Three SNPs, CASP8: rs1045494 (C > T), PIK3R1: rs3756668 (A > G) and CASP7: rs4353229 (T > C), were associated with longer overall survival in LD-SCLC patients after chemoradiotherapy. The adjusted hazard ratios (95% confidence intervals) were 0.480 (0.258-0.894), 0.405 (0.173-0.947) and 0.446 (0.247-0.802), respectively, and remained significant after multiple comparison correction. Moreover, subset analysis showed these SNPs were still predictive of overall survival in stage III patients. Recursive partitioning analysis enabled patients to be classified into three risk subgroups based on unfavorable genotype combinations of the rs1045494 and rs4353229 SNPs. These findings suggest miRNA-related polymorphisms in the apoptosis pathway may be useful biomarkers for selection of LD-SCLC patients likely to benefit from chemoradiotherapy.

Survey on the use of radiotherapy to treat early breast cancer following breast-conserving surgery in China.

AIMS: The use of radiotherapy to treat early stage breast cancer following breast-conserving surgery has markedly increased. The study aimed to evaluate the clinical practice of radiotherapy in China. MATERIALS AND METHODS: A survey concerning the characteristics of breast-conserving radiotherapy for early stage breast cancer was distributed to all radiotherapy departments in mainland China in 2009. The results were analyzed. RESULTS: Three hundred and ninety-six departments replied (41.6%), and 328 (34.4%) launched breast-conserving radiotherapy. Adjuvant chemotherapy followed by radiotherapy was the most common combination and was performed in 55.2% of the responding centers. The median time from surgery to radiotherapy was 9 weeks. Three hundred and nineteen (97.3%) centers treated the whole breast, 273 (83.2%) the supraclavicular area, 138 (43.3%) the axilla, and 85 (26.8%) the internal mammary region; 97.5% (310/319) of all centers performed irradiation of the whole breast in all candidates. One hundred and fourteen (41.8%) treated the supraclavicular area, and 37 (26.8%) treated the axilla in 1-3 positive lymph nodes. Eighty-six (31.5%) and 40 (29.0%) performed the corresponding irradiation in N 2-3 patients. Fifty-six (72.9%) treated the internal mammary region for tumors of the center or inner quadrant. The conformal technique was used in 51.8% of the centers. CONCLUSIONS: Although a consensus has been reached, debate still exists about the target of postoperative radiotherapy in early stage breast cancer.

A novel ATM-dependent pathway regulates protein phosphatase 1 in response to DNA damage.

Protein phosphatase 1 (PP1), a major protein phosphatase important for a variety of cellular responses, is activated in response to ionizing irradiation (IR)-induced DNA damage. Here, we report that IR induces the rapid dissociation of PP1 from its regulatory subunit inhibitor-2 (I-2) and that the process requires ataxia-telangiectasia mutated (ATM), a protein kinase central to DNA damage responses. In response to IR, ATM phosphorylates I-2 on serine 43, leading to the dissociation of the PP1-I-2 complex and the activation of PP1. Furthermore, ATM-mediated I-2 phosphorylation results in the inhibition of the Aurora-B kinase, the down-regulation of histone H3 serine 10 phosphorylation, and the activation of the G(2)/M checkpoint. Collectively, the results of these studies demonstrate a novel pathway that links ATM, PP1, and I-2 in the cellular response to DNA damage.

[Abrogation effect of UCN-01 on radiation-induced G2 phase arrest of tumor cells and its mechanism].

BACKGROUND & OBJECTIVE: Irradiation often causes cell cycle arrest in tumor cells. This study was to observe the abrogation of radiation-induced G(2) phase arrest of p53 mutated human cancer cell lines by 7-hydroxystaurosporine (UCN-01), and explore the mechanism. METHODS: Human nasopharyngeal carcinoma cell line CNE-1 and human lung adenocarcinoma cell line 973, both with p53 mutation, were used in this study. Human fibroblastoma cell line HT-1080 was used as control. Flow cytometry was used to observe the effects of irradiation on cell cycle of these 3 cell lines, and abrogation effect of UCN-01 on radiation-induced G(2) phase arrest. Western blot was used to detect phosphorylated CDC2-Tyr15 during the abrogation process. RESULTS: Irradiation resulted in G(2) phase arrest in CNE-1 cells and 973 cells. Proportion of cells in G(2) phase increased from 18.4% to 43.6% in CNE-1 cell line, and from 14.8% to 42.8% in 973 cell line after 2 Gy of irradiation. G(1) phase arrests, measured by "S phase cells consumption", of CNE-1 cells and 973 cells were much lower than that of HT-1080 cells (14.8% and -1.2% vs. 57.0%). Radiation-induced G(2) phase arrests were abrogated by UCN-01 from 63.5% to 16.1% in CNE-1 cell line, and from 35.4% to 16.3% in 973 cell line. UCN-01 suppressed the expression of radiation-induced phosphorylation of CDC2-Tyr15, which was in accordance with the abrogation of radiation-induced G(2) phase delay. CONCLUSIONS: Main effect of irradiation on cell cycle of p53 mutated CNE-1 cells and 973 cells is G(2) phase arrest. UCN-01 is able to abrogate radiation-induced G(2) phase, which is associated with the reduction of phosphorylated CDC2-Tyr15.

[Post-mastectomy radiotherapy with different fractionated dose schemes in early breast cancer].

OBJECTIVE: To study the effect of post-mastectomy radiotherapy with different fractionated dose schemes for early breast cancer. METHODS: From January 1987 to January 1993, 367 patients with early breast cancer were given post-mastectomy radiotherapy with three different fractionated dose schemes. 149 patients received conventional radiotherapy with 50 Gy/25 fractions/5 weeks (Group A). 177 patients received 45 Gy/15 fractions/5 weeks (Group B). Forty-one patients were treated with 23 Gy/4 fractions/17 days (Group C). 257 patients received systemic therapy (chemotherapy and/or endocrine therapy). RESULTS: The overall 5-year survival and 5-year disease-free survival rates were 87.4% and 89.6%. The 5-year disease-free survival rate were 90.8%, 86.5% and 84.6% for A, B and C groups (P = 0.16). The corresponding loco-regional failure rates were 2.7%, 2.8% and 2.4%, respectively. There was no statistically significant difference in the local control and efficacy of the three groups. CONCLUSION: With similar 5-year tumor-free survival rates by the conventional fractionation and hypofractionation, the scheme with 45 Gy/15 fractions/5 weeks has the advantage of giving less factions, which is suitable for a unit with limited radiation resources. The course of hypofractionation with 23 Gy/4 fractions/17 days is much shorter than conventional radiotherapy, which may benefit patients with higher risk of metastasis who need to undergo chemotherapy earlier. This study warrants further investigations.

[Abrogation of radiation-induced G2 arrest and radiosensitization by 7-hydroxystaurosporine (UCN-01) in human nasopharyngeal carcinoma cell line].

BACKGROUND & OBJECTIVE: To enhance the radiosensitivity of cancer cell is one of the most important way to improve the effect of radiotherapy. This study was designed to investigate the radiosensitization of 7-hydroxystaurosporine(UCN-01) by its abrogation of radiation-induced G2 arrest. METHODS: Flow cytometry was used to observe the effect of irradiation and UCN-01 on cell cycle of human nasopharyngeal carcinoma cells (CNE-1) with mutated p53. The effect on radiosensitivity was determined by clonogenic assay and was quantified by calculating the sensitive enhancement ratio (SER). RESULTS: Irradiation resulted in G2 arrest in a dose-dependent manner. The proportion of cells at G2 phase, comparing to the control group (18.4%), was increased to 43.6%, 77.4% and 86.4% after 12 hours with irradiation of 2, 4 and 6 Gy, respectively. Radiation-induced G2 arrest was abrogated by UCN-01 in a concentration-dependent manner. UCN-01 at the concentrations of 50, 100, 200 and 400 nmol/L decreased the proportion of cells in G2 phase from 63.5% in the control group to 28.5%, 25.0%, 16.1% and 13.7%, respectively. UCN-01 resulted in a radiosensitization in CNE-1 cells. The SERs were 2.60 and 3.09, for 100 nmol/L and 200 nmol/L of UCN-01, respectively. CONCLUSION: Radiosensitization of UCN-01 in CNE-1 cells characterized by mutated p53 is associated with its abrogation of radiation-induced G2 arrest.