Risk Prediction for Locoregional Recurrence in Epidermal Growth Factor Receptor-Mutant Stage III-pN2 Lung Adenocarcinoma after Complete Resection: A Multi-center Retrospective Study.

Background: This study aimed to develop a predictive model based on the risk of locoregional recurrence (LRR) in epidermal growth factor receptor (EGFR)-mutant stage III-pN2 lung adenocarcinoma after complete resection. Methods: A total of 11,020 patients with lung surgery were screened to determine completely resected EGFR-mutant stage III-pN2 lung adenocarcinoma. Patients were excluded if they received preoperative therapy or postoperative radiation therapy (PORT). The time from surgery to LRR was recorded. Clinicopathological variables with statistical significance predicting LRR in the multivariate Cox regression were incorporated into the competing risk nomogram. Patients were then sub-grouped based on different recurrence risk as a result of the nomogram. Results: Two hundred and eighty-eight patients were enrolled, including 191 (66.3%) with unforeseen N2 (IIIA1-2), 75 (26.0%) with minimal/single station N2 (IIIA3), and 22 (7.6%) with bulky and/or multilevel N2 (IIIA4). The 2-year overall cumulative incidence of LRR was 27.2% (confidence interval [CI], 16.3%-38.0%). IIIA4 disease (hazard ratio, 2.65; CI, 1.15-6.07; P=0.022) and extranodal extension (hazard ratio, 3.33; CI, 1.76-6.30; P<0.001) were independent risk factors for LRR and were incorporated into the nomogram. Based on the nomogram, patients who did not have any risk factor (low-risk) had a significantly lower predicted 2-year incidence of LRR than those with any of the risk factors (high-risk; 4.6% vs 21.9%, P<0.001). Conclusions: Pre-treatment bulky/multilevel N2 and pathological extranodal extension are risk factors for locoregional recurrence in EGFR-mutant stage III-pN2 lung adenocarcinoma. Intensive adjuvant therapies and active follow-up should be considered in patients with any of the risk factors.

Early postoperative radiotherapy is associated with improved outcomes over late postoperative radiotherapy in the management of completely resected (R0) Stage IIIA-N2 non-small cell lung cancer.

AIMS: The aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC. PATIENTS AND METHODS: Between January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy ("early PORT") or with PORT administered after two cycles of chemotherapy ("late PORT") at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan-Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS. RESULTS: Of 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS. CONCLUSIONS: Early PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.

Receipt of thoracic radiation therapy and radiotherapy dose are correlated with outcomes in a retrospective study of three hundred and six patients with extensive stage small-cell lung cancer.

BACKGROUND: The importance of the thoracic radiation therapy (TRT) dose has not been clearly defined in extensive stage small-cell lung cancer (ES-SCLC) and it is unclear whether improved TRT dose translates into a survival benefit. METHODS: 306 patients with ES-SCLC were retrospectively reviewed, of which 170 received IMRT/CRT fractionation RT after ChT, and 136 received chemotherapy (ChT) alone. We adopted the time-adjusted BED (tBED) for effective dose fractionation calculation. Due to the nonrandomized nature of this study, we compared the ChT+RT with ChT groups that matched on possible confounding variables. RESULTS: Patients achieved 2-year OS, PFS and LC rates of 19.7%, 10.7% and 28.4%, respectively. After propensity score matching, (113 cases for each group), the rates of OS, PFS and LC at 2 years were 21.4%, 7.7% and 34.5% for ChT+TRT, and 10.3% (p<0.001), 4.6% (p<0.001) and 6.3% for ChT only (p<0.001), respectively. Among propensity score matching patients, 56 cases for each group received the high dose (tBED>50 Gy) TRT and received low dose (tBED≤50 Gy) TRT. Two-year OS, PFS and LC rates were 32.3%, 15.3% and 47.1% for the high dose compared with 17.0% (p<0.001), 12.9% (p=0.097) and 34.7% (p=0.029) for low dose radiotherapy. CONCLUSIONS: TRT added to ChT improved ES-SCLC patient OS. High dose TRT improved OS over lower doses. Our results suggest that high-dose thoracic radiation therapy may be a reasonable consideration in select patients with ES-SCLC.

Thoracic radiotherapy (TRT) improved survival in both oligo- and polymetastatic extensive stage small cell lung cancer.

There has been no previous study on the efficacy of the thoracic radiotherapy (TRT) in oligometastatic or polymetastatic extensive stage small-cell lung cancer (ES-SCLC) to the overall survival (OS). In a group of 270 ES-SCLC cases retrospective study, 78 patients (28.9%) had oligometastases and 192 (71.1%) had polymetastases, among which 51 oligometastatic patients (65.4%) and 93 polymetastatic patients (51.6%) received TRT. Propensity score matching (PSM) was utilized. The 2-year OS, progression free survival (PFS) and local control (LC) in oligometastatic and polymetastatic patients were 22.8% and 4.5% (p < 0.001), 12.0% and 3.8% (p < 0.001), and 36.7% and 6.1% (p < 0.001), respectively. The 2-year OS in oligometastatic patients with the chemotherapy + radiotherapy and chemotherapy alone were 25.2% and 12.7% (p = 0.002), in contrast to 10.0% and 6.8% (p = 0.030) in polymetastatic patients. The estimated hazard ratios for survival were 2.9 and 1.7 for both oligometastatic and polymetastatic patients with radiotherapy. The polymetastatic group has a lower LC (6.1% v.s. 36.7%, (p < 0.001)), due to polymetastases patients receiving involved-sites radiotherapy with low dose schemas. TRT improved OS of patients with oligometastases and polymetastases. Our study demonstrated that aggressive TRT might be a suitable addition of chemotherapy when treating ES-SCLC patients with oligometastases and polymetastases.

Feasibility and efficacy of concurrent chemoradiotherapy in elderly patients with esophageal squamous cell carcinoma: a respective study of 116 cases from a single institution.

BACKGROUND: To evaluate the safety and efficacy of combined chemoradiotherapy or radiotherapy alone in elderly patients with esophageal carcinoma to identify the best method of treatment. MATERIALS AND METHODS: One hundred and sixteen patients with esophageal carcinoma aged 70 and older who received definitive radiotherapy or chemoradiotherapy entered the study. Overall survival (OS), disease-free survival (DFS) and treatment- related toxicities were assessed. RESULTS: The median OS of the overall population was 17.9 months. For patients treated with cCRT, sCRT and radiotherapy alone, the median OS was 22.3 months, 18.0 months and 12.4 months respectively(P=0.044). Median OS for patients treated with radiotherapy dose ≥60Gy and <60Gy was 20.2 months and 10.9 months respectively (p=0.017). By univariate analysis, Chemoradiotherapy (include cCRT and sCRT) and radiotherapy dose ≥60Gy were found to achieve higher survival rates compared with radiotherapy alone and radiotherapy dose <60Gy (P=0.015, P=0.017). By multivariate analysis, chemoradiotherapy (HR=1.645, P=0.022) and radiotherapy dose ≥60Gy (HR=1.642, P=0.025) were identified as independent prognostic factors of OS. CONCLUSIONS: Definitive concurrent chemoradiotherapy could be considered as a feasible and effective treatment in esophageal carcinoma patients aged 70 and older. Radiotherapy dose 60Gy is an effective treatment option compared with standard dose radiotherapy, while higher doses are not beneficial to improve survival.

Prognostic value of epidermal growth factor receptor mutations in resected lung adenocarcinomas.

The purpose of this study was to evaluate the association between epidermal growth factor receptor (EGFR) mutations and prognosis in patients with completely resected lung adenocarcinoma. A total of 131 patients were included in this study. EGFR mutation status in exons 18-21 of the tyrosine kinase-binding domain was detected using nested PCR amplification of individual exon. The χ (2) test was used to analyze the associations between EGFR mutations and the different variables. The log-rank test and Cox regression model were used to evaluate the factors influencing disease-free survival (DFS) and overall survival (OS). EGFR mutations in 18-21 exons were detected in 58 of the 131 patients (44.3 %). Smoking status (P = 0.029), N stage (P = 0.021), and pathologic stage (P = 0.048) were significantly associated with EGFR mutations. The median DFS in mutant EGFR and wild-type EGFR groups was 36.6 and 25.7 months, respectively (P = 0.533). No significant correlation was observed between EGFR mutations and OS (P = 0.564). However, patients with exon 19 mutation tended to have longer DFS than those with exon 21 mutation (46.2 vs. 21.9 months, P = 0.056), and the 1-, 2-, and 3-year OS rates were significantly higher in patients with exon 19 mutation compared to patients with exon 21 mutation (100, 96.7, 93.3 vs. 91.3, 82.6, 60.9 %, respectively, P = 0.01). Our data demonstrated that EGFR mutations do not have significant prognostic value in primary resected lung adenocarcinomas, but patients with exon 19 mutation tended to have better prognostic value compared to patients with exon 21 mutation.

Rare myeloid sarcoma/acute myeloid leukemia with adrenal mass after allogeneic mobilization peripheral blood stem cell transplantation.

Myeloid sarcoma (MS) is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia (AML). This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission. A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010. After one month, bone marrow biopsy and aspiration confirmed the diagnosis of AML. Allogeneic mobilization peripheral blood stem cell transplantation was performed, with the sister of the patient as donor, after complete remission (CR) was achieved by chemotherapy. Five months after treatment, an adrenal mass was detected by positron emission tomography-computed tomography (PET-CT). Radiotherapy was performed for the localized mass after a multidisciplinary team (MDT) discussion. The patient is still alive as of May 2013, with no evidence of recurrent MS or leukemia.

Radiotherapy and chemotherapy are associated with improved outcomes over surgery and chemotherapy in the management of limited-stage small cell esophageal carcinoma.

BACKGROUND: This retrospective study evaluates the efficacy and safety of surgery and chemotherapy (S +CT) vs. radiotherapy and CT (RT+CT) in patients with limited stage small cell esophageal cancer (LS-SCEC). PATIENTS AND METHODS: Patients included in analysis (from our hospital and the literature) were treated with S+CT or RT+CT between 1989 and 2012. The primary end point was overall survival (OS); secondary end points included tumor response and toxicity. Kaplan-Meier OS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS. RESULTS: A total of 127 patients were included: 14 from our hospital and 113 from the literature. Fifty-four (43%) and 73 (57%) patients received S+CT or RT+CT, respectively. The median OS of all patients was 21.0 months. OS was longer for those who received RT+CT rather than S+CT (33.0 vs. 17.5 months, p=0.02), especially those with N1 disease. Uni- and multi-variate analyses showed tumor location (upper 1/3rd of esophagus) and type of treatment (S+CT) were poor prognostic factors of OS. CONCLUSION: LS-SCEC patients treated with RT+CT had an improved OS compared to those treated with S+RT. Thus, RT+CT should be considered as a primary approach for these patients.

Late course accelerated hyperfractionation radiotherapy for locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Late course accelerated hyperfractionation radiotherapy (LCAHR) is used as a standard treatment option for locally advanced esophageal squamous cell carcinoma (LAESCC) in China, but concerns remain regarding its efficacy and safety. The purpose of this paper was to evaluate the efficacy and safety of LCAHR. The comparisons examined were as follows: LCAHR versus conventional fractionation radiotherapy (CFR) and LCAHR plus chemotherapy (CT) versus LCAHR alone. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE, CENTRAL, CBMdisc, and CNKI, as well as employing manual searches. The primary end points were survival and local control. The second end point was toxicities. RESULTS: Based on search criteria, we found 29 trials involving 3187 patients. Our results showed that LCAHR, compared with CFR, improved the survival and local control, and was, thus, more therapeutically beneficial. Further analysis revealed that LCAHR plus CT proved to be better for patients' survival and local control compared to LCAHR alone. Acute toxicities were increased rather than late toxicities. CONCLUSIONS: There was a significant survival and local control benefit of LCAHR over CFR, as well as LCAHR plus CT over LCAHR alone. Considering the strength of the evidence, the results of this study indicate that this regimen would be a new promising modality worth further investigation.

[Concurrent chemoradiotherapy for stage III non-small cell lung cancer].

OBJECTIVE: To evaluate the immediate efficacy and acute toxicity of cisplatin-based induction chemotherapy followed by weekly concomitant chemoradiotherapy and concomitant chemoradiotherapy followed by consolidation chemotherapy in unresectable stage III NSCLC. METHODS: A total of 118 patients were pathologically diagnosed as stage III N SCLC. Among them, 77 patients (A group) received two cycles of cisplatin-based induction chemotherapy, followed by 6 weekly cycles of paclitaxel 45 mg/m(2) (n = 45) and gemcitabine 350 mg/m(2) (n = 32) in combination with thoracic radiotherapy; 41 patients (B group) received concomitant chemoradiotherapy (cisplatin 50 mg/m(2), d1, 8, 29, 36/etoposide 50 mg/m(2), d1-5, 29-33, n = 18, paclitaxel 45 mg/m(2)/weekly × 6/carboplatin AUC = 2/weekly × 6, n = 23) followed by consolidation chemotherapy. All thoracic radiotherapy dose are 2 Gy per fraction and day to a total dose of 58-60 Gy. RESULTS: The total response rate of A and B groups was 80.5% and 75.6% respectively (P = 0.534). According to subgroup analyses, no statistically significant differences existed according to chemotherapy (P = 0.557). The main side-effects were neutropenia, radiation esophagitis, radiation pneumonitis and nausea/vomiting. The gemcitabine group was statistically significant different in neutropenia. CONCLUSION: Different chemotherapeutic agents in combination with thoracic radiotherapy are clinically feasible with a moderate toxicity. Their profiles of efficacy and toxicity are comparable to each other.

Basic research of the relationship between irradiation dose and volume in radiation-induced pulmonary injury.

BACKGROUND: Irradiation dose and volume are the major physical factors of radiation-induced lung injury. The study investigated the relationships between the irradiation dose and volume in radiation-induced lung injury by setting up a model of graded volume irradiation of the rat lung. METHODS: Animals were randomly assigned to three groups. The ELEKTA precise 2.03 treatment plan system was applied to calculate the irradiation dose and volume. The treatment plan for the three groups was: group 1 received a "high dose to a small volume" (25% volume group) with the mean irradiation volume being 1.748 cm(3) (25% lung volume); the total dose and mean lung dose (MLD) were 4610 cGy and 2006 cGy, respectively (bilateral AP-PA fields, source to axis distance (SAD) = 100 cm, 6MVX, single irradiation); Group 2 received a "low dose to a large volume" (100% volume group) with the mean irradiation volume being 6.99 cm(3) (100% lung volume); the total dose was 1153 cGy. MLD was 2006 cGy, which was the same as that of group 1 (bilateral AP-PA fields, SAD = 100 cm, 6MVX, single irradiation); Group 3 was a control group. With the exception of receiving no irradiation, group 3 had rest steps that were the same as those of the experimental groups. After irradiation, functional, histopathological, and CT changes were compared every two weeks till the 16th week. RESULTS: Functionally, after irradiation breath rate (BR) increases were observed in both group 1 and group 2, especially during the period of 6th - 8th weeks. The changes of BR in the 100% volume group were earlier and faster. For the 25% volume group, although pathology was more severe, hardly any obvious increase in BR was observed. Radiographic changes were observed during the early period (the 4th week) and the most obvious changes manifested during the mediated period (the 8th week). The extensiveness of high density and the decreased lung permeability were presented in the 100% volume group, and ground glass opacity and patchy consolidation were presented in the 25% volume group without pleural effusion, pleural thickening, and lung shrinking. Morphologically, the 100% volume group mainly presented signs of vascular damage, including signs of vascular wall edemas, hypertrophy, and sclerosis. The 25% volume group mainly presented with erythrocyte cell exudation, inflammation, and parenchymal damage. CONCLUSIONS: The delivery of a small dose of radiation to a large volume is not safe. A low dose smeared out over large volumes, albeit reversible, may lead to fatal respiratory dysfunction. Damage to the lung may be more dependent on the volume of irradiation than on the radiation dose. Clinically, the safest approach is to limit both the volume of the irradiated normal lung and the amount of received radiation.

[Weekly paclitaxel and carboplatin with concurrent three dimensional conformal radiotherapy for locally advanced non small cell lung cancer].

OBJECTIVE: To evaluate the toxicity and efficacy of weekly chemotherapy of paclitaxel and carboplatin with concurrent three dimensional conformal radiotherapy (3D-CRT)for locally advanced non small cell lung cancer(NSCLC). METHODS: From July 2002 to July 2004, a non-randomized prospective study of 52 patients with locally advanced NSCLC treated with 3D-CRT and chemotherapy by paclitaxel and carboplatin were carried out. Of the 52 patients, 21 received concurrent chemoradiation with 3D-CRT and weekly paclitaxel and carboplatin (concurrent chemoradiation group), 31 received sequential chemoradiation with paclitaxel and carboplatin and 3D-CRT (sequential chemoradiation group). In the concurrent chemoradiation group, paclitaxel 40 mg/m2 was administered intravenously for 1 hour. Carboplatin of 1.5 AUC/cycle was used after administration of paclitaxel on D1, D8, D15, D29, D36 and D143. In the sequential chemoradiation group, two cycles of chemotherapy were given at two weeks before radiotherapy. Paclitaxel 150 mg/m2 and carboplatin 5 AUC/cycle were administered on D1 and D21. 3D-CRT was given at two weeks after the second cycle of chemotherapy provided that the hematological examination was normal. 3D-CRT was given at 1.8-2.0 Gy/f to a total dose of 60-66 Gy/6-8 weeks. RESULTS: All the patients completed the trial, but 12 had prolongation of treatment time for more than 1 week due to severe leucopenia with 5 in concurrent chemoradiation group and 7 in sequential chemoradiation group. The rate of complete response (CR), partial response (PR), progress of disease (NC + PD) and overall response was 9.5% (2/21), 71.4% (15/21), 19.0% (4/21) and 81.0%, respectively, in concurrent group, versus 6.5% (2/31), 67.7% (21/31), 25.8% (8/31) and 74.2% in sequential group (CR), respectively. II-III grade of esophagitis, pneumonia and leukocytopenia observed in concurrent chemoradiation group was 61.9% (13/21), 41.9% (13/31) and 23.8% (5/21) ,versus 22.6% (7/31), 42.9 % (9/21) and 19.4% (6/31), respectively, in the sequential chemoradiation group. One of those patients in concurrent chemoradiation group had IV grade of leukocytopenia. The overall median survival time was 17.5 months with 19.0 months for concurrent chemoradiation group, 15.8 months for sequential chemoradiation group. The Overall 1-, 2-year survival rate was 72.0%, 37.0%, respectively and 1 - and 2 - year local control rate was 75.0% and 75.0%. CONCLUSION: Our data indicate that concurrent chemoradiotherapy is safe and effective for locally advanced non small cell lung cancer. Concurrent chemoradiotherapy may be helpful in improving response and survival than sequential one, but no significant difference is observed between two groups in this series(P > 0.05). Further randomized prospective study is still needed to prove it.