Locoregional Failure-free Survival Research Articles

The evaluation of adding induction chemotherapy to concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma: a meta-analysis.

We performed a meta-analysis to compare the efficacy and safety of induction chemotherapy (IC) followed by cisplatin-based concurrent chemoradiotherapy (CCRT) versus cisplatin-based CCRT for patients with locally advanced nasopharyngeal carcinoma (LA-NPC). We systematically searched PubMed, the Cochrane Library and Embase until February 29, 2020, for eligible randomized controlled trials (RCTs). The quality of the studies was assessed with the Cochrane Collaboration risk of bias tool. The following outcomes of interest were analyzed: 1) progression-free survival (PFS); 2) overall survival (OS); 3) distant metastasis-free survival (DMFS); 4) locoregional failure-free survival (LRFFS); and 5) any grade 3 or 4 treatment-related adverse events (AEs). The data were pooled with the use of hazard ratios (HRs) or odds ratios (ORs). Subgroup, heterogeneity and sensitivity analyses were performed. After screening all studies selected from the initial search, seven trials with 2233 patients met the inclusion criteria. Compared to cisplatin-based CCRT alone, there was reliable evidence that IC significantly improved PFS (HR 0.65, 95% CI 0.55-0.75, P < 0.00001), OS (HR 0.61, 95% CI 0.45-0.83, P = 0.002), DMFS (HR 0.65, 95% CI 0.53-0.79, P < 0.0001) and LRFFS (HR 0.68, 95% CI 0.53-0.88, P = 0.003) and was associated with a markedly increased risk of AEs (grade 3/4) during the IC and CCRT phases. No significant difference in the incidence of late AEs (grade 3/4) was observed between different arms. Compared to cisplatin-based CCRT alone, IC followed by cisplatin-based CCRT confers real and substantial favorable survival outcomes with controllable toxicities. Therefore, it is reasonable to define IC followed by cisplatin-based CCRT as one of the standard treatment strategies for patients with LA-NPC.

Survival impacts of different nodal characteristics and T-classification in N3 nasopharyngeal carcinoma patients.

We investigated the survival impacts of various nodal characteristics and T-classification on nasopharyngeal carcinoma (NPC) patients with the 8th AJCC/UICC staging criteria N3. Pretreatment MRIs from 110 staged N3 NPC patients were reviewed. There were 23 T1, 25 T2, 32 T3, and 30 T4, respectively. All except one patient belonged to WHO type II pathology. All patients received curative radiotherapy 68.0-76.8Gy plus different chemotherapy, including induction, concurrent, adjuvant or any combination. Various endpoints, including OS (overall survival), DFS (disease-free survival), LRFFS (locoregional failure-free survival), DMFFS (distant metastasis failure-free survival) were compared between different nodal characteristics and T-classification. There were no statistically significant differences in all analyzed survival curves between various nodal characteristics, including unilateral N3 vs. bilateral N3, "large" nodes (>6 cm) alone vs. "low" nodes (below the caudal border of cricoid cartilage) alone vs. combined "large" and "low" nodes, risk score 1 vs. 2 vs. 3 vs. 4 (by counting the sum of "large" and "low" nodes in the same case), and radiologic extra-nodal extension. Patients with T4, compared with those of T1-3 have worse OS (5-year rates, 42.2% vs. 82.8%, P<0.0001), DFS (5-year rates, 43.9% vs. 68.9%, P=0.0037), LRFFS (5-year rates, 69.3% vs. 82.7%, P=0.0432), and DMFFS (5-year rates, 57.2% vs. 77.7%, P=0.0163). Our results support merging previous N3a and N3b as a N3 category in the 8th edition new staging system. Patients with T4N3 diseases have extremely poor outcome and deserve to strengthen the treatment intensity in future trials.

Interaction between the Number of Chemotherapy Cycles and Brachytherapy Dose/Volume Parameters in Locally Advanced Cervical Cancer Patients

Scarce data exist on concurrent chemotherapy in locally advanced cervical cancer (LACC) patients (pts) treated with image-guided adaptive brachytherapy (IGABT). We examined the effect of a number of chemotherapy cycles and their interaction with brachytherapy dose/volume parameters. Clinical records of 209 consecutive pts treated for a LACC were reviewed. Pts received CRT concurrently with cisplatin 40 mg/m² or carboplatin AUC2. An additional cycle could have been delivered during the pulse-dose rate (PDR)-IGABT. The impact of a number of chemotherapy cycles on outcome was examined, as well as the interactions with dose volume parameters. The number of cycles was four in 55 (26.3%) pts, five in 154 (73.7%) including 101 receiving the fifth cycle during IGABT. Median follow-up was 5.5 years. Pts receiving five cycles had a better outcome on all survival endpoints, including three year local control rate (93.9% vs. 77.2%; p < 0.05). In the subgroup, only pts with tumor FIGO (Fédération Internationale de Gynécologie Obstétrique) stage ≤IIB or with CTVHR > 25 cm3 had a better outcome. Pts receiving four cycles with D90CTVHR > 80GyEQD2 had the same locoregional control–(LRC) as those receiving five cycles and achieving D90CTVHR ≤ 80 GyEQD2 (p = 0.75). An optimal propensity score matching the balance for the FIGO stage, CTVHR volume and D90CTVHR confirmed the effect, with the largest life expectancy benefit for locoregional failure-free survival (absolute gain: 1.5 years; p = 0.017). Long-term radiation-induced toxicity was not increased. Increasing the total number of cycles from 4 to 5 improved LFS, suggesting a place for systemic strategies aimed at in-field cooperation. Delivering an additional cycle at the time of brachytherapy did not increase morbidity and there permitted an increase in chemotherapy dose intensity.

Propensity score-based comparison of survival and radiation pneumonitis after definitive chemoradiation for esophageal cancer: Intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy

PurposeTo compare survival outcomes and radiation pneumonitis (RP) between intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT) in patients with esophageal cancer (EC) who underwent definitive chemoradiation therapy (CRT). MethodsClinical characteristics and dose-volume histogram parameters were collected for 388 EC patients who received definitive CRT with either IMRT (n = 297) or 3DCRT (n = 91) from 2010 through 2017. Dosimetric parameters, survival end-points, and symptomatic RP (grade ≥2) were compared between groups. Propensity score matching (PSM) was performed to balance potential confounding factors. Univariate and multivariate logistic regression analyses were applied to identify predictors of RP. ResultsCompared with 3DCRT, IMRT was significantly associated with better overall survival (OS; P = 0.001), progression-free survival (PFS; P = 0.008), and distant metastasis-free survival (P = 0.011), but not with locoregional failure-free survival (P = 0.721). Moreover, IMRT demonstrated a remarkably lower risk of RP than 3DCRT (5.4% vs 23.1%, P < 0.001). PSM analysis further confirmed the clinical benefit of IMRT. In the matched cohort, radiation modality was independently correlated with OS and PFS. On multivariate analysis, smoking history (odds ratio [OR]: 4.225, P = 0.002), primary tumor length (OR: 2.764, P = 0.049), radiation modality (OR: 10.760, P < 0.001), planning target volume (OR: 1.004, P < 0.001), and lung V20 (OR: 1.286, P = 0.002) were found to be significant predictors of RP. ConclusionsCompared with 3DCRT, IMRT was associated with more favorable survival and a reduced risk of RP after definitive CRT, supporting the routine use of IMRT for EC.

The efficacy and toxicity of induction chemotherapy plus concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: A meta-analysis of randomized controlled trials.

A systemic review and meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy, toxicity and safety of concurrent chemoradiotherapy (CCRT) with or without induction chemotherapy (IC) for locoregionally advanced nasopharyngeal carcinoma (NPC). Research searching was performed in Web of Science, PubMed, The Cochrane Library, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Chongqing VIP Database for Chinese Technical Periodicals and Wanfang Database. RCTs including patients diagnosed with locoregionally advanced NPC without metastasis and randomly treated with IC plus CCRT and CCRT alone were included. Survival and outcome data were extracted and meta-analysis was performed using the Revman 5.3.0 software. Ten RCTs (2280 patients) were selected and used for pooled meta-analysis. In comparison with CCRT, IC plus CCRT treatment significantly improved the overall survival (OS; HR = 0.70, 95%CI 0.56-0.87, P = .002), progression-free survival (PFS; HR = 0.75, 95%CI 0.65-0.87, P < .0001), distant metastasis failure-free survival (DMFS; HR = 0.71, 95%CI 0.58-0.85, P = .0003) and loco-regional failure-free survival (LFES; HR = 0.72, 95%CI 0.59-0.88, P = .002) of patients with locoregionally advanced NPC. Patients treated with IC and CCRT had higher incidence of grade 3-4 leucopenia and thrombocytopenia than patients treated with CCRT alone (P < .0001). No significant difference in other grade 3-4 adverse events and radiation toxicity was observed between the two groups. IC combined with CCRT improved the survival of patients with locoregionally advanced NPC. Combined IC and CCRT therapy was an efficacy treatment regimen for locoregionally advanced NPC.

Prognostic factors and outcomes of multimodality treatment in olfactory neuroblastoma.

The clinical data on olfactory neuroblastomas (ONBs) are scarce owing to their rarity. This study aimed to assess the potential prognostic factors, outcomes, and optimal treatment strategies in patients with ONB. The data of 217 patients with ONB between 1991 and 2019 were retrospectively reviewed. Long-term survival, potential prognostic factors, and outcomes with combined treatment strategies were analyzed. All patients received radiotherapy (RT); 185 patients underwent surgery, and 139 patients received chemotherapy. The 5-year overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFS), and distant metastasis-free survival (DMFS) of the entire cohort were 80.0%, 79.0%, 79.3%, and 80%, respectively. On univariate analyses, R0/R1 resection, early Kadish stage, negative lymph nodes, absence of orbital invasion, and administration of surgery with RT were found to be favorable factors. Conversely, combined sequential treatment with surgery, RT, and chemotherapy was not associated with survival. Multivariate analysis demonstrated lymph node status, orbital invasion, and the combination of surgery and RT to be independent prognostic factors. Patients with ONB, who had lymph node metastases, orbital invasion diseases, advanced Kadish stages, R2 resection margins, and received RT alone, had poor outcomes. Combined administration of surgery and RT may be a potentially useful strategy in patients with advanced Kadish stages; the role of chemotherapy in these stages requires further evaluation.

Effects of Epstein-Barr virus viral load and different treatment modality for stage III nasopharyngeal carcinoma.

We investigated treatment results, the effects of different treatment modality, and pretreatment Epstein-Barr virus (EBV) viral load for stage III nasopharyngeal carcinoma (NPC) patients. The initial definitive treatment for 356 stage III NPC patients consisted of concurrent chemoradiotherapy (CCRT) or induction chemotherapy plus radiotherapy (IndCT-RT). The pretreatment EBV DNA level separated patients into a high (n = 106) or low (n = 250) viral load (≥ or < 1000 copies/mL) subgroup. Outcome measures include relapse rates and various survivals. The 5-year rates of overall survival (OS), progression-free survival (PFS), distant metastasis failure-free survival (DMFFS), and locoregional failure-free survival (LRFFS) were 88.6%, 83.0%, 90.5%, and 90.5%, respectively. Patient characteristics and pretreatment viral load between IndCT-RT and CCRT were no significant differences except for a higher percentage of N2 disease in the IndCT-RT subgroup. Both treatment modality resulted in similar relapse rates (P = .56), OS (P = .20), PFS (P = .53), DMFFS (P = .89), and LRFFS (P = .35). However, patients with a high viral load experienced a higher relapse rate (33.0% vs 12.4%, P < .001) and worse OS (5-year rate, 79.0% vs 92.8%, P < .001), PFS (73.7% vs 88.4%, P < .001), DMFFS (80.2% vs 95.0%, P < .001), and LRFFS (85.6% vs 92.6%, P = .005) than those with a low viral load. Long-term treatment results for stage III NPC patients are rather good. IndCT-RT can achieve the same treatment outcome as CCRT. Risk grouping by pretreatment viral load identified a subgroup (30%) of patients associated with a significantly higher relapse rates and worse survivals. These high-risk patients need to strengthen treatment intensity in future trials.

Prognostic factors and patterns of loco-regional failure in patients with R0 resected gallbladder cancer

BackgroundIn this study, risk factors for loco-regional recurrence in curative R0 resected gallbladder adenocarcinoma were investigated. MethodsPatients with gallbladder adenocarcinoma with curative R0 resections between 2000 and 2016 were retrospectively reviewed. Loco-regional failure-free survival (LRFFS) and overall survival (OS) were analyzed using the Kaplan–Meier method; prognostic factors were analyzed using the Cox proportional hazards model. Based on the identified risk factors, patients were grouped for further analysis. ResultsA total of 272 patients were included for analysis; overall, 5-year LRFFS and OS were 83% and 81%, respectively. On multivariate analysis, 3 risk factors for LRFFS were identified; lymphovascular invasion, T3, and N1, by which patients were grouped; group 1 for 0 factor, group 2 for 1 factor and group 3 for 2 to 3 factors. The 5-year LRFFS in groups 1, 2, and 3 were 94%, 73%, and 40%, and the 5-year OS in groups 1, 2, and 3 were 90%, 75%, and 47%, respectively. LRFFS and OS differed significantly among groups (p < 0.05). ConclusionIn patients with R0 resected gallbladder cancer, the presence of >1 risk factor increased the risk of loco-regional recurrence. Additional therapeutic strategy for these patients needs further consideration.

Maintenance chemotherapy using S-1 following definitive chemoradiotherapy in patients with N3 nasopharyngeal carcinoma

BackgroundPatients with N3 stage nasopharyngeal carcinoma (NPC) are at high risk for treatment failure. This study aims to assess the efficacy of maintenance chemotherapy (MC) using S-1 (MC-S1), a novel oral fluoropyrimidine agent, following definitive chemoradiotherapy (CRT) using intensity-modulated radiotherapy (IMRT) in patients with N3 nasopharyngeal carcinoma (N3-NPC).MethodsA retrospective review was conducted for all N3-NPC treated with CRT with MC (CRT-MC) or without MC (CRT-non-MC) during 2014–2016. Toxicities with MC were recorded. Overall survival (OS), locoregional failure-free survival (LFFS) and distant metastasis free survival (DMFS) were compared between CRT-MC vs. CRT-non-MC cohorts.ResultsA total of 130 N3 patients were identified, of whom 21 (16.2%) were treated with CRT-MC, and 109 (83.8%) with CRT-non-MC. Patient characteristics did not significantly differ between the CRT-MC and CRT-non-MC groups, with the exception of the number of cycles of neoadjuvant chemotherapy. Following IMRT 69 patients achieved a complete response (CR) (CRT-MC: 10; CRT-non-MC: 59), 61 had a partial response (PR) (11 vs. 50), and none maintained stable disease (SD) or developed progression of disease (PD). After a median follow-up of 41 months for surviving patients, a significant differences in OS (76.3% vs. 95.2%, p = 0.046) and DMFS (70.3% vs. 90.5%, p = 0.043) but not LFFS (84.9% vs. 100%, p = 0.091) at 3 years were observed between the CRT-non-MC and CRT-MC groups. Skin hyperpigmentation, leucopenia, fatigue, neutropenia, anorexia and nausea were the common but not severe (grade 1–2) toxicities of MC.ConclusionsUsing MC-S1 in N3-NPC patients following IMRT achieved superior survival to the CRT-non-MC patients. The toxicities of MC-S1 were mild and tolerable. Further clinical trials are required to evaluate the efficacy of MC-S1 in N3-NPC patients.

1070PD - Treatment outcomes and pattern of failure in primary gastric diffuse large B cell lymphoma with complete remission following R-CHOP chemotherapy

BackgroundThe optimal treatment for primary gastric diffuse large B cell lymphoma (DLBCL) is unclear. The treatment for primary gastric DLBCL is in accordance with the principle of treatment for general DLBCL. We aimed to evaluate the treatment outcomes and pattern of failure in primary gastric DLBCL. MethodsBetween April 2001 and November 2018, 120 patients with stage I–IV primary gastric DLBCL were retrospectively reviewed in this study. All patients had been in complete remission after receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ninety patients (75%) were treated with R-CHOP alone, and the other 30 patients (25%) underwent R-CHOP with local treatment for gastric lesions. Twelve patients (10%) underwent gastrectomy, and 18 patients (15%) received consolidation radiotherapy (RT). ResultsThe median follow-up time was 49 (range, 5 to 197) months. The 5-year locoregional failure-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates were 85.6%, 86.5%, 83.4%, and 90.3%, respectively. During the follow-up, 17 patients (14.2%) experienced disease recurrence. Only 3 patients developed distant metastasis without locoregional failure (LRF). All except two cases of LRF included gastric failure. There was no LRF in patients who received R-CHOP with local treatment. On multivariate analysis, poor performance status was an independent prognostic factor for LRFS, and multiple gastric lesions influenced LRFS, DMFS, DFS, and OS. ConclusionsThe main pattern of initial failure is LRF, especially in the stomach in patients with primary gastric DLBCL. Gastric local treatment such as consolidation RT can effectively prevent gastric failure. Therefore, gastric local treatment should be considered for patients at high risk of LRF, such as multiple gastric lesions. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Prognostic Values Of Preoperative Serum CEA And CA125 Levels And Nomograms For Young Breast Cancer Patients.

BackgroundYoung breast cancer patients have poor prognosis compared to older patients in both overall survival (OS) and loco-regional failure-free survival. Carcinoembryonic antigen (CEA) and Cancer antigen 125 (CA125) have been widely used, but their prognostic value in young breast cancer patients remains unknown. The objectives of this study were to evaluate the prognostic value of preoperative CEA and CA125 serum levels and to build nomograms for better prognostic prediction of young Chinese breast cancer patients using both tumor markers.MethodsWe included 576 young breast cancer patients (≤40 years at diagnosis) and collected their preoperative information. The best cut-off values of the CEA and CA125 were identified with receiver operating characteristic (ROC) curves. Univariate and multivariate analyses were used to identify the relative risks of factors for the overall survival (OS), and disease-free survival (DFS), and nomograms were constructed based on these identified factors.ResultsThe best cut-off values for CEA and CA125 in young breast cancer patients was 3.38 ng/mL and 19.38 U/mL, respectively. Kaplan-Meier analysis showed that young patients with low levels of CEA and/or CA125, had longer OS and DFS. Multivariate analysis suggested that both CEA and CA125 levels were independent predictive elements for OS. Nomograms were built and showed a better predictive ability for OS (AUC = 0.856) and DFS (AUC = 0.702) in young breast cancer patients.ConclusionPreoperative serum CEA and CA125 levels could be the independent prognostic factors for OS, and the nomograms including these two variables provide more personal forecasts information to help physicians optimize treatment for young breast cancer patients better.

Clinical outcomes and prognostic factor analysis after salvage surgery for recurrent squamous cell carcinoma of the oral cavity

The purpose of this study was to analyze the oncological outcomes and predictive factors for successful curative salvage surgery after recurrent oral cavity squamous cell carcinoma. A retrospective study was conducted involving 73 patients who received surgery-based salvage treatment. The pattern of failure for primary treatment was local failure in 29 patients, regional failure in 29 patients, and loco-regional failure in 15 patients. The 5-year overall, loco-regional failure-free, and disease-free survival rates were 54.8%, 58.9% and 49.3%, respectively. Patients with an advanced initial N stage, previous treatment with combined modality therapy, loco-regional recurrence, advanced recurrent T stage, a disease-free survival of less than 8 months prior to salvage, and recurrence in a previously treated field had a significantly worse prognosis. Given the potential surgical morbidity, salvage surgery should be undertaken after careful consultation with patients who have factors for a poor prognosis.

The 2-year Results of Phase II Clinical Trial of Brachytherapy with Single-Channel Applicator For Cervical Carcinoma

To evaluate whether the patent single-channel applicator( China Patent number:200710050108.1), which was modified from the traditional tandem applicator and wrapped with an oval-shield alloy around the source channel, has the same clinical efficacy and safety as the standard Fletcher-type applicator in the high-dose-rate brachytherapy for carcinoma of the cervix. This was a single blind, prospective, parallel randomized trial. This trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR-TRC-12002321). All the eligible patients were randomized by random computer generation to 1 of 2 treatment groups: the Fletcher applicator group or the patent single-channel applicator group. Patients in both groups were treated with concurrent cisplatin chemotherapy and external beam radiotherapy(EBRT) followed by HDR brachytherapy (not includingⅡa1). Whole pelvis irradiation was given with 6-MV photons via a four-field box variants or anterior and posterior parallel fields. The standard prescribed dose was 46 to 50 Gy, consisting of 23 to 25 fractions 5 to 6 weeks apart. Five to six fractions with a dose of 7 Gy per fraction of intracavitary brachytherapy at point A once a week were designed for all patients after the third week of pelvic irradiation. This regimen gives a total equivalent dose in 2-Gy fractions (EQD2) of 80-90 Gy to Point A. Chemotherapy was given with intravenous cisplatin 40 mg/m2 once a week during the EBRT. The acute toxicities and the late toxicities were evaluated according to the RTOG grading scale. The Kaplan-Meier analysis was used to compare the overall survival (OS), the Progression-Free-Survival (PFS) and the locoregional failure-free survival (LRFFS). From December 1st 2011 to February 2017, 299 patients with pathologically confirmed International Federation of Gynecology and Obstetrics (FIGO 2009) stage Ⅰb2-Ⅳa carcinoma of the cervix were randomly assigned to the Fletcher applicator group(n=150) and the single-channel group (n=149). All but eight patients were treated with concurrent chemoradiotherapy. Up to February 2019, all the patients had achieved a minimum follow-up of 2 years. The 2-year OS, PFS and LRFSS was 81.4%, 77.7% and 79.5% for the Fletcher group, and for the single-channel group was 88.2%, 83.6% and 87.0%, respectively. The seriousness of acute treatment-related toxicities was similar in the two groups. The cumulative rate of late rectal complications for Grade 3-4 in the Fletcher group and the single-channel group was 4.0% and 5.4%, respectively. The cumulative rate of Grade 3-4 bladder complications was 1.3% for the Fletcher group and 0.7% for the single-channel group. The 2-year results of our study shows that the patent single-channel intracavitary applicator may be able to provide a protection for the rectum and bladder, and seems to have the same clinical efficacy as the standard Fletcher type three-channel applicator in the high-dose-rate brachytherapy for carcinoma of the cervix.

Comparison of Induction Chemotherapy Versus Adjuvant Chemotherapy in Locally Advanced Nasopharyngeal Carcinoma Treated with IMRT and Concurrent Cisplatin

To compare the efficacy and toxicities of concurrent chemoradiation (CCRT) with adjuvant chemotherapy (ACT) (CCRT+ACT) versus induction chemotherapy (ICT) plus CCRT (ICT+CCRT) in locally advanced nasopharyngeal cancer (LANPC). Patients with stage III-IVB NPC (7th ed AJCC staging) treated from January 2011 to January 2017 at 3 centers in China were retrospectively reviewed. All patients were treated with IMRT with concurrent cisplatin (80 mg/m2 on day 1, 22, and 43). Three chemo regimens were used in ICT or ACT. They are PF (5 FU 500-750 mg/m2, continuous infusion 1-5 days, cisplatin 25 mg/m2, day 1-3), TP (docetaxel 75 mg/m2, day 1, and cisplatin 25 mg/m2, day 1-3), or TPF (docetaxel 60-75 mg/m2, day 1, cisplatin 20-25 mg/m2, day 1-3, and 5 FU 500-750 mg/m2, continuous infusion 1-5 days). Two to three cycles of chemo were delivered every 21 days. The primary endpoint was overall survival (OS). Secondary endpoints included locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), and toxicities. Survivals were calculated with Kaplan-Meier method. The differences between survivals were calculated by Log-rank test. Toxic effects were analyzed using the χ2 test. All statistical tests were two-side. A total of 350 patients were identified and 301 were eligible for analysis. 155 patients were treated with ICT+CCRT and 146 with CCRT+ACT. With a median follow-up of 61.5 months (range:5.81-89.70 months), there was no significant difference between the ICT+CCRT group and CCRT+ACT group in 5-year OS (83.2% vs. 79.5%, p=0.190 ), LRFS (84.7% vs. 83.2%, p=0.486 ) or DMFS (78.9% vs. 74.3%, p=0.119 ). However, in patients with early T-stage and advanced N-stage disease (stage T1-2N2-3), ICT+CCRT significantly improved 5-year OS (84.1% vs. 74.6%, p=0.043) and DMFS (71.4% vs. 60.3%, p=0.039), but not LRFS (93.2% vs. 92.4%, p=0.624). There was no statistical difference in OS, LRFS, and DMFS between two groups in patients with advanced T-stage and early N-stage disease (stageT3-4N0-1) (81.7% vs.76.7%, p=0.535; 77.5% vs.73.3%, p=0.463; 84.0% vs. 79.4%, p=0.452, respectively). In the ICT+CCRT group, 43 patients received PF, 54 TP, and 58 TPF. There were no statistical differences in survivals between different chemo regimens. In the CCRT+ACT group, 83 patients received PF, 61 TP, and 2 TPF. Again, there were no statistical differences in survivals between different chemo regimens. In addition, there were no statistical differences in survivals with the same chemo regimen either it was given before or after CCRT. The grade 3 or 4 adverse events of two groups had no statistical difference in both hematologic and non-hematologic toxicities (P>0.05). There was no statistical difference in efficacy and toxicities between ICT+CCRT versus CCRT+ACT in LANPC. However, ICT+CCRT may be superior in patients with early T-stage and advanced N-stage disease (T1-2N2-3). Randomized trial may be warranted in this patient population.

Changes of Circulating Lymphocyte Populations and Its Association with Outcome after Hypofractionated Radiation Therapy in Patients with Non-small-cell Lung Cancer

Hypofractionated radiation therapy may have significant immunomodulatory effects and could enhance anti-tumor immune effect. The purposes of this study were to investigate changes of peripheral blood lymphocytes at different time points during and after radiotherapy and their association with survival. We collected serial blood samples before treatment and about day 14 of radiotherapy, at the end of radiotherapy, 1 month and 3 months after radiotherapy from 42 patients with non-small-cell lung cancer from November 2016 to October 2018 . 40.5% (17/42) of the patients received 60-84Gy in 10-12 fractions of Stereotactic ablation radiotherapy. Other patients (59.5%, 25/42) were treated with Partial Stereotactic Ablative Boost Radiotherapy，the GTVb（GTV-boost）received 18-32Gy in 3-4 fractions, then the PTV was treated with conventional fractionated radiotherapy to a median dose of 55.44 Gy（48-60Gy）. We used flow cytometry to measure the changes of total CD3+, CD4+, CD8+ T cells, CD3+HLADR+ T cells, CD19+ B lymphocytes and CD16+CD56+ natural killer cells. The median follow up time was 10.6 months(range, 3.3 to 31.3). The one-year and two-year PFS was 73.0% and 58.0%, the one-year and two-year OS was 80.0% and 68.5%, and the one-year and two-year locoregional failure-free survival rate was 87.7% and 71.4%, respectively. The number of all the lymphocytes decreased gradually at the beginning of radiotherapy, reached the minimum at the end of radiotherapy, and gradually returned to the baseline level after radiotherapy. However, the fractions of CD3+HLADR+ T cells（activated T lymphocytes） decreased slightly at the beginning of radiotherapy, then gradually increased during radiotherapy until 3 months after radiotherapy. Moreover, 1 month after radiotherapy, the proportion of CD4+T cells was lower than the baseline, and the proportion of CD8+T cells was higher than the baseline, and the ratio of the two was lower than the baseline. Longer OS was significantly correlated with higher CD4+/CD8+Tcell ratio after radiotherapy (p＜0.05). And we found hypofractionated radiation therapy of patients with large tumor size produced more significant immune effects, while large tumor size may lead to worse OS, which still needs further exploration. The proportion of CD8+T cells and CD3+HLADR+ T cells（activated T lymphocytes）increased one month after the hypofractionated radiation therapy. We found longer OS was significantly correlated with higher CD4+/CD8+Tcell ratio after radiotherapy (p＜0.05), and this may be because the larger irradiation volume related to significant immunological effects of the tumor. These results may provide reference for future studies to determine the optimal treatment schedules when combining irradiation with specific immunotherapy approaches.

Is Negative Lymph Node Count Another Clinico-pathological Predictor in Breast Cancer with Neoadjuvant Chemotherapy?

To investigate the survival impact of negative lymph nodes (NLNs) in breast cancer (BC) patients who received neoadjuvant chemotherapy (NAC). We retrospectively evaluated 435 BC patients who presented and received NAC at our institute. The prognostic value of the number of NLNs and other clinic-pathological factors with respect to disease-free survival (DFS) and overall survival (OS) was analyzed. The median age was 49 years old. 385 patients were in ypT0-2, 187 patients in ypT3-4; 99 cases ypN0, 99 cases were ypN1, 108 cases were ypN2, and 129 cases were ypN3. With a median follow-up time of 61 months, the 5-year OS (5y-OS), 5-year loco-regional failure-free survival (5y-LRFS), 5-year distant metastasis-free survival (5y-DMFS) were 74.8%, 84.1%, and 71.4%, respectively. Negative LN count, estrogen receptor status, pathological T and N stage were independent prognostic factors associated with 5y-LRFS. A critical relationship was observed between NLNs and 5y-LFRS, with an HR of 0.948 (95% CI: 0.917-0.981), p=0.002. Patients with NLNs more than 10 showed significantly superior 5y-LRFS than those with NLNs no more than 10 (5y-LRFS were 90.6% in NLNs vs. 64.8% in ≤10 NLNs, p=0.000). The most survival benefit was found in patients with N-positive disease (5y-LRFS were 87.4% in >10 NLNs vs. 64.0% in ≤10 NLNs, p=0.000), relative to the N0 disease (5y-LRFS were 96.9% in >10 NLNs vs. 100% in ≤10 NLNs, p=0.724). In this survival beneficial group with >10 NLNs, post-mastectomy radiotherapy (PMRT) could not improve 5y-LRFS (5y-LRFS were 88.4% vs. 85.1% with or without PMRT, p=0.257), otherwise than that in patients with ≤10 NLNs (5y-LRFS were 69.0% vs. 27.6% with or without PMRT, p=0.002). This is the first study to confirm the relationship between negative lymph node count and prognosis of breast cancer with NAC. More NLNs imply higher local control and longer survival. This result might let NLNs be a prognostic factor for considering treatment decisions, such as PMRT.

Patterns of local recurrence after curative resection and reconstruction for oropharyngeal and oral cancers: Implications for postoperative radiotherapy target volumes.

We aimed to determine the patterns of local recurrence after curative resection and reconstruction for oropharyngeal and oral cancers. One hundred-fourteen patients with oropharyngeal and oral cancers underwent resection and reconstruction. The local recurrences were classified as "intra-flap" (the recurrent tumor was located in the flap tissue), "marginal" (≤5 mm from the flap anastomosis), and "outside" (in the original tissue and >5 mm from the anastomosis) recurrences. Twenty-seven patients (23.7%) experienced local recurrence, while 32 (28.1%) experienced regional, and nine (7.9%) recurred distantly. Among those who showed local recurrence, one developed "outside" recurrence and the remaining 26 developed "marginal" recurrences. Age >60 years and lymph node metastasis were associated with poor disease-free survival and overall survival (OS), while the perineural invasion was related to poor locoregional failure-free survival and OS. Most recurrences developed at the anastomosis marginal site, while none developed in the flap tissue.

Radiotherapy dose escalation in the primary treatment of nasopharyngeal carcinoma: a systematic review and meta-analysis

Background: Dose escalation with radiotherapy (RT) in nasopharyngeal carcinoma (NPC) remains underutilized despite significant advances in methods of radiation delivery. RT boost during primary treatment has been shown to improve local control rates, which could have an impact on survival. We summarize the currently available evidence for dose escalation in the primary treatment of NPC. Methods: Databases were systematically searched for eligible studies from the year 2000. Included studies utilized RT dose escalation (BED >70 Gy) in the form of brachytherapy, external beam RT or stereotactic RT boost after external beam RT for primary treatment of NPC. Local recurrence-free survival (LRFS), overall survival (OS), toxicities and other relevant factors for the chosen studies were then pooled and analyzed. Results: Two randomized trials and 7 retrospective cohort studies with a total of 2,145 patients were included in the final analysis. Nine hundred and eighty-eight patients received dose escalation, mainly in the form of brachytherapy (90%). Patients were mostly male, from China/Southeast Asia, had T1-T2 disease (80%), underwent RT via conventional techniques (87%). Less than half received concurrent chemotherapy. Three-year LRFS (RR 1.04; 95% CI: 0.85–1.28, P=0.71) and OS were not significantly improved with dose escalation. However, the subset of patients pooled from the retrospective studies who did not receive concurrent chemotherapy showed significant a 5-year locoregional failure-free survival (RR 1.05; 95% CI: 1.02–1.09, P=0.005) benefit. Toxicities were not significantly increased with dose escalation. Conclusions: RT dose escalation in the primary treatment of NPC does not lead to an increase in LRFS, OS, progression free-survival and disease free-survival. However, there seems to be a LRFS benefit with dose escalation using brachytherapy in patients with T1-T2 disease and in patients who did not receive concurrent chemotherapy. Dose escalation with brachytherapy is likewise not significantly associated with any increase in the rate of complications. Data for the efficacy and toxicity of EBRT and SRT boost is currently still lacking.

A phase II multicenter randomized controlled trial to compare standard chemoradiation with or without recombinant human endostatin injection (Endostar) therapy for the treatment of locally advanced nasopharyngeal carcinoma: Long-term outcomes update

Purpose: This study aimed to observe the feasibility and safety of addition of recombinant human endostatin injection to standard chemoradiation for the locally advanced nasopharyngeal carcinoma. Current follow-up results updated long-term efficacy and late toxicity of the trial.Methods: Between July 2012 and December 2013, we enrolled 114 patients that are older than 18 years with stage Ⅲ-Ⅳb nasopharyngeal carcinoma from 3 centers in Guizhou, China. Fifty six patients who received standard chemoradiation combined with recombinant human endostatin injection (Endostar) were included in the study group. Another 58 patients were randomly assigned to the control group without using Endostar. Patients in both groups received the same 2 cycles of induction chemotherapy (Docetaxel 75 mg/m2, cisplatin 80 mg/m2), followed by 2 cycles of concurrent intensity-modulated radiation therapy with cisplatin (DDP; 80 mg/m2 on days 1 and 22). The patients in the experimental group received 2 cycles Endostar (7.5 mg/m2 d8-d21 during induction chemotherapy and d1-d14 during concurrent chemoradiation).Results: There were no significant differences of toxicities between the 2 groups. Chemotherapy and radiotherapy compliance between the 2 groups was similar. No hemorrhage and coagulation dysfunction in the experimental group were observed. There was a median follow-up of 67.1 months. Comparing the short-time effect of 3 months to the completion of chemoradiotherapy, there was a little higher objective response rate in the experimental group. Compared with the control group, the experimental group improved in the complete remission rate of cervical lymph node metastasis (91.1% vs 72.4%, χ2 = 3.897, P = 0.048). However, there was no significant difference in the curative effect of nasopharyngeal lesions between the 2 groups. (78.6% vs 74.1%, χ2 = 0.310, P = 0.578). The 5-year overall survival, progression-free of survival, metastasis-free survival, and locoregional failure-free survival rates in the 2 groups were 69.6%, 67.8%, 78.75, and 83.0%, respectively, for the experimental group, these rates were 73.2%, 80.1%, 81.7%, and 91.0%, respectively, and for the control group, no significant difference was found (P > 0.05).Conclusions: Patients show good tolerance and compliance with a manageable toxicity profile to the regimen of chemoradiation plus Endostar. There was a little higher objective response rate in the study group. A phase 3 randomized study is needed to substantiate our findings.

The efficacy and safety of docetaxel, cisplatin and fluorouracil (TPF)-based induction chemotherapy followed by concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: a meta-analysis.

In recent years, docetaxel, cisplatin and fluorouracil (TPF)-based induction chemotherapy (IC) has been widely applied in the treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, it remains unclear whether TPF is the ideal IC regimen. Thus, we carried out a meta-analysis to compare the efficacy and safety of TPF-based IC plus concurrent chemoradiotherapy (CCRT) versus CCRT alone or double-drug-based IC plus CCRT for LA-NPC. We systematically searched PubMed, Embase and the Cochrane Library from inception until December 2018. After rigorous screening of all relevant studies that reported the use of TPF-based IC followed by CCRT for patients with LA-NPC, eight studies met the inclusion criteria and were assessed for design and quality. Among them, three articles were classified as having a high risk of bias and were excluded from the meta-analysis. The outcomes, including overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), locoregional failure-free survival (LRFFS) and incidence of adverse events, were pooled with the use of hazard ratio (HR) or odds ratio (OR). Heterogeneity and sensitivity analyses were also carried out. Five trials involving 4223 patients were included in the meta-analysis. Compared to CCRT alone, TPF-based IC plus CCRT significantly improved OS (HR 0.54, 95% confidence interval [CI] 0.35-0.84, P = 0.006), PFS (HR 0.64, 95% CI 0.46-0.88, P = 0.006), LRFFS (HR 0.57, 95% CI 0.34-0.94, P = 0.03), and DMFS (HR 0.58, 95% CI 0.38-0.88, P = 0.01). Moreover, compared to double-drug-based IC plus CCRT, OS (HR 0.74, 95% CI 0.62-0.87, P = 0.0004), PFS (HR 0.76, 95% CI 0.66-0.88, P = 0.0001) and LRFFS (HR 0.75, 95% CI 0.61-0.92, P = 0.006) were also significantly improved by TPF-based IC plus CCRT. Notably, TPF-based IC plus CCRT mainly led to an increased risk of hematologic toxicities, such as leucopenia (OR = 3.20, 95% CI 2.13-4.81, P < 0.0001) and neutropenia (OR = 3.84, 95% CI 0.66-22.36, P = 0.13). However, these were uncomplicated and manageable with growth factor support. Compared to CCRT alone or double-drug-based IC plus CCRT, TPF-based IC plus CCRT results in better survival outcomes with manageable toxicities. Thus, it is reasonable to recommend the addition of TPF-based IC to CCRT as an excellent choice for patients with LA-NPC.