Yu Tang

Nimotuzumab combined with radiotherapy for esophageal cancer: preliminary study of a Phase II clinical trial.

Objective To determine the safety and therapeutic effects of nimotuzumab (h-R3) combined with radiotherapy in esophageal cancer. Methods This Phase II clinical trial involved 42 patients with stage II (inoperable or refused surgery) to stage IV (supraclavicular lymph node metastasis only) esophageal cancers treated between November 2008 and July 2010. All patients had squamous cell carcinomas, and all received three-dimensional conformal radiotherapy and 200 mg nimotuzumab per week during radiotherapy. Results There were 9, 25, and 8 patients with stage II, III and IV disease, respectively. All except two patients received 50–70 Gy radiation; 37 patients (88.1%) received more than five nimotuzumab doses. Grade III toxicities (21.4% of all adverse events) included esophagitis and gastrointestinal, dermatological and hematological toxicities. Complete response, partial response, stable disease, and progressive disease were observed in 0, 22 (52.4%), 17 (40.5%) and 3 (7.1%) patients at 1 month after the treatment. The epidermal growth factor receptor (EGFR) overexpression rate was 95.2%. After a median follow-up of 37 months, the median survival time (MST) was 14 months. The 2 year and 3 year overall survival (OS) rates were 33.3% and 26.2%, respectively. The median progression-free survival (PFS) time was 10 months. The 2 year and 3 year PFS rates were 24.5% and 22.1%, respectively. The MST in the 13 patients with (+++) EGFR expression (group A) and 7 patients with (++) EGFR expression (group B) was 15 and 11 months, respectively. The 2 year and 3 year OS rates were 46.2% and 38.5% in group A and 28.6% and 28.6% in group B, respectively (P = 0.405). Conclusion Although concurrent chemoradiotherapy was the standard care for locally advanced esophageal cancer, radiotherapy was the choice for those who were refused or could not tolerate chemoradiotherapy. Our study shows that nimotuzumab combined with radiotherapy was well tolerated in patients with esophageal cancer. EGFR overexpression was more common than previously reported. OS was higher after combined therapy than after historical control radiotherapy alone. Further studies are required to confirm the therapeutic efficacy of nimotuzumab in esophageal cancer.

Patterns of Primary Tumor Invasion and Regional Lymph Node Spread Based on Magnetic Resonance Imaging in Early-Stage Nasal NK/T-cell Lymphoma: Implications for Clinical Target Volume Definition and Prognostic Significance

PURPOSEnThis study aimed to determine the pathways of primary tumor invasion (PTI) and regional lymph node (LN) spread based on magnetic resonance imaging (MRI) in early-stage nasal NK/T-cell lymphoma (NKTCL), to improve clinical target volume (CTV) delineation and evaluate the prognostic value of locoregional extension patterns.nnnMETHODS AND MATERIALSnA total of 105 patients with newly diagnosed early-stage nasal NKTCL who underwent pretreatment MRI were retrospectively reviewed. All patients received radiation therapy with or without chemotherapy.nnnRESULTSnThe incidences of PTI and regional LN involvement were 64.7% and 25.7%, respectively. Based on the incidence of PTI, involved sites surrounding the nasal cavity were classified into 3 risk subgroups: high-risk (>20%), intermediate-risk (5%-20%), and low-risk (<5%). The most frequently involved site was the nasopharynx (35.2%), followed by the maxillary (21.9%) and ethmoid (21.9%) sinuses. Local disease and regional LN spread followed an orderly pattern without LN skipping. The retropharyngeal nodes (RPNs) were most frequently involved (19.0%), followed by level II (11.4%). The 5-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) rates for all patients were 72.8%, 65.2%, and 90.0%, respectively. The presence of PTI and regional LN involvement based on MRI significantly and negatively affected PFS and OS.nnnCONCLUSIONSnEarly-stage nasal NKTCL presents with a high incidence of PTI but a relatively low incidence of regional LN spread. Locoregional spread followed an orderly pattern, and PTI and regional LN spread are powerful prognostic factors for poorer survival outcomes. CTV reduction may be feasible for selected patients.

Dosimetric and Clinical Outcomes With Intensity Modulated Radiation Therapy After Chemotherapy for Patients With Early-Stage Diffuse Large B-cell Lymphoma of Waldeyer Ring

PURPOSEnTo assess the dosimetric benefit, prognosis, and toxicity of intensity modulated radiation therapy (IMRT) for early-stage, diffuse large B-cell lymphoma of Waldeyer ring (WR-DLBCL).nnnMETHODS AND MATERIALSnSixty-one patients with early-stage WR-DLBCL who received chemotherapy followed by IMRT were retrospectively reviewed. Dosimetric parameters for the target volume and critical normal structures were evaluated, and survival was calculated. Linear regression analysis was used to assess the effect of the mean dose (Dmean) to the parotid glands on xerostomia.nnnRESULTSnThe median conformity index and homogeneity index of the planning target volume (PTV) were 0.83 and 0.90, respectively, demonstrating very good coverage of the target volume. The mean dose to the parotid glands was 24.9xa0Gy. The 5-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) were 94.7%, 93.1%, and 98.3%, respectively. Early and late toxicities were mild, and no patient experienced late grade ≥3 toxicities. The Dmean to the parotid glands had a linear correlation with late grade ≥2 xerostomia.nnnCONCLUSIONSnIMRT after chemotherapy can provide excellent dose conformity and achieve favorable survival and LRC with mild toxicities in patients with early-stage WR-DLBCL. Dose constraints for the parotid glands should be limited to <24xa0Gy for early-stage WR-DLBCL.

Fully automatic and robust segmentation of the clinical target volume for radiotherapy of breast cancer using big data and deep learning

PURPOSEnTo train and evaluate a very deep dilated residual network (DD-ResNet) for fast and consistent auto-segmentation of the clinical target volume (CTV) for breast cancer (BC) radiotherapy with big data.nnnMETHODSnDD-ResNet was an end-to-end model enabling fast training and testing. We used big data comprising 800 patients who underwent breast-conserving therapy for evaluation. The CTV were validated by experienced radiation oncologists. We performed a fivefold cross-validation to test the performance of the model. The segmentation accuracy was quantified by the Dice similarity coefficient (DSC) and the Hausdorff distance (HD). The performance of the proposed model was evaluated against two different deep learning models: deep dilated convolutional neural network (DDCNN) and deep deconvolutional neural network (DDNN).nnnRESULTSnMean DSC values of DD-ResNet (0.91 and 0.91) were higher than the other two networks (DDCNN: 0.85 and 0.85; DDNN: 0.88 and 0.87) for both right-sided and left-sided BC. It also has smaller mean HD values of 10.5u202fmm and 10.7u202fmm compared with DDCNN (15.1u202fmm and 15.6u202fmm) and DDNN (13.5u202fmm and 14.1u202fmm). Mean segmentation time was 4u202fs, 21u202fs and 15u202fs per patient with DDCNN, DDNN and DD-ResNet, respectively. The DD-ResNet was also superior with regard to results in the literature.nnnCONCLUSIONSnThe proposed method could segment the CTV accurately with acceptable time consumption. It was invariant to the body size and shape of patients and could improve the consistency of target delineation and streamline radiotherapy workflows.

Comparison of Treatment Outcomes With Breast-conserving Surgery Plus Radiotherapy Versus Mastectomy for Patients With Stage I Breast Cancer: A Propensity Score-matched Analysis

Background To investigate the superiority of breast‐conserving surgery (BCS) plus radiotherapy (RT) compared with mastectomy alone for patients with stage I breast cancer in a real‐world setting. Patients and Methods The data from patients with histologically confirmed stage I breast cancer treated from 1999 to 2014 were retrospectively reviewed. The association of outcomes with the choice of treatment (BCS plus RT vs. mastectomy) was evaluated using multivariable proportional hazards regression and further confirmed using propensity score matching methods. Results Of 6137 eligible patients in the present study, 1296 underwent BCS plus RT and 4841 underwent mastectomy plus axillary lymph node dissection without RT (mastectomy group). Multivariate analysis revealed that BCS plus RT was related to similar locoregional recurrence‐free survival but greater distant metastasis‐free survival (P = .003) and overall survival (P = .036) compared with mastectomy. For the 1252 pairs of patients matched using propensity score matching, the BCS plus RT groups enjoyed significantly greater 5‐year overall survival (99.1% vs. 96.1%; P = .001), distant metastasis‐free survival (97.0% vs. 92.2%; P < .001), and disease‐free survival (95.3% vs. 90.2%; P = .001) compared with the mastectomy group. Conclusion BCS plus RT provided better outcomes than mastectomy for eligible patients with stage I breast cancer and should be offered as a preferred treatment option. Micro‐Abstract In the present study, we retrospectively compared the outcomes of breast‐conserving surgery (BCS) plus radiotherapy (RT) versus mastectomy for stage I breast cancer patients in a large real‐world setting. To avoid bias from an uneven distribution between groups, we used propensity scores to adjust for factors related to tumor biology and therapy. The results demonstrated the superiority of BCS plus RT compared with mastectomy.

Continuous intravenous infusion of recombinant human endostatin combined with concurrent etoposide plus cisplatin and radiotherapy for treatment of unresectable stage III non-small-cell lung cancer (HELPER): a phase 2, multicentre study

Abstract Background Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small lung cancer, with frequently unsatisfactory results. We aimed to evaluate the efficacy and safety of the addition of continuous intravenous infusion of recombinant human endostatin (Endostar) to concurrent chemoradiotherapy. Methods We did this prospective, phase 2 study (HELPER) in patients with inoperable stage III non-small-cell lung cancer (defined by the American Joint Committee on Cancer 7th edn staging system) with an E performance score of 0–2; diagnoses were made on the basis of pathology or cytology results. All enrolled patients received thoracic radiation at doses of 60–66 Gy and continuous intravenous infusions of Endostar (7·5 mg/m 2 per 24h, 120 h continuously, 120 h per cycle; from day −5 to day −1, days 10–13, days 24–28, and days 38–42). Additionally, patients received two cycles of etoposide (50 mg/m 2 ; days 1–5 and days 29–33) plus cisplatin (50 mg/m 2 ; day 1, 8, 29, and 36). The primary endpoint was progression-free survival and the secondary endpoints were objective response, overall survival, local recurrence-free survival, and toxicities. Findings From November, 2012, to June, 2015, 73 patients were enrolled and 67 patients were evaluable. 56 patients were male and 11 patients were female. The median age was 59 years (range 31–69). Most patients (44, 66%) had squamous cell carcinoma. 27 patients (40%) had stage IIIa disease, and 40 (60%) had stage IIIb disease. Severe adverse events were observed in two patients (one had massive haemoptysis and one had pneumonia). The most common adverse event was leucopenia (96%; 45% were grade 3–4). The complete response was 12% and partial response was 64%. The median follow-up time was 37·1 months (range 20·1–52·1). The median overall survival was 34·7 months (21·9–47·4), progression-free survival was 13·3 months (5·5–21·0), and local recurrence-free survival was 27·1 months. Progression-free survival was 51% at 1 year, 35% at 2 years, and 28% at 3 years, overall survival was 82% at 1 year, 60% at 2 years, and 48% at 3 years, and local recurrence-free survival was 73% at 1 year, 55% at 2 years, and 50% at 3 years. Interpretation For patients with unresectable stage III non-small-cell lung cancer, continuous intravenous human recombinant endostatin in combination with concurrent chemoradiotherapy is an effective treatment with tolerable toxicities. A phase 3 study is warranted. Funding None.

Possible contribution of IMRT in postoperative radiochemotherapy for rectal cancer: analysis on 1798 patients by prediction model

The evidence for adjuvant therapy in locally advanced rectal cancer after TME surgery is sparse. The aim of this study was to identify predicting factors of overall survival (OS) in these patients and combine them into a nomogram for individualized treatment. 1798 patients with pathologically staged II/III rectal adenocarcinoma treated by radical TME surgery from a single centers database were reviewed. The nomogram was derived by Cox proportional hazards regression. Its performance was assessed by concordance index and calibration curve in internal validation with bootstrapping. Pooled Cox model analysis identified age, sex, grade of histology, pathological T and N stage, residual tumor, concurrent radiochemotherapy (RTCT), adjuvant chemotherapy cycles (CT), radiotherapy (RT) unexpected interruption days and intensity-modulated radiation therapy (IMRT) as significant covariates for 5-year OS (P<0.05). Postoperative RTCT, CT and IMRT all improved OS. The proposed model can predict 5-year OS with a C-index of 0.7105. IMRT significantly benefited OS in multivariate analysis (p=0.0441). In conclusion, our nomogram can predict 5-year OS after TME surgery for locally advanced rectal cancer with simple and effective advantage. This model may provide not only baseline OS estimate but also a tool for candidates selecting of adjuvant treatment in prospective studies.

Adjuvant treatment may benefit patients with high-risk upper rectal cancer: a nomogram and recursive partitioning analysis of 547 patients

Purpose The role of adjuvant chemoradiotherapy (ACRT) or adjuvant chemotherapy (ACT) in treating patients with locally advanced upper rectal cancer (URC) after total mesorectal excision (TME) surgery remains unclear. We developed a clinical nomogram and a recursive partitioning analysis (RPA)-based risk stratification system for predicting 5-year cancer-specific survival (CSS) to determine whether these individuals require ACRT or ACT. Materials and Methods This retrospective analysis included 547 patients with primary URC. A nomogram was developed based on the Cox regression model. The performance of the model was assessed by concordance index (C-index) and calibration curve in internal validation with bootstrapping. RPA stratified patients into risk groups based on their tumor characteristics. Results Five independent prognostic factors (age, preoperative increased carcinoembryonic antigen and carcinoma antigen 19-9, positive lymph node [PLN] number, tumor deposit [TD], pathological T classification) were identified and entered into the predictive nomogram. The bootstrap-corrected C-index was 0.757. RPA stratification of the three prognostic groups showed obviously different prognosis. Only the high-risk group (patients with PLN ≤ 6 and TD, or PLN > 6) benefited from ACRT plus ACT when compared with surgery followed by ACRT or ACT, and surgery alone (5-year CSS: 70.8% vs. 57.8% vs. 15.6%, P < 0.001). Conclusions Our nomogram predicts 5-year CSS after TME surgery for locally advanced rectal cancer and RPA-based stratification indicates that ACRT plus ACT post-surgery may be an important treatment plan with potentially significant survival advantages in high-risk URC. This may help to select candidates of adjuvant treatment in prospective studies.

Preoperative chemoradiation with capecitabine for rectal cancer in elderly patients: a phase I trial.

Dear Editor: Rectal cancer mainly occurs in older patients; however, elderly patients, especially those aged ≥75 years, are often under-represented in clinical trials. The appropriate treatment strategy for them remains controversial. Preoperative concurrent chemoradiotherapy (CRT) is recommended as the first choice for locally advanced rectal cancer (LARC) based on several randomized controlled trials, yet in practice, few elderly patients receive such treatment. Nevertheless, pooled analysis has demonstrated benefit in local control and cancer specific survival with preoperative radiotherapy (RT) regardless of age. Therefore, it is reasonable to hypothesize that fit elderly patients with rectal cancer might benefit from the best available treatment. We performed a phase I study in order to evaluate the maximum tolerated dose (MTD) of capecitabine with neoadjuvant CRT in elderly LARC patients, as well as the safety and efficacy of the regimen in this type of patients. Local ethics committee approval for this study was obtained as well as informed consent from all included patients. Trial was conducted according to the guidelines of Good Clinical Practice and the Declaration of Helsinki (ClinicalTrials.gov number, NCT01584544). Patients ≥75 years with clinical stage II/III rectal adenocarcinoma were eligible for this study. Other inclusion criteria were Karnofsky performance status ≥70 and Charlson comorbidity index ≤3, and adequate bone marrow, kidney, and hepatic function. Clinical stage was evaluated by chest and abdominal computed tomography, endorectal ultrasound, and/or pelvic magnetic resonance imaging. Patients with life-threatening comorbidities were excluded. The planned five escalating dose levels of capecitabine were 1000, 1200, 1350, 1500, and 1650 mg/m/day. Three patients were enrolled at each dose level initially. If none of them experienced DLT, recruitment continued at the next dose level. Otherwise, when dose-limiting toxicity (DLT) was seen in 1 patient out of 3, 3 additional patients were recruited at the same dose level. The dose escalation continued until DLTs were observed in 2 or more of 3–6 patients on a certain dose level which was defined as the MTD. Given that the dose of 1650 mg/m/day widely applied in the standard treatment for younger patients, we decided to stop dose escalation at that dose level even if the MTD was not reached. Capecitabine was given concurrently with preoperative RT for two cycles of 14 days separated by a 7-day rest, administered orally twice daily in escalating dose levels as described previously. All patients underwent computed tomography-based simulation with the marker placed at the anal verge for RT planning, and were treated in a prone or supine position using megavoltage photons (6MV), with 5-field simplified intensity-modulated radiotherapy technique at a dose of 50 Gy in 25 fractions (2 Gy/day) to The abstract of this paper in part has been presented as a poster in the 18th ECCO 40th ESMO European Cancer Congress, 25–29 Sep. 2015, Vienna.

Evaluation of nimotuzumab combined with radiotherapy on esophageal carcinoma: A phase II clinical trial.

e14637 Background: To evaluate the safety and efficacy of nimotuzumab in combination with radiotherapy on esophageal carcinoma (ESO).nnnMETHODSn42 patients with stage II to IVa of ESO were assigned at random into this prospective, phase II clinical trial during Nov. 2008 to Jul. 2010. All patients received 50-70 Gy of three-dimensional conformal radiotherapy. 200mg of nimotuzumab was administered via intravenous infusion once a week during the radiotherapy.nnnRESULTSnThe primary cancer lesions were located upper, middle and lower thoracic segments of the esophagus in 10, 26 and 3 patients, respectivley. Among those, there were 9, 25 and 8 patients with stage II, III and IVa of ESO, respectively. All patients received 50-70 Gy of radiation and 37 patients (88.1%) received nimotuzumab for more than 5 times. The grade 3 toxicities were nause and vomitting, esophagitis, skin reactions, hematology in 1, 3, 4, 1 patients, respectively. There was only one patient who had allergic to nimotuzumab. The CR, PR, SD and PD were observed in 4 (9.5%), 21 (50%), 2 (4.8%) and 15 (35.7%) patients, respectively. The overall disease control rate was 64.3%. With a 6 months of median follow-up, the local recurrence and distance metastasis were observed in 6 (14.3%) and 10 (23.8%) patients. There were 10 patients died with 8 possible cancer-related deaths. The median survival time has not been reached yet. The 6-month and 1-year overall survival rate were 82.4% and 57.8%.nnnCONCLUSIONSnNimotuzumab in combination with radiotherapy is well-tolerated and effective for the treatment of ESO. Long-period toxicity and long-term efficacy need to be further evaluated.