Comparative efficacy and safety of immunotherapy for patients with advanced or metastatic esophageal squamous cell carcinoma: a systematic review and network Meta-analysis.

BACKGROUND: The study aimed to compare efficacy and safety of various immune checkpoint inhibitors for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). METHODS: We searched Medline, Web of Science, Cochrane Central Register of Controlled Trials, Embase, Clinical Trials.gov and several international conference databases from January 1, 2000 to December 19, 2021. We conducted Bayesian network meta-analysis to assess the relative effects among treatments. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate and adverse events. RESULTS: Ten eligible trials with 5250 patients were included. Toripalimab and Camrelizumab plus chemotherapy were preferred to rank first on OS (probability, 61%) and PFS (probability, 37%) in the first-line setting, respectively. In refractory patients, Sintilimab and Camrlizumab were most likely to be ranked first on OS (probability, 37%) and PFS (probability, 94%). The toxicity related to immunotherapy was manageable in clinical trials. Camrelizumab and Nivolumab had the less adverse events of grade 3 or higher in the first and refractory setting, respectively. CONCLUSIONS: This study found that Toripalimab and Camrelizumab plus chemotherapy were likely to be the best option in terms of OS and PFS in the first-line setting for patients with advanced or metastatic ESCC respectively. Sintilimab and Camrelizumab were the preferred options for OS and PFS in refractory patients respectively. The toxicity of immunotherapy was different from conventional chemotherapy, but manageable in patients with ESCC. TRIAL REGISTRATION: PROSPERO registration number: (CRD 42021261554).

Concurrent chemoradiotherapy with/without induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: Long-term results of phase 3 randomized controlled trial.

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III-IVB (except T3-4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2 /d civ d1-5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein-Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.

Prognosis of Fibrosarcoma in Patients With and Without a History of Radiation for Nasopharyngeal Carcinoma.

PURPOSE: To determine whether radiation-induced fibrosarcoma (RIF) in patients with a history of radiotherapy for nasopharyngeal carcinoma (NPC) was associated with an inferior prognosis compared to sporadic fibrosarcoma of the head and neck. METHODS: Forty-two patients with RIF who previously received radiotherapy for NPC and 124 patients with sporadic fibrosarcoma of the head and neck were identified between January 1965 and December 2013 at our institution. Information on clinicopathologic characteristics and treatment was abstracted from medical records. The primary end point was disease-specific survival (DSS). RESULTS: The median latency from NPC diagnosis to RIF diagnosis was 9.9 years (range 3.1-36.8 years). RIF was diagnosed at an older age than sporadic fibrosarcoma. Treatment modality was significantly different between the two groups, with only 64.3 % of the RIF group receiving surgery ± adjuvant treatment versus 91.1 % in the sporadic fibrosarcoma group (P < 0.001). Patients with RIF had poorer 5-year DSS compared to the sporadic fibrosarcoma group (36.2 vs. 50.4 %; P = 0.026). Multivariate analysis of the combined group indicated that patient group (P = 0.032), tumor, node, metastasis classification system stage (P = 0.019), histologic grade (P = 0.046) and treatment modality (P < 0.001) were independent variables affecting DSS. CONCLUSIONS: Compared to patients with sporadic fibrosarcoma, NPC survivors who develop RIF are older at diagnosis of fibrosarcoma and have an inferior prognosis.

Comparing docetaxel plus cisplatin versus fluorouracil plus cisplatin in esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy.

OBJECTIVE: The optimal neoadjuvant chemoradiotherapy (CRT) regimen in esophageal cancer has not yet been defined. This study was aimed to compare the differences in pathologic response and survival between docetaxel/cisplatin and fluorouracil/cisplatin as neoadjuvant CRT in locally advanced esophageal squamous cell carcinoma (SCC). METHODS: We retrospectively analyzed patients with thoracic esophageal SCC who received neoadjuvant CRT followed by esophagectomy from 2000 to 2014. After adjusting for sex, age, performance status, tumor length, tumor location and clinical TNM stage, 32 docetaxel/cisplatin-treated patients were matched to 62 patients who received fluorouracil/cisplatin at a ratio of 1:2. Treatment toxicity, pathologic complete response (pCR) and survival outcomes were compared between groups. RESULTS: Baseline characteristics were well balanced between groups. The pCR rate in the docetaxel/cisplatin group was higher than that in the fluorouracil/cisplatin group but without significant difference (40.6% vs. 30.6%, P = 0.333). The 3-year overall survival rate in the docetaxel/cisplatin group was 64.9% versus 46.0% in the fluorouracil/cisplatin group (P = 0.039). There were no significant differences in incidence of treatment toxicity during CRT or surgical complications between groups, with the exception of Grade 3-4 hematologic toxicity (37.5% vs. 17.7%, P = 0.035), which was more frequent in the docetaxel/cisplatin group. CONCLUSIONS: Docetaxel/cisplatin might be associated with more favorable survival than fluorouracil/cisplatin in esophageal SCC treated with neoadjuvant CRT. Prospective validation is warranted.

Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial.

BACKGROUND: The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial. METHODS: We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III-IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18-59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m2 on day 1), intravenous cisplatin (60 mg/m2 on day 1), and continuous intravenous fluorouracil (600 mg/m2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT01245959. FINDINGS: Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38-49), 3-year failure-free survival was 80% (95% CI 75-85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66-78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48-0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 [42%] vs 17 [7%]), leucopenia (98 [41%] vs 41 [17%]), and stomatitis (98 [41%] vs 84 [35%]). INTERPRETATION: Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities. FUNDING: Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).

Is There a Correlation Between Clinical Complete Response and Pathological Complete Response After Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Cancer?

OBJECTIVE: The aim of this study was to investigate the correlation between clinical complete response (cCR) and pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (CRT) for esophageal squamous cell cancer (ESCC). METHODS: Between May 2001 and April 2013, a total of 158 patients with thoracic ESCC treated with neoadjuvant CRT followed by surgery were analyzed. Of these patients, 31 had stage IIb disease and 127 had stage III disease. All patients received concurrent platinum-based chemotherapy with conformal radiotherapy (40 Gy in 20 fractions, five fractions per week for 4 weeks). RESULTS: A total of 65 patients (41.1 %) achieved pCR. Of 44 patients (27.8 %) who achieved cCR after neoadjuvant CRT, 32 (72.7 %) also achieved pCR. On the other hand, only 33 (28.9 %) of 114 patients with non-cCR had pCR. The sensitivity, specificity, positive predictive value, and negative predictive value of cCR for predicting pCR was 87.1, 49.2, 71.1, and 72.7 %, respectively. The median follow-up period was 28.9 months, and overall survival (OS) for the entire group was 38.1 months. Patients who achieved cCR had significantly better 3-year OS than those with non-cCR (71.6 % vs. 46.9 %; p = 0.012). CONCLUSIONS: Our results indicate that cCR after neoadjuvant CRT is significantly correlated with pCR and survival of patients with ESCC. Further studies are required to confirm the prognostic value of cCR after neoadjuvant CRT.

Epidermal Growth Factor Receptor Mutation Status and Treatment Outcome for R0-Resected Patients with Stage 3 Non-small Cell Lung Cancer.

BACKGROUND: This study aimed to investigate the association of epidermal growth factor receptor (EGFR) mutation status with treatment outcome for patients with stage 3 non-small cell lung cancer (NSCLC) who had undergone a complete (R0) resection. METHODS: The study identified 3445 NSCLC patients tested for EGFR mutations between September 2001 and December 2011 at the Sun Yat-Sen University Cancer Center. Of these patients, 224 were stage 3 patients who had undergone R0 resections. RESULTS: These 224 R0-resected, pathologic stage 3A and 3B patients included 150 patients with wild-type EGFR and 74 patients with EGFR mutations. During a median follow-up period of 42 months (range, 4-133 months), pathologic stage was shown to be the only prognostic factor. The 3-year overall survival (OS) rates did not differ significantly from the OS rates for the wild-type and mutant EGFR groups (62.0 vs 67.2 %; p = 0.789). Multivariate analyses indicated that the patients in the mutant EGFR group with EGFR exon 19 mutations had a better OS rate (73.0 vs 61.1 %; p = 0.026). CONCLUSIONS: Cancer stage remained the significant prognostic factor in R0-resected stage 3 NSCLC patients. The presence of an EGFR mutation is more likely to be a predictive marker for the response to treatment with tyrosine kinase inhibitors. In the EGFR mutant group, the patients with an exon 19 mutation had better 3-year OS rates. These findings might be considered in future study designs.

Association of insulin-like growth factor-binding protein-3 with radiotherapy response and prognosis of esophageal squamous cell carcinoma.

BACKGROUND: Insulin-like growth factor-binding protein-3 (IGFBP-3) is suggested to predict the radiosensitivity and/or prognosis of patients with esophageal squamous cell carcinoma (ESCC). The present study was designed to investigate the clinical and prognostic effects of IGFBP-3 on ESCC. METHODS: IGFBP-3 was detected by immunohistochemistry in paraffin-embedded tissues from 70 ESCC patients treated with radiotherapy alone and further examined by western blotting analysis in 10 pairs of fresh ESCC tissues and adjacent non-malignant esophageal specimens. Receiver operating characteristic (ROC) analysis was used to determine cut-off scores for tumor positivity and to evaluate patient survival status. The χ(2) test was performed to analyze the association of IGFBP-3 expression with clinical characteristics and radiotherapy response. Associations between prognostic outcomes and IGFBP-3 expression were investigated using Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: The threshold for IGFBP-3 positivity was set to greater than 65% [area under the ROC curve (AUC)=0.690, P<0.019]. Of the 70 ESCC patient tissues tested, 32 (45.7%) were defined as having high IGFBP-3 expression. The levels of IGFBP-3 protein expression were decreased in 70.0% (7 of 10) of ESCC tissues compared with adjacent non-malignant esophageal tissue. In addition, IGFBP-3 expression was associated with pathologic classification (P<0.05 for T, N, and M categories and clinical stage). Patients with elevated protein level of IGFBP-3 in the tumor had an improved radiotherapy response and prolonged overall survival (P<0.001). CONCLUSIONS: High level of IGFBP-3 expression in ESCC associates with early clinical stages and are predictive for favorable survival of the patients treated with radiotherapy.

Dosimetric benefit to organs at risk following margin reductions in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy.

INTRODUCTION: It is important to decrease the radiation exposure of normal tissue in intensity-modulated radiation therapy (IMRT). Minimizing planning target volume (PTV) margins with more precise target localization techniques can achieve this goal. This study aimed to quantify the extent to which organs at risk (OARs) are spared when using reduced margins in the treatment of nasopharyngeal carcinoma (NPC). METHODS: Two IMRT plans were regenerated for 40 patients with NPC based on two PTV margins, which were reduced or unchanged following cone beam computed tomography online correction. The reduced-margin plan was optimized based on maximal dose reduction to OARs without compromising target coverage. Dosimetric comparisons were evaluated in terms of target coverage and OAR sparing. RESULTS: Improvements in target coverage occurred with margin reduction, and significant improvements in dosimetric parameters were observed for all OARs (P < 0.05) except for the right optic nerve, chiasm, and lens. Doses to OARs decreased at a rate of 1.5% to 7.7%. Sparing of the left parotid and right parotid, where the mean dose (Dmean) decreased at a rate of 7.1% and 7.7%, respectively, was greater than the sparing of other OARs. CONCLUSIONS: Significant improvements in OAR sparing were observed with margin reduction, in addition to improvement in target coverage. The parotids benefited most from the online imaging-guided approach.

Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China.

BACKGROUND: The objective of this study was to evaluate the long-term survival and late toxicities of concurrent-adjuvant chemotherapy in patients with stage III through IVB nasopharyngeal carcinoma (NPC) from endemic regions of China. METHODS: Patients with stage III to IVB NPC were assigned randomly to receive radiotherapy (RT) alone (the RT group) or RT plus concurrent adjuvant chemotherapy (the CRT group). CRT patients received concurrent cisplatin (40 mg/m2) weekly during RT followed by cisplatin (80 mg/m2) and fluorouracil (800 mg/m(2) daily for 5 days) every 4 weeks for 3 cycles. The primary endpoint was overall survival. RESULTS: In total, 316 patients underwent randomization, with 158 to each group. At a median follow-up of 70 months, the 5-year overall survival rate was 72% for the CRT group and 62% for the RT group (hazard ratio, 0.69; 95% confidence interval, 0.48-0.99; P = .043). Failure-free survival was significantly higher in the CRT group (P = .020). Most late toxicities were similar (33% vs. 26%; P = .089), except for cranial neuropathy (P = .042), peripheral neuropathy (P = .041), and ear damage (P = .048), which were significantly increased in the CRT group. CONCLUSIONS: The addition of concurrent adjuvant chemotherapy to RT provides survival benefits to patients with stage III through IVB NPC in endemic regions of China, and it does not increase most late toxicities apart from cranial neuropathy, peripheral neuropathy, and ear damage.

Assessing the role of volumetric-modulated arc therapy in hepatocellular carcinoma.

The role of volumetric-modulated arc therapy (VMAT) in hepatocellular carcinoma (HCC) remains controversial. The purpose of this study was to determine the potential clinical role of VMAT compared with three-dimensional conformal radiotherapy (3D CRT) for liver irradiation. Four-dimensional CT scans of 24patients with unresectable HCC were included and divided into two groups: (1) adjacent group (n = 11), with planning target volumes overlapping or within 1 cm adjacent to the alimentary tract; (2) nonadjacent group (n = 13), in which the normal liver itself was the dose-limiting structure. Target coverage, organs-at-risk (OARs) doses, delivery parameters, and treatment accuracy were evaluated. Superior target coverage, conformity, and homogeneity were achieved with VMAT compared with 3D CRT. In the adjacent group, VMAT provided superior sparing of serial functioning OARs including the stomach, small intestine, and spinal cord. In the nonadjacent group, VMAT provided inferior sparing of most OARs including the liver, stomach, and small intestine. For the whole group, the effective treatment time was 2.1 ± 0.3 min for 3D CRT and 3.1 ± 0.2 min for VMAT. For liver lesions adjacent to the alimentary tract, this study indicates that VMAT should be selected due to the plan quality, delivery efficiency, and superior sparing of stomach and small intestine. However, for liver lesions away from the alimentary tract, VMAT is not superior to 3D CRT for normal tissue protection.

[Value of postoperative adjuvant chemotherapy in locally advanced rectal cancer patients with ypT1-4N0 after neo-adjuvant chemoradiotherapy].

OBJECTIVE: The purpose of this study was to investigate the value of postoperative chemotherapy for locally advanced rectal cancer patients who reached pathological ypT1-4N0 after neo-adjuvant chemoradiotherapy. METHODS: We performed a retrospective study of 104 patients treated with preoperative chemoradiotherapy followed by radical resection, who achieved pathological ypT1-4N0, between Mar 2003 and Dec 2010. There were 73 patients who received postoperative adjuvant chemotherapy, and the other 31 patients did not. The distribution of final pathologic stages for these patients was ypT1-2N0 in 39 cases and ypT3-4N0 in 65 cases. RESULTS: The median follow-up was 41 months. The 3-year overall survival rate (OS) and recurrence-free survival rate (RFS) for the whole group (ypT1-4N0) were 93.4% and 85.3%, respectively. The 3-year OS and RFS in the adjuvant chemotherapy group and non-adjuvant chemotherapy group were 95.5%, 88.6% and 88.6%, 77.2%, respectively. There were no significant differences in 3-year RFS (P = 0.108) and OS (P = 0.106) between the two groups. The 3-year local recurrence and distant metastasis rates in the adjuvant chemotherapy group were 4.1% (3/73) and 5.5% (4/73), while for the non-adjuvant chemotherapy group, the 3-year local recurrence rate and distant metastasis rate were 3.2% (1/31) and 16.1% (5/31), respectively. Significant difference was found in distant metastasis rates (P = 0.030) between the two groups, but not in local recurrence rates (P = 0.676).Further subgroup analysis indicated that for the ypT1-2N0 patients, there were no significant differences in 3-year OS (P = 0.296) and RFS (P = 0.939) between the adjuvant and non-adjuvant chemotherapy groups, while negative results displayed in 3-year local recurrence rates (P = 0.676) and distant metastasis rates (P = 0.414). However, for patients with ypT3-4N0, significant differences were showed in both the 3-year OS (P = 0.034) and RFS (P = 0.025), and further analysis revealed that the 3-year distant metastasis rate was significantly higher in the non-adjuvant chemotherapy group than in the adjuvant chemotherapy group (P = 0.010) , but with non-significant difference in the 3-year local recurrence (P = 0.548). CONCLUSIONS: Adjuvant chemotherapy may not improve survival for ypT1-2N0 patients. However, it may be clinically meaningful for ypT3-4N0 patients by decreasing distant metastasis rate. Further randomized controlled clinical trials are needed to confirm our results.

[Retrospective analysis of effectiveness of intensity-modulated radiotherapy combined with chemotherapy or not for locoregionally advanced nasopharyngeal carcinoma].

OBJECTIVE: To analyze the effectiveness and toxicity of intensity-modulated radiotherapy (IMRT) combined with chemotherapy or not for locoregionally advanced nasopharyngeal carcinoma. METHODS: A total of 226 patients with locoregionally advanced nasopharyngeal carcinoma were retrospectively reviewed and classified into three groups:67 patients treated by radiotherapy alone (RT group), 82 patients by concurrent chemoradiotherapy (CRT group) and 77 patients by cisplatin+5-fluorouracil (PF regimen) combined with CRT (PF+CRT group). All patients using IMRT technique.Outcomes were overall survival, failure patterns, and toxicities. RESULTS: For the RT, CRT and PF+CRT group, the 5-year overall survival rate was 67.6%, 74% and 71.1% (P = 0.664), respectively; progress-free survival rate 66.9%, 72.6% and 75.6% (P = 0.410); relapse-free survival rate 82.4%, 86.4% and 86.8% (P = 0.447) and distant metastasis-free survival rate 83.8%, 83.8% and 85.8% (P = 0.827). Significantly more grade 3-4 acute toxicities happened in patients treated by chemotherapy (P = 0.002). CONCLUSION: Comparing with IMRT alone, cisplatin-IMRT or PF regimen induction chemotherapy plus cisplatin-IMRT do not significantly improve survival, but increased grade 3-4 acute toxicities.

Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial.

BACKGROUND: The effect of the addition of adjuvant chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to assess the contribution of adjuvant chemotherapy to concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone. METHODS: We did an open-label phase 3 multicentre randomised controlled trial at seven institutions in China. Randomisation was by a computer-generated random number code. Patients were stratified by treatment centre and randomly assigned in blocks of four. Treatment allocation was not masked. We randomly assigned patients with non-metastatic stage III or IV (except T3-4N0) nasopharyngeal carcinoma to receive concurrent chemoradiotherapy plus adjuvant chemotherapy or concurrent chemoradiotherapy alone. Patients in both groups received 40 mg/m(2) cisplatin weekly up to 7 weeks, concurrently with radiotherapy. Radiotherapy was given as 2·0-2·27 Gy per fraction with five daily fractions per week for 6-7 weeks to a total dose of 66 Gy or greater to the primary tumour and 60-66 Gy to the involved neck area. The concurrent chemoradiotherapy plus adjuvant chemotherapy group subsequently received 80 mg/m(2) adjuvant cisplatin and 800 mg/m(2) per day fluorouracil for 120 h every 4 weeks for three cycles. Our primary endpoint was failure-free survival. We did efficacy analyses in our intention-to-treat population. Our trial is ongoing; in this report we present the 2 year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT00677118. FINDINGS: 251 patients were assigned to the concurrent chemoradiotherapy plus adjuvant chemotherapy group and 257 to the concurrent chemoradiotherapy alone group. After a median follow-up of 37·8 months (range 1·3-61·0), the estimated 2 year failure-free survival rate was 86% (95% CI 81-90) in the concurrent chemoradiotherapy plus adjuvant chemotherapy group and 84% (78-88) in concurrent chemoradiotherapy only group (hazard ratio 0·74, 95% CI 0·49-1·10; p=0·13). Stomatitis was the most commonly reported grade 3 or 4 adverse event during both radiotherapy (76 of 249 patients in the concurrent chemoradiotherapy plus adjuvant chemotherapy group and 82 of 254 in the concurrent chemoradiotherapy alone group) and adjuvant chemotherapy (43 [21%] of 205 patients treated with adjuvant chemotherapy). INTERPRETATION: Adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve failure-free survival after concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma. Longer follow-up is needed to fully assess survival and late toxic effects, but such regimens should not, at present, be used outside well-designed clinical trials. FUNDING: Sun Yat-sen University Clinical Research 5010 Programme (No 2007037), Science Foundation of Key Hospital Clinical Programme of Ministry of Health PR China (No 2010-178), and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2010).

Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3.

BACKGROUND: Epidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody) on ESCC radiotherapy (RT) and underlying mechanisms. METHODS: Nimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model. RESULTS: Nimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression) in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR) induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (P<0.05), and even after the administration of Nimotuzumab, the RT response of IGFBP-3 silenced KYSE30 cells was not enhanced (P>0.05). In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029), and also with IGFBP-3 up-regulation in tumor tissue. CONCLUSIONS: Nimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.

The overexpression of IGFBP-3 is involved in the chemosensitivity of esophageal squamous cell carcinoma cells to nimotuzumab combined with cisplatin.

Nimotuzumab is an antibody against epidermal growth factor receptor (EGFR). The objective of this study was to examine the capacity and specific underlying mechanisms of nimotuzumab to modulate cytotoxicity of cisplatin (DDP) in esophageal squamous cell carcinoma (ESCC) cell lines with different EGFR expression levels. Nimotuzumab was administrated to two ESCC cell lines KYSE30 and TE-1 treated with DDP. Cell growth, colony formation, and apoptosis were analyzed by MTT and flow cytometry assays. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells chemosensitivity treated with nimotuzumab. Combination of nimotuzumab and DDP resulted in a DDP cytotoxicity increase in overexpressing EGFR cells (KYSE30) but not in low-expressing EGFR cells (TE-1). Meantime, DDP activated the EGFR pathway in the two cell lines in a ligand-independent fashion. Furthermore, DDP-induced EGFR activation was inhibited by nimotuzumab in KYSE30 cells, and this result was not observed in TE-1 cells. EGF reduced the expression of IGFBP-3 in KYSE30 cells; however, nimotuzumab could reverse the downregulation of IGFBP-3, and this result was also not observed in TE-1 cells. After IGFBP-3 was silenced by small interfering RNA, the potential of nimotuzumab to enhance DDP-mediated cytotoxicity was inhibited in KYSE30 cells. The results indicated that the increased ESCC chemosensitivity to DDP by nimotuzumab might be dependent on IGFBP-3 upregulation through EGFR-dependent pathway, which would facilitate preselection of ESCC patients for treatment of nimotuzumab combined with DDP.

[A multi-centered randomized controlled study of neo-adjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of esophagus: an interim analysis].

OBJECTIVE: To evaluate the safety and validity of neo-adjuvant chemoradiotherapy followed by surgery for locally advanced esophageal carcinoma. METHODS: Patients with IIB, III staged squamous cell carcinoma of thoracic esophagus were randomly allocated to either preoperative chemoradiotherapy followed by surgery (arm A) or surgery alone (arm B). In arm A, chemotherapy and radiotherapy were performed concurrently. Patients received two cycles of vinorelbine and cisplatin. Vinorelbine at 25 mg/m(2) per day was administered as a bolus infusion at d1, d8, d22 and d29. Cisplatin at 75 mg/m(2) was administered by an intravenous infusion at d1 and d22 (or 25 mg/m(2) days 1 - 4 and 22 - 25). A total radiotherapeutic dose of 40 Gy was delivered in 20 daily fractions of 2.0 Gy each (5 d/wk for 4 weeks). Three-incisioned esophagectomy was performed at Weeks 4 - 6 after chemoradiotherapy. Primary outcome was overall survival time. An interim analysis was performed in June 2011. RESULTS: From July 2007 to June 2011, 123 eligible patients were randomly assigned at 7 cooperative cancer centers (54 cases in arm A vs 69 cases in arm B). In arm A, the clinical response rate of chemoradiotherapy was 90.7%. All patients finished the preoperative chemoradiotherapy. Forty-nine cases continued to receive esophagectomy. The pathological complete response rate was 29.6%. The rate of R0 resection in arm A was significant higher than that in arm B(96.0% vs 85.5%, P = 0.015). The most common grade 3/4 toxicity of chemoradiotherapy was leukopenia occurring in 33 cases (61.1%). Vomiting and esophagitis were usually of Grade 1/2. No patient died or abandoned surgery because of chemoradiation toxicity. Between arms A and B, operative duration, blood loss, duration of chest tube drainage and length of postsurgical hospital stay were similar. The incidences of postoperative heart failure (2.0% vs 1.4%, P = 1.000), anastomotic leakage (8.2% vs 11.6%, P = 0.759) and hoarseness (6.1% vs 4.3%, P = 0.691) were not significantly different. The incidence of pulmonary infection in arm A was slightly higher than that in arm B (8.2% vs 1.4%, P = 0.094). No perioperative deaths occurred in either group. There were no significant differences in overall survivals at 1, 2 years between arms A and B (85.6%/75.5% vs 79.1%/66.1%, P = 0.207). The disease-free survivals at 1, 2 years in arm A were slightly higher than in arm B (86.6%/83.2% vs 70.9%/61.8%, P = 0.075). CONCLUSION: Neo-adjuvant chemoradiation followed by surgery may achieve a high clinical response rate and pathologic complete tumor regression rate. It significantly increases the R0 resection rate and down stage the esophageal cancer patients. But its ultimate efficacy awaits further follow-up studies.

Progression-free survival at 3 years is a reliable surrogate for 5-year overall survival for patients suffering from locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Despite 3-year survival being used as a primary endpoint in some randomized controlled trials (RCTs), limited evidence supports the use of intermediate endpoints to evaluate the effect of new therapies in esophageal squamous cell cancer (ESCC). This study aimed to systematically evaluate progression-free survival at 3 years (3-year PFS) and overall survival (OS) among patients with ESCC. METHODS: We identified 528 patients newly diagnosed with locally advanced ESCC who received definitive radiotherapy. OS was compared with an age- and sex-matched general Chinese population using the standardized mortality ratio (SMR). Regression analysis was used to validate the correlation between PFS and OS using published data. RESULTS: The annual risk of progression decreased to 11.5% after 3 years. Patients who did not achieve 3-year PFS had a median postprogression survival (PPS) of 7.3 months, with a 5-year OS rate of 9.6% and a SMR of 15.0 (95% confidence interval [CI], 12.9-17.5). Conversely, the SMR for patients who achieved 3-year PFS was 0.9 (95% CI, 0.6-1.3). We observed a significant correlation between log hazard ratio (HR) (PFS) and log HR (OS) at the trial level (r = 0.89; 95% CI, 0.88-0.90). The strongest correlation was observed between 3-year PFS and 5-year OS in RCTs and retrospective studies. CONCLUSIONS: Patients exhibiting progression within 3 years experienced poor survival, whereas patients achieving 3-year PFS had excellent outcomes. Our study supports 3-year PFS as a reliable primary endpoint for study design and risk stratification in locally advanced ESCC.

Overexpression of eIF5A-2 is an adverse prognostic marker of survival in stage I non-small cell lung cancer patients.

We have previously isolated an oncogene EIF5A2 (eukaryotic initiation factor 5A2) from a frequently amplified region at 3q of a primary ovarian cancer cell line, and demonstrated its impact on prognosis in human ovarian cancer. Amplification of chromosome 3q has also been detected frequently in non-small cell lung cancer (NSCLC), however, abnormalities of EIF5A2 and its clinicopathologic significance in NSCLC haven't been studied. In our study, the methods of immunohistochemistry and fluorescence in situ hybridization were utilized to examine protein expression and amplification of EIF5A2 in 248 surgically resected NSCLCs (learning cohort) and another validation cohort of 120 stage I NSCLC patients. Overexpression and amplification of EIF5A2 was detected informatively in 48.7% and 13.7% of NSCLCs in learning cohort, 33.3% and 6.0% of NSCLCs in validation cohort. Overexpression of eIF5A-2 was found to correlate with gene amplification, increased cell proliferation and advanced T stage. In learning cohort, eIF5A-2 expression was evaluated as a strong prognostic factor on disease-specific survival, but in subgroup analyses, it only retained its stratified significance in stage I set (Hazards ratio = 2.799, p = 0.001). In validation cohort, the impact of eIF5A-2 expression on survival in stage I NSCLC patients was also observed (Hazard ratio = 2.097, p = 0.014). Our findings suggested that overexpression of eIF5A-2 correlates with local invasion of NSCLC, and might serve as an adverse prognostic marker of survival for stage I NSCLC patients.

High expression of EZH2 is associated with tumor aggressiveness and poor prognosis in patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.

The enhancer of zeste homolog 2 (EZH2), a known repressor of gene transcription, has been reported to be associated with biological malignancy in several cancers. The potential oncogenic role of EZH2 and its clinical/prognostic significance, however, in esophageal squamous cell carcinoma (ESCC) are unclear. In this study, the methods of immunohistochemistry and fluorescence in-situ hybridization were used to examine protein expression and amplification of EZH2 in 98 pretreatment biopsy specimens of ESCC who received definitive chemoradiotherapy (CRT). High expression of EZH2 and amplification of EZH2 was found in 54.1% and 12.0% of ESCCs, respectively. High EZH2 expression was significantly correlated with increased cell proliferation (p = 0.009), high histopathological grade (p = 0.002), regional (p = 0.025) and distant lymph node metastasis (p < 0.001) and lack of clinical complete response to CRT (p = 0.028). Univariate analysis revealed that high expression of EZH2 was associated with poor metastasis-free survival (MFS) (p = 0.003), poor progression-free survival (PFS) (p = 0.001) and poor disease-specific survival (DSS) (p < 0.001). In multivariate analysis, high expression of EZH2, together with lack of clinical complete response, were evaluated as significant independent prognostic factors of MFS, PFS and DSS for patients with ESCC. These findings suggest that high expression of EZH2 correlates with tumor aggressiveness and adverse patient outcome in ESCC treated with definitive CRT. Evaluation of EZH2 expressions might be useful for predicting tumor response to CRT and prognosis for patients with ESCC.