Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by chemoradiotherapy in patients with stage III-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. METHODS: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. FINDINGS: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. INTERPRETATION: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. FUNDING: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Splenic irradiation combined with tumor irradiation promotes T cell infiltration in the tumor microenvironment and helps in tumor control.

Locally applied radiation to the tumor is reported to stimulate systemic immune response. During radiotherapy to the abdominal cancer, spleen often receives certain dose, though as an important immune organ, little is known about the impact of splenic irradiation (SI) on systemic immune and local tumor control. Through a mice model, we found that the combination of SI with tumor irradiation (TI) helped in local control. The analysis of the tumor infiltrating leucocytes demonstrated that SI plus TI brought more T cell aggregation in the tumor microenvironment (TME), which helped in tumor control. Increased T cell infiltration may be partly due to higher expression of T cell chemokine in the TME and more expression of CXCR3 on the T cells in the spleen after SI. SI produced more IL-1ß in the spleen, IL-1ß stimulated the expression of CXCR3 on the T cells, and enhanced their migration ability. Taken together, radiation to the spleen combined with TI helped in local control through promoting T cell infiltration, and may be a considerable means to enhance the immunomodulatory of radiotherapy.

Neoadjuvant chemoradiotherapy combined with sequential perioperative toripalimab in locally advanced esophageal squamous cell cancer.

BACKGROUND: Programmed death 1 (PD-1) inhibitor demonstrated durable antitumor activity in advanced esophageal squamous cell carcinoma (ESCC), but the clinical benefit of perioperative immunotherapy in ESCC remains unclear. This study evaluated the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) combined with the PD-1 inhibitor toripalimab in patients with resectable ESCC. METHODS: From July 2020 to July 2022, 21 patients with histopathologically confirmed thoracic ESCC and clinical staged as cT1-4aN1-2M0/cT3-4aN0M0 were enrolled. Eligible patients received radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week) with concurrent chemotherapy of paclitaxel/cisplatin (paclitaxel 45 mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22, 29 and two cycles of toripalimab 240 mg every 3 weeks after nCRT for neoadjuvant therapy before surgery, four cycles of toripalimab 240 mg every 3 weeks for adjuvant therapy after surgery. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints were safety and survival outcomes. RESULTS: A total of 21 patients were included, of whom 20 patients underwent surgery, 1 patient refused surgery and another patient was confirmed adenocarcinoma after surgery. The MPR and pathological complete response (pCR) rates were 78.9% (15/19) and 47.4% (9/19) for surgery ESCC patients. 21 patients (100.0%) had any-grade treatment-related adverse events, with the most common being lymphopenia (100.0%), leukopenia (85.7%), neutropenia (52.4%). 14 patients (66.7%) had adverse events of grade 3 with the most common being lymphopenia (66.7%). The maximum standardized uptake value and total lesion glycolysis of positron emission tomography/CT after neoadjuvant therapy well predicted the pathological response. The peripheral CD4+%, CD3+HLA-DR+/CD3+%, CD8+HLA-DR+/CD8+%, and IL-6 were significant differences between pCR and non-pCR groups at different times during neoadjuvant therapy. Three patients had tumor relapse and patients with MPR have longer disease-free survival than non-MPR patients. CONCLUSIONS: nCRT combined with perioperative toripalimab is effective and safe for locally advanced resectable ESCC. Long-term survival outcomes remain to be determined. TRIAL REGISTRATION NUMBER: NCT04437212.

Radiographic characteristics of bone metastases from hepatocellular carcinoma.

AIM OF THE STUDY: Different carcinomas have different characteristics, which may play a crucial role in diagnosis and treatment. Our study was aimed at understanding the development pattern of bone metastasis from hepatocellular carcinoma, based on its imaging characteristics, so as to provide a more targeted treatment. MATERIAL AND METHODS: Forty two patients (123 lesions) with hepatocellular carcinoma hospitalized from June 2006 to June 2011 underwent radiotherapy for bone metastasis in our department. Clinical and imaging data were analyzed retrospectively (based on CT imaging, also with reference to MRI, ECT, or PET-CT, etc.). RESULTS: One hundred of 123 lesions were vertebral metastases; 23 were non-vertebral. The major form of bone destruction was osteolytic change. Metastasis in the vertebral body was found in 87.8%, and lesions were well distributed in various sections. Vertebral appendix metastasis accounted for 52%, where lesions could be independent of vertebral body metastasis. Formation of a soft tissue mass in bone metastasis was found in 68.6% of all patients. The center of the mass from a vertebral body metastasis was mostly located at the site of the lesion; masses from the vertebral appendix and the pelvis, on the other hand, often presented as a "peripheral mass". Masses were not formed in lesions with pure osteoblastic changes. CONCLUSIONS: The most common radiographic feature is an osteolytic lesion, either replaced by soft tissue mass, or invaded by soft tissue mass from the vicinity, which often cause compression syndrome. Vertebral appendix metastasis can exist independently from vertebral body metastasis, which should be paid more attention to avoid missed diagnosis.

Identification of Cytosolic DNA Sensor cGAS-STING as Immune-Related Risk Factor in Renal Carcinoma following Pan-Cancer Analysis.

Background: The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays critical functions in innate immune responses via the production of the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which stimulates the adaptor stimulator of interferon genes (STING). However, the clinical relevance and prognostic value of the cGAS-STING pathway in human cancers remains largely unexplored. Methods: A gene signature related to the cGAS-STING score was identified. The pan-cancer landscape of cGAS-STING expression was calculated using the RNAseq data acquired from the TCGA cohort. Tumor-infiltrating immune cells (TIICs) were determined by the ssGSEA method. Kaplan-Meier curves, Cox regression analyses, and the area under the curve (AUC) were employed to decipher the predictive value of cGAS-STING risk score and TIICs across several human cancers. Results: Most tumor tissues displayed a higher cGAS-STING score compared with their corresponding nontumor tissues, except for prostate adenocarcinoma (PRAD) and uterine corpus endometrial carcinoma (UCEC). Higher cGAS-STING score was closely associated with poor clinical outcome of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP), whereas the cGAS-STING score predicted a better prognosis in pheochromocytoma and paraganglioma (PCPG). Enrichment analysis showed that cGAS-STING was profoundly implicated in diverse immune-related pathways in KIRC, KIRP, and PCPG. Significant positive correlations were noticed between cGAS-STING score and TIICs, including activated CD8+ T cells, activated CD4+ T cells, monocytes, and mast cells. Finally, the cGAS-STING score was revealed to be an independent prognostic factor for KIRC patients and possessed a strong predictive power for the prognostic evaluation of KIRC and KIRP patients. Conclusions: We constructed a cGAS-STING gene signature to predict survival and tumor immunity across human cancers, which can serve as a novel prognostic indicator and therapeutic target, especially in KIRC and KIRP.

The predictive value of peripheral blood cells and lymphocyte subsets in oesophageal squamous cell cancer patients with neoadjuvant chemoradiotherapy.

Purpose: Neoadjuvant chemoradiotherapy (nCRT) is a standard treatment option for patients with stage III oesophageal cancer. Approximately 30% of oesophageal cancer patients will have a pathological complete response (pCR) after nCRT. However, available clinical methods cannot accurately predict pCR for patients. We aimed to find more indicators that could be used to predict the pathological response to nCRT. Method: A total of 84 patients with stage III oesophageal squamous cell cancer were enrolled in this study. Ten patients failed to have surgery as a result of progressive disease (PD). Among the patients who underwent surgery, 32 patients had a pathologic complete response (pCR), whereas 42 patients showed no or partial response (npCR) after nCRT. Routine blood test results and lymphocyte subset assessments before and after nCRT were retrospectively analysed. Univariate and multivariate analyses were used to identify independent predictors of the clinical curative effect of nCRT. Eventually, nomograms were established for predicting the PD and pCR rates. Results: The numbers of lymphocytes, B lymphocytes, T lymphocytes, Th lymphocytes, Ts lymphocytes, and NK cells and the percentages of B lymphocytes and NK cells were decreased significantly after nCRT (P < 0.0001), whereas the percentages of T lymphocytes and Ts lymphocytes increased (P < 0.0001). Univariate analysis showed that age, the length of the lesion, the level of haemoglobin before nCRT, and the amount of change in haemoglobin were related to PD, and the percentage of NK cells after nCRT was related to pCR. Multivariate logistic analysis demonstrated that the length of the lesion, the neutrophil-to-lymphocyte ratio (NLR) before nCRT, and the amount of change in haemoglobin were independent predictors of PD, whereas the percentage of NK cells after nCRT was an independent predictor of pCR. Conclusion: Lymphocyte subsets changed dramatically during nCRT, and these changes together with baseline and posttreatment lymphocyte subsets have predictive value in determining the response to nCRT for oesophageal cancer.

Drug-related problems among hospitalized cancer pain patients: an investigative single-arm intervention trial.

BACKGROUND: To evaluate the characteristics of drug-related problems (DRPs) in cancer pain patients, and to identify the impact of pharmacists' intervention in cancer pain associated DRPs. METHODS: In this investigative, single-arm intervention study, clinical pharmacists identified DRPs in cancer pain patients and provided interventions based on medication information, direct patient-pharmacist interview, and ward rounds with multi-disciplinary team (MDT). Types and causes of DRPs, interventions, acceptance and outcome were sorted based on Pharmaceutical Care Network Europe (PCNE) DRP classification V9.0, which includes 3 primary domains for problems, 9 for causes, 5 for interventions, 3 for acceptance, and 4 for DRPs status. RESULTS: Totally, 42 cancer pain patients were enrolled, and 47 DRPs in 33 (78.6%) patients were identified by clinical pharmacists. The major type of DRPs was treatment effectiveness (30; 63.8%) and treatment safety (17; 36.2%). For the "treatment effectiveness" category, the "effect of drug treatment not optimal" was dominant category (27/30; 90%). A total of 66 DRP causes were identified, and most of DRPs were caused by "drug selection" (27; 40.9%) and "dose selection" (16; 24.2%). Within the "drug selection" category, "no or incomplete drug treatment in spite of existing indication" was dominant category (25/27; 92.6%). According to DRPs, 159 interventions were provided by clinical pharmacists and 99.4% of interventions were accepted by prescribers or patients. Finally, 44 (93.6%) DRPs were solved. CONCLUSIONS: In cancer pain patients, insufficient pain control mainly caused by inappropriate selection and dosage of analgesics. Clinical pharmacists' interventions dramatically ameliorate these problems and bring about positive effects in cancer pain pharmacotherapy.

Diffusion-weighted MRI and 18F-FDG PET/CT in assessing the response to neoadjuvant chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is a currently widely used strategy for locally advanced esophageal cancer (EC). However, the conventional imaging methods have certain deficiencies in the evaluation and prediction of the efficacy of nCRT. This study aimed to explore the value of functional imaging in predicting the response to neoadjuvant chemoradiotherapy (nCRT) in locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Fifty-four patients diagnosed with locally advanced ESCC from August 2017 to September 2019 and treated with nCRT were retrospectively analyzed. DW-MRI scanning was performed before nCRT, at 10-15 fractions of radiotherapy, and 4-6 weeks after the completion of nCRT. 18F-FDG PET/CT scans were performed before nCRT and 4-6 weeks after the completion of nCRT. These 18F-FDG PET/CT and DW-MRI parameters and relative changes were compared between patients with pathological complete response (pCR) and non-pCR. RESULTS: A total of 8 of 54 patients (14.8%) were evaluated as disease progression in the preoperative assessment. The remaining forty-six patients underwent operations, and the pathological assessments of the surgical resection specimens demonstrated pathological complete response (pCR) in 10 patients (21.7%) and complete response of primary tumor (pCR-T) in 16 patients (34.8%). The change of metabolic tumor volume (∆MTV) and change of total lesion glycolysis (∆TLG) were significantly different between patients with pCR and non-pCR. The SUVmax-Tpost, MTV-Tpost, and TLG-Tpost of esophageal tumors in 18F-FDG PET/CT scans after neoadjuvant chemoradiotherapy and the ∆ SUVmax-T and ∆MTV-T were significantly different between pCR-T versus non-pCR-T patients. The esophageal tumor apparent diffusion coefficient (ADC) increased after nCRT; the ADCduring, ADCpost and ∆ADCduring were significantly different between pCR-T and non-pCR-T groups. ROC analyses showed that the model that combined ADCduring with TLG-Tpost had the highest AUC (0.914) for pCR-T prediction, with 90.0% and 86.4% sensitivity and specificity, respectively. CONCLUSION: 18F-FDG PET/CT is useful for re-staging after nCRT and for surgical decision. Integrating parameters of 18F-FDG PET/CT and DW-MRI can identify pathological response of primary tumor to nCRT more accurately in ESCC.

Preliminary exploration on the role of clinical pharmacists in cancer pain pharmacotherapy.

BACKGROUND: More than half of cancer patients affected by cancer experience pain of moderate-tosevere intensity. Therefore, facilitating appropriate and safe administration of analgesics is crucial to the comprehensive management of cancer patients. In this article, we assessed medication adherence, pain relief, drug related problems (DRPs) and analgesics adverse events (AEs) in cancer pain patients based on a model of clinical pharmacy services. METHODS: In this prospective, single-arm intervention study, cancer pain patients admitted to our institution were eligible. According to different adherence, heterogeneity of pain, and individual treatment strategy, clinical pharmacists (CPs) provided comprehensive pain assessment and medication education for patients, as well as provided consultation and recommendation for physicians. CPs' pharmacy services were assessed through medication adherence, numbers of DRPs, acceptance of recommendation, pain intensity (PI), daily interference and AEs. RESULTS: A total of 42 patients were enrolled between November, 2018 and November, 2019. Compared to baseline, patients' medication adherence evaluated with a medication adherence scale showed a significantly improvement at 14 and at 28 days after receiving CPs' interventions (8 score vs. 7 score at 14 days and at 28 days, P<0.01). During the 28-day follow-up, a total of 63 interventions were put forward according to 57 identified DRPs in 33 patients (78.6%), and approximately 95% (60/63) of the interventions were accepted by physicians. PI and daily interference significantly improved on the third day after the interventions of CPs, and the improvement continued until day 28 (P<0.01). AEs caused by opioids occurred in 19 patients (45.2%), and the most common one was constipation (14 patients, 33.3%). CONCLUSIONS: CPs' comprehensive interventions for cancer pain patients were efficacious in improving their medication adherence and pain relief, as well as reducing incidence of AEs. Therefore, this promising model should be replicated in other medical centers.

Research of Biological Dose Conversion Platform Based on a Modified Linear Quadratic Model.

The study aimed to develop a novel dose conversion platform by improving linear-quadratic (LQ) model to more accurately describe radiation response for high fraction/acute doses. This article modified the LQ model via piecewise fitting the biological dose curve using different fractionated dose and optimizing the consistency between mathematical model and experimental data to gain a more reasonable transform. That mathematical development of the LQ model further amended certain deviations of various cell curves with high doses and implied the rationality of the present model at low dose range. The modified biologically effective dose model that solved the dilemma of inaccurate LQ model had been used in comparing between hypofractionated and conventional fractioned dose. It has been verified that the calculated values are similar in the treatment of same efficacy, no matter what α/ß is, and provided a more rational explanation for significant differences among various hypofractionations. The equivalent uniform dose based on the subsection function could represent arbitrary inhomogeneous dose distributions including high-dose fractions, providing a foundation for the implementation of detailed evaluation of different cell dose effects.

Inhibiting the CD8+ T cell infiltration in the tumor microenvironment after radiotherapy is an important mechanism of radioresistance.

Endogenous immune response participates in tumor control, and radiotherapy has immune modulatory capacity, but the role of immune modulation in the tumor microenvironment invoked by radiotherapy in radiosensitivity is poorly defined. In the present study, a radio-resistant melanoma cell line was obtained after repeated irradiation to the parental tumor in C57BL/6 mice. Radiotherapy resulted in aggregation of CD8+ and CD3+ T cells, and decrease of myeloid-derived suppressor cells and dendritic cells in the parental tumor, but not in the resistant tumors. CD4+ T cells and B cells did not change significantly. The CD8+ T cell infiltration after radiotherapy is important for tumor response, because in the nude mice and CD8+ T cell-depleted C57BL/6 mice, the parental and resistant tumor has similar radiosensitivity. Patients with good radiation response had more CD8+ T cells aggregation after radiotherapy. Radiotherapy resulted in robust transcription of T cell chemoattractant in the parental cells, and the expression of CCL5 was much higher. These results reveal a novel mechanism of radioresistance, tumor cells inhibit the infiltration of CD8+ T cell after radiotherapy and become radioresistant. Increasing CD8+ T cell infiltration after RT may be an effective way to improve tumor radiosensitivity.

FDG-PET, CT, MRI for diagnosis of local residual or recurrent nasopharyngeal carcinoma, which one is the best? A systematic review.

PURPOSE: To perform a systematic review to compare FDG-PET, CT, and MRI imaging for diagnosis of local residual or recurrent nasopharyngeal carcinoma. MATERIALS AND METHODS: MEDLINE, EMBASE, the CBMdisc databases and some other databases were searched for relevant original articles published from January 1990 to June 2007. Inclusion criteria were as follows: Articles were reported in English or Chinese; FDG-PET, CT, or MRI was used to detect local residual or recurrent nasopharyngeal carcinoma; histopathologic analysis and/or close clinical and imaging follow-up for at least 6 months were the reference standard. Two reviewers independently extracted data. A software called "Meta-DiSc" was used to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver operating characteristic (SROC) curves, and the Q* index. RESULTS: Twenty-one articles fulfilled all inclusion criteria. The pooled sensitivity estimates for PET (95%) were significantly higher than CT (76%) (P<0.001) and MRI (78%) (P<0.001). The pooled specificity estimates for PET (90%) were significantly higher than CT (59%) (P<0.001) and MRI (76%) (P<0.001). The pooled DOR estimates for PET (96.51) were significantly higher than CT (7.01) (P<0.001) and MRI (8.68) (P<0.001). SROC curve for FDG-PET showed better diagnostic accuracy than CT and MRI. The Q* index for PET (0.92) was significantly higher than CT (0.72) (P<0.001) and MRI (0.76) (P<0.01). For PET, the sensitivity and diagnostic OR for using qualitative analysis were significantly higher than using both qualitative and quantitative analyses (P<0.01). For CT, the sensitivity, specificity, diagnostic OR, and the Q* index for dual-section helical and multi-section helical were all significantly higher than nonhelical and single-section helical (P<0.01). And the sensitivity for 'section thickness <5 mm' was significantly lower than ' =5 mm' (P<0.01), while the specificity was significantly higher (P<0.01). For MRI, there were no significant differences found between magnetic field strength <1.5 and > or =1.5 T (P>0.05). CONCLUSION: FDG-PET was the best modality for diagnosis of local residual or recurrent nasopharyngeal carcinoma. The type of analysis for PET imaging and the section thickness for CT would affect the diagnostic results. Dual-section helical and multi-section helical CT were better than nonhelical and single-section helical CT.

Comparison and Prognostic Analysis of Adjuvant Radiotherapy versus Salvage Radiotherapy for Treatment of Radically Resected Locally Advanced Esophageal Squamous Cell Carcinoma.

Objective. To compare adjuvant radiotherapy and salvage radiotherapy after radical resection for treatment of esophageal squamous cell carcinoma (ESCC). Methods. Data from 155 patients with locally advanced ESCC who underwent radical resection and received postoperative radiotherapy from 2005 to 2011 were reviewed. Seventy-nine patients received adjuvant radiotherapy and 76 received salvage radiotherapy after locoregional recurrence. Results. The median disease-free survival (DFS) and overall survival (OS) were significantly higher in the adjuvant radiotherapy group than the salvage radiotherapy group (DFS 25.73 months versus 10.73 months, P < 0.001; OS 33.33 months versus 26.22 months, P = 0.006). The independent prognostic factors for DFS were performance status (PS) before radiotherapy and pathological stage in the adjuvant radiotherapy group, compared with lymph node metastasis, tumor location, and adjuvant chemotherapy in the salvage radiotherapy group. The independent prognostic factors for OS were age and PS in both groups. No differences in median DFS and OS between the groups were observed in patients aged > 65 years or with PS ≥ 2. Conclusion. Compared to salvage radiotherapy, postoperative adjuvant radiotherapy can prolong DFS and OS for patients with radically resected local advanced ESCC but cannot improve survival for patients aged > 65 years or with PS ≥ 2.

Influence of hepatic arterial blockage on blood perfusion and VEGF, MMP-1 expression of implanted liver cancer in rats.

AIM: To investigate the influence of hepatic arterial blockage on blood perfusion of transplanted cancer in rat liver and the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-1 (MMP-1), and to explore the mechanisms involved in transarterial embolization (TAE)-induced metastasis of liver cancer preliminarily. METHODS: Walker 256 carcinosarcoma was transplanted into rat liver to establish the liver cancer model. Hepatic arterial ligation (HAL) was used to block the hepatic arterial blood supply and simulate TAE. Blood perfusion of tumor in control, laparotomy control, and HAL group was analyzed by Hoechst 33342 labeling assay, the serum VEGF level was assayed by ELISA, the expression of VEGF and MMP-1 mRNA was detected by in situ hybridization. RESULTS: Two days after HAL, the number of Hoechst 33342 labeled cells which represent the blood perfusion of tumor directly and hypoxia of tumor indirectly in HAL group decreased significantly compared with that in control group (329+/-29 vs 384+/-19, P<0.01). The serum VEGF level in the HAL group increased significantly as against that of the control group (93 ng.L(-1)+/-44 ng.L(-1) vs 55 ng.L(-1)+/-19 ng.L(-1), P<0.05). The expression of VEGF and MMP-1 mRNA in the tumor tissue of the HAL group increased significantly compared with that of the control and the laparotomy control groups (P<0.05). The blood perfusion data of the tumor, represented by the number of Hoechst 33342 labeled cells, showed a good linear inverse correlation with the serum VEGF level (r=-0.606, P<0.05) and the expression of VEGF mRNA in the tumor tissue ( r =-0.338, P<0.01). CONCLUSION: Blockage of hepatic arterial blood supply results in decreased blood perfusion and increased expression of metastasis-associated genes VEGF and MMP-1 of transplanted liver cancer in rats. Decreased blood perfusion and hypoxia may be the major cause of up-regulated expression of VEGF.

Intensity modulated radiation therapy and chemotherapy for locally advanced pancreatic cancer: results of feasibility study.

AIM: To explore whether intensity modulated radiation therapy (IMRT) in combination with chemotherapy could increase radiation dose to gross tumor volume without severe acute radiation related toxicity by decreasing the dose to the surrounding normal tissue in patients with locally advanced pancreatic cancer. METHODS: Twenty-one patients with locally advanced pancreatic cancer were evaluated in this clinical trial. Patients would receive the dose of IMRT from 21Gy to 30Gy in 7 to 10 fractions within two weeks after conventional radiotherapy of 30Gy in 15 fractions over 3 weeks. The total escalation tumor dose would be 51, 54, 57, 60Gy, respectively. 5-fluororacil (5-FU) or gemcitabine was given concurrently with radiotherapy during the treatment course. RESULTS: Sixteen patients who had completed the radiotherapy plan with doses of 51Gy (3 cases), 54Gy (3 cases), 57Gy (3 cases) and 60Gy (7 cases) were included for evaluation. The median levels of CA19-9 prior to and after radiotherapy were 716 U/ml and 255 U/ml respectively (P<0.001) in 13 patients who demonstrated high levels of CA19-9 before radiotherapy. Fourteen patients who suffered from pain could reduce at least 1/3-1/2 amount of analgesic intake and 5 among these patients got complete relief of pain. Ten patients improved in Karnofsky performance status (KPS). The median follow-up period was 8 months and one-year survival rate was 35%. No patient suffered more than grade III acute toxicities induced by radiotherapy. CONCLUSION: Sixty Gy in 25 fractions over 5 weeks with late course IMRT technique combined with concurrent 5-FU chemotherapy can provide a definitely palliative benefit with tolerable acute radiation related toxicity for patients with advanced pancreatic cancer.

Octreotide augments the effects of hepatic arterial occlusion in treating a rat liver tumor model.

BACKGROUND/AIMS: To observe if octreotide can augment the effects of hepatic arterial occlusion for transplanted cancer in rat's liver. METHODOLOGY: Walker 256 carcinosarcoma was transplanted into rat's liver to create the liver cancer model. Hepatic arterial ligation was used to block the hepatic arterial blood supply. Rats bearing tumor were divided into three groups: control group, HAL (hepatic arterial ligation) group, and HAL plus octreotide group. Change of tumor volume and tumor growth inhibiting rate after therapy were evaluated. Hoechst 33342 labeling assay was used to analyze the blood perfusion of tumor (the labeled cells' number presenting blood perfusion). Expression of vascular endothelial growth factor and matrix metalloproteinase-1 mRNA was detected by in situ hybridization, and the level of serum vascular endothelial growth factor was assayed by ELISA. RESULTS: Six days after hepatic arterial ligation, the mean tumor volume in control group, HAL group, and HAL plus octreotide group was 0.103 +/- 0.043 cm3, 0.030 +/- 0.018 cm3, and 0.016 +/- 0.005 cm3, respectively. The tumor volume in the two behind groups was smaller than that in the control group (P < 0.01), and the tumor growth-inhibiting rate was 70.8%, and 84.5%, respectively. Compared with the HAL group, the tumor volume in HAL plus octreotide group decreased significantly (P < 0.05). Hoechst 33342 labeled cells' number in control group, HAL group, and HAL plus octreotide group was 369.7 +/- 30.2, 344.1 +/- 26.0, and 323.2 +/- 40.4, respectively. The number in HAL combined with octreotide group decreased significantly compared with that in control group (P < 0.05), which suggested that the blood perfusion of tumor in HAL plus octreotide group decreased significantly. The expression of vascular endothelial growth factor and matrix metalloprotenase-1 mRNA decreased slightly, but not significantly in HAL plus octreotide group compared with that in HAL group (P > 0.05). CONCLUSIONS: The results suggest that octreotide can promote the effects of hepatic arterial occlusion therapy for transplanted cancer in rat's liver. Decreasing the blood perfusion of tumor after hepatic arterial blockage maybe one of its major mechanisms.

Esophageal perforation during or after conformal radiotherapy for esophageal carcinoma.

The aim of this study was to analyze the risk factors and prognosis for patients with esophageal perforation occurring during or after radiotherapy for esophageal carcinoma. We retrospectively analyzed 322 patients with esophageal carcinoma. These patients received radiotherapy for unresectable esophageal tumors, residual tumors after operation, or local recurrence. Of these, 12 had radiotherapy to the esophagus before being admitted, 68 patients had concurrent chemoradiotherapy (CRT), and 18 patients had esophageal perforation after RT (5.8%). Covered self-expandable metallic stents were placed in 11 patients. Two patients continued RT after stenting and control of infection; one of these suffered a new perforation, and the other had a massive hemorrhage. The median overall survival was 2 months (0-3 months) compared with 17 months in the non-perforation group. In univariate analysis, the Karnofsky performance status (KPS) being ≤ 70, age younger than 60, T4 stage, a second course of radiotherapy to the esophagus, extracapsular lymph nodes (LN) involving the esophagus, a total dose >100 Gy (biologically effective dose-10), and CRT were risk factors for perforation. In multivariate analysis, age younger than 60, extracapsular LN involving the esophagus, T4 stage, and a second course of radiotherapy to the esophagus were risk factors. In conclusion, patients with T4 stage, extracapsular LN involving the esophagus, and those receiving a second course of RT should be given particular care to avoid perforation. The prognosis after perforation was poor.

Analysis of simultaneous modulated accelerated radiotherapy (SMART) for nasopharyngeal carcinomas.

The purpose of this study was to analyze the clinical outcomes of simultaneous modulated accelerated radiotherapy (SMART) in patients with nasopharyngeal carcinoma (NPC). A total of 97 patients who underwent SMART for NPC between August 2005 and November 2011 were evaluated. The prescribed dose was 69.9 Gy/30 fractions at 2.33 Gy/fraction to the primary gross tumor volume (PGTV) including the nasopharynx gross target volume and the positive neck lymph nodes, and 60 Gy/30 fraction at 2.0 Gy/fraction to the PCTV1; 54 Gy/30 fractions at 1.8 Gy/fraction was given to the PCTV2. Among 59 patients with local advanced disease, 31 patients received concurrent chemoradiotherapy (chemo-RT) with a regimen consisting of 135 mg/m(2) paclitaxel on Day 1 and 25 mg/m(2) cisplatin on Days 1-3. The median follow-up period was 42 months. The local control rate (LCR), distant metastases-free survival (DMFS) and overall survival (OS) rates were 93.3%, 90.3% and 91.6% at 3 years, and 87.6%, 87.9% and 85.7% at 5 years, respectively. There was no significant difference in outcome with respect to these three indicators for Stage III and IV disease treated with/without concurrent chemoradiotherapy (P > 0.05). Acute toxicities included Grade 3 mucositis, skin desquamation, and leucopenia, which occurred in 78 (80.4%), 8 (8.2%), and 45 (46.4%) patients, respectively. No patient had a Grade 3-4 late toxicity. SMART was associated with a favorable outcome for NPC with acceptable toxicity. The local-regional control was excellent but distant metastasis remains the main risk. The combination of SMART and chemotherapy needs to be optimized through further studies to enhance outcomes for locally advanced diseases.

Effectiveness and toxicities of intensity-modulated radiotherapy for patients with locally recurrent nasopharyngeal carcinoma.

PURPOSE: To analyze the effectiveness and toxicities in the re-irradiation of locally recurrent nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT). METHODS: This is a retrospective analysis of 54 NPC patients with local recurrence re-irradiated with IMRT. The re-staging for rT1, rT2, rT3, rT4 were 3 (5.6%), 8 (14.8%), 9 (16.7%), 34 (63%) respectively. The average dose to GTV was 69.95 Gy (49.8-76.58 Gy), the average BED(3Gy) was 116.8 Gy (83.5-127.9 Gy). V95 was 96%, and D95 was 65.75 Gy. 33.3% of them received concurrent chemoradiotherapy. RESULTS: Median overall survival (OS) was 21 months (1-93 mon). The 1-, 2-year local progression free survival (LPFS) rate was 84.5%, 64% and OS rate was 71.7%, 44.3%. Severe late adverse events (SLAE) occurred in 48.1% of patients, including 31.5% with ulcer or necrosis of the nasopharyngeal mucosa, 20.4% with difficulty in feeding, 18.5% with temporal lobe necrosis, 11.1% with massive hemorrhage. 15.4% died of local regional progression, 5.8% died of distant metastasis, 25% died of SLAE, 9.6% died of both local regional progression and SLAE that could not be differentiated, 5.8% died of other medical complications. Concurrent chemoradiotherapy was the independent negative prognostic factors for LPFS; PTV>100 ml was a predictive factor of poor OS; patients with invasion of post-styloid space were at higher risk of SLAE. CONCLUSIONS: The present study demonstrated that IMRT with 70Gy was efficient for local tumor control. However, we observed a high frequency of serious late complications. More optimized combination treatment and patient selection are required to achieve excellent local control without significant late morbidities in locally recurrent NPC.