Personalized designs of adjuvant radiotherapy for pancreatic cancer based on molecular profiles.

This study aims to identify postoperative recurrence patterns of pancreatic cancer with different molecular profiles, which provides evidence for personalized target volumes of adjuvant radiotherapy. Patients with pathologically confirmed resectable pancreatic ductal adenocarcinoma were included. Recurrences were treated with stereotactic body radiation therapy. Immunohistochemical staining of Ki-67, P53, and programmed cell death-ligand 1 (PD-L1) was carried out. Both of the intensities of Ki-67 and P53 were classified as 10% or less, 11%-49%, and 50% or more. Eighty-nine patients had PD-L1 tested, stratified as TC0 and IC0, and TC1/2 or IC1/2. Distances with significant differences among different levels or beyond 10 mm were of interest. With the increasing intensity of Ki-67, the distance from the superior and posterior border of 80% recurrences to the celiac axis (CA) ranged from 10.1 to 13.8 mm and 9.2 to 11.0 mm. The distance from the inferior and posterior border of 80% recurrences to the superior mesenteric artery (SMA) ranged from 9.4 to 9.9 mm and 9.4 to 11.0 mm. Similarly, with the increasing intensity of P53, the distance from the superior and posterior border of 80% recurrences to the CA ranged from 9.7 to 13.2 mm and 10.1 to 10.6 mm. The distance from the inferior and anterior border of 80% recurrences to the SMA ranged from 9.5 to 9.9 mm and 8.6 to 9.4 mm. Regarding the increasing level of PD-L1, the distance from the superior border of 80% recurrences to the CA ranged from 10.9 to 13.5 mm. A biologically effective dose of more than 65 Gy to local recurrences was predictive of favorable outcomes in all levels of Ki-67, P53, and PD-L1. Nonuniform expansions of regions of interest based on different levels of molecular profiles to form target volumes could cover most recurrences, which might be feasible for adjuvant radiotherapy.

A Predictive Model to Evaluate Pathologic Complete Response in Rectal Adenocarcinoma.

Introduction: Neoadjuvant chemo-radiotherapy (nCRT) before surgery was a standard treatment strategy for locally advanced rectal cancer (LARC). The aim of this study was to assess the relationship between the predictive factors and pathological complete response (pCR) in rectal cancer patients, especially in ultra-low ones. Method: A total of 402 patients were involved in this retrospective study. The logistic regression analyses were used to compare the different subgroups in univariate analysis. Multivariate analysis was performed to determine the independent predictive factors of pCR by using a logistic regression model. Results: A total of 402 patients received preoperative CRT. In all patients, multivariate analysis revealed that circumferential tumor extent rate (CER) (≤ 2/3cycle vs >2/3 cycle, P < .001, OR = 4.834, 95% CI: 2.309-10.121), carcinoembryonic antigen (CEA) level (both ≤ 5 vs pre > 5 and post ≤ 5 vs both > 5, P = .033, OR = 1.537, 95% CI: 1.035-2.281), and interval time between the end of CRT and surgery (P = .031, OR = 2.412, 95% CI: 1.086-5.358) were predictive factors for pCR. The area under the curve (AUC) of the predictive model was 0.709 (95% CI: 0.649-0.769), which was significantly higher than the CER (0.646, 95% CI: 0.584-0.709), interval time (0.563, 95% CI: 0.495-0.631) and CEA level (0.586, 95% CI: 0.518-0.655). In ultra-low rectal patients, multivariate logistic regression analysis revealed that CER (≤ 2/3 cycle vs > 2/3 cycle, P = .003, OR = 7.203, 95% CI: 1.934-26.823) and mismatch repair (MMR) status (pMMR vs dMMR, P = .016, OR = 0.173, 95% CI: 0.041-0.720) were predictive factors for pCR. The AUC of the predictive model was 0.653 (95% CI: 0.474-0.832). Conclusion: New predictive models were varied by the histologic types and MMR statuses to evaluate the trend of tumor response to nCRT in all RC cases and ultra-low RC patients, which may be used to individualize stratify for selected LARC patients.

Phase I study of dose-escalated stereotactic body radiation therapy for locally advanced pancreatic head cancers: Initial clinical results.

PURPOSE: To establish the maximum tolerated dose (MTD) of stereotactic body radiation therapy (SBRT) for locally advanced pancreatic head cancers. METHODS: A total of 16 patients were included in the single-institution phase I dose-escalation study. The initial dose level was 35 Gy in five fractions, doses were then sequentially escalated to 37.5 Gy, 40 Gy, 42.5 Gy, and 45 Gy. The dose-limiting toxicity (DLT) was defined as III/IV GI (gastrointestinal) toxicity. RESULTS: A total of 16 patients with locally advanced pancreatic head cancers were analyzed, 14 patients had received gemcitabine or S1-based chemotherapy. Median OS and LPFS were 14.5 months and 12.5 months, respectively; The OS rates at 1 and 2 years were 68.8% and 25%, respectively. No grade 3 or 4 acute or late GI toxicities were observed. Grade 3 toxicities were observed in four patients with three hematologic toxicities and one biliary obstruction for acute toxicities, G1-2 of GI late toxicity were in 31.25% of patients. CONCLUSIONS: SBRT doses ranging from 35 to 45 Gy in five fractions could be given for patients with locally advanced pancreatic head cancers without severe GI toxicities, whereas the side effect of biliary obstruction should be paid more attention. TRIAL REGISTRATION: Clinical trials:NCT02716207.

Re-Irradiation With Stereotactic Body Radiotherapy for In-Field Recurrence of Pancreatic Cancer After Prior Stereotactic Body Radiotherapy: Analysis of 24 Consecutive Cases.

PURPOSE/OBJECTIVES: Locally recurrent pancreatic cancer is a therapeutic challenge, and aggressive approaches are needed to improve its clinical outcomes. Stereotactic body radiotherapy (SBRT) is a promising treatment for pancreatic cancer with an excellent local control and acceptable toxicity. However, the safety and efficacy of SBRT for in-field recurrence after initial SBRT remain unknown. The aim of the study was to investigate the feasibility of re-irradiation with SBRT for locally recurrent pancreatic cancer after prior definitive SBRT. MATERIAL/METHODS: Twenty-four consecutive patients with pancreatic cancer received two courses of SBRT in our center between January 2014 and December 2016. The median prescription dose of the initial and second courses of SBRT was 35.5 Gy/5-7f and 32 Gy/5-8f, respectively. Clinical outcomes including overall survival (OS), disease control, and toxicity were evaluated after treatment. RESULTS: The median interval between two courses of SBRT was 13 months (range: 6-29 months). From the first SBRT, the median OS of 18 patients with limited diseases was 26 months (95% CI: 19.1-32.95 months). The median OS of 12 patients without metastasis was 14 months (95% CI: 10.6-17.4 months) from re-irradiation of SBRT. The overall response rate and disease control rate were 50% and 13%, and 100% and 86.9% after each SBRT, respectively. Carbohydrate antigen 19-9 (CA19-9) levels declined dramatically after re-irradiation within 1 month (p = 0.002) and 3 months (p = 0.028). Twelve (75%) out of 16 patients had pain relief after re-irradiation. None of the patients experienced gastrointestinal toxicity. CONCLUSIONS: Re-irradiation with SBRT can provide favorable outcomes and effective analgesia with mild toxicity after prior SBRT for in-field recurrent pancreatic cancer, which might be feasible for locally relapsed pancreatic cancer.

Failure patterns and outcomes of dose escalation of stereotactic body radiotherapy for locally advanced pancreatic cancer: a multicenter cohort study.

OBJECTIVE: This study aims to compare recurrence patterns and outcomes of biologically effective dose (BED10, α/ß = 10) of 60-70 Gy with those of a BED10 >70 Gy for locally advanced pancreatic cancer (LAPC). METHODS: Patients from three centers with a biopsy and a radiographically proven LAPC were retrospectively included and data were prospectively collected from June 2012 to June 2019. Radiotherapy was delivered by stereotactic body radiation therapy. Recurrences were categorized as in-field, marginal, and outside-the-field recurrence. Patients in two groups were required to receive abdominal enhanced contrast CT or MRI every 2-3 months and CA19-9 examinations every month during follow-up. Treatment-related toxicities were evaluated every month. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. RESULTS: After propensity score matching, there were 486 patients in each group. The median prescription dose of the two groups was 37 Gy/5-8 f (range: 36-40.8 Gy/5-8 f) and 42 Gy/5-8 f (range: 40-49.6 Gy/5-8 f), respectively. The median OS of patients with a BED10 >70 Gy and a BED10 60-70 Gy was 20.3 months (95% CI: 19.1-21.5 months) and 18.2 months (95% CI: 17.8-18.6 months) respectively (p < 0.001). The median PFS of the two cohorts was 15.4 months (95% CI: 14.2-16.6 months) and 13.3 months (95% CI: 12.9-13.7 months) respectively (p < 0.001). A higher incidence of in-field and marginal recurrence was found in patients with BED10 of 60-70 Gy (in-field: 97/486 versus 72/486, p = 0.034; marginal: 109/486 versus 84/486, p = 0.044). However, more patients with BED10 >70 Gy had grade 2 or 3 acute (87/486 versus 64/486, p = 0.042) and late gastrointestinal toxicities (77/486 versus 55/486, p = 0.039) than those with BED10 of 60-70 Gy. CONCLUSION: BED10 >70 Gy was found to have the best survival benefits along with a higher incidence of acute and late gastrointestinal toxicities. Therefore, a higher dose may be required in the case of patients' good tolerance.

Validation of the eighth edition of the AJCC staging system for patients with pancreatic adenocarcinoma initially receiving chemoradiotherapy and proposal of modifications.

Objective: To validate the eighth edition of the AJCC staging system in patients with pancreatic adenocarcinoma receiving only stereotactic body radiation therapy and chemotherapy, and to propose modifications to improve prognostic accuracy. Methods: Patients with pathologically confirmed pancreatic adenocarcinoma without metastasis who were undergoing only chemoradiotherapy were included and staged according to the seventh and eighth editions of the AJCC staging system. Meanwhile, another group of stage T4 patients from the above enrollment with only portal vein involvement with or without tumor thrombi (PV ± PVTT) were retrieved for survival comparisons. Modifications were proposed according to the survival comparisons. A cohort from the SEER database was used for external validation of the modified staging system. Results: A total of 683 patients were included. Patients with N2 or N1 but different T stages had significantly different survival outcomes according to the eighth edition. The survival of patients with PV ± PVTT was comparable to that of patients with T4 tumors. The concordance index of the seventh and eighth editions, and the modified staging system was 0.744 (95%CI: 0.718-0.769), 0.750 (95%CI: 0.725-0.775), and 0.788 (95%CI: 0.762-0.813), respectively. For external validation, the concordance index was 0.744 (95%CI: 0.718-0.770), 0.750 (95%CI: 0.724-0.776), and 0.788 (95%CI: 0.762-0.814), respectively. Conclusions: The modified staging system is suggested to have the most accurate prognostic value. Hence, PV ± PVTT should be added to the definition of T4 tumors regardless of tumor size. Patients with N2 or N1 in different T stages could be regrouped into different substages. Additionally, stage III should be subclassified into IIIA (T3N2 and T4N0) and IIIB (T4N1-2).

Patterns of Local Failure After Stereotactic Body Radiation Therapy and Sequential Chemotherapy as Initial Treatment for Pancreatic Cancer: Implications of Target Volume Design.

PURPOSE: To identify patterns of local failure in patients with pancreatic cancer receiving stereotactic body radiation therapy plus chemotherapy as initial treatment, for the optimal design of target volumes encompassing a majority of local recurrences. METHODS AND MATERIALS: Consecutive patients with resectable or borderline resectable but medically inoperable cancer owing to comorbidities and locally advanced pancreatic cancer undergoing stereotactic body radiation therapy and chemotherapy were reviewed. Local recurrences were plotted with respect to the celiac trunk (CT), superior mesenteric artery (SMA), and splenic artery on 1 computed tomographic scan of a template patient. RESULTS: Five hundred and ten patients were included. Median follow-up of the entire group was 21.8 months (range, 3.1-54.9 months). Two hundred and seventeen patients had locoregional recurrences, whereas local and distant progressions were found in 293 patients. One hundred and sixty-nine (33.2%) and 144 (28.2%) patients had recurrences closer to the CT and SMA, respectively, whereas both invasions of the CT and SMA were found in 115 patients (22.5%). In addition, 33 patients (6.5%) and 49 patients (9.6%) had recurrences at the hepatic hilum and the splenic artery, respectively. Besides these patterns of failure, 138 patients (27.1%) also experienced retroperitoneal progressions. The mean distance to the CT, SMA, and retroperitoneal recurrence was 9.0, 8.3, and 11.7 mm, respectively. Multivariable analysis demonstrated that advanced pancreatic cancer, recurrences at both the CT and SMA and the hepatic hilum, CA19-9 nonresponders, and BED10 <60 Gy were predictive of worse survival. CONCLUSIONS: Areas closer to the CT, SMA, and retroperitoneal space were at a high risk of local recurrences. Nonuniform and sufficient expansions from the gross tumor volume might be necessary, and the splenic vessels abutting the tumor might also be included in the target volume without compromise of dose constraints of organs at risk. In addition, at least BED10 ≥60 Gy might be required to achieve better outcomes.

Stereotactic Radiation Therapy (SRT) for Brain Metastases of Multiple Primary Tumors: A Single Institution Retrospective Analysis.

Purpose: To evaluate the efficiency and side effects of stereotactic radiation therapy (SRT) with or without other treatments for brain metastases (BM) from various primary tumors. Methods: This was a retrospective analysis of 161 patients with brain metastases treated with SRT. Clinical data, EGFR mutation status and survival data were collected. Follow-up data was analyzed until December 2018. Kaplan-Meier and Cox proportional hazards regression analyses were used for the survival analysis. Results: The median overall survival (OS) was 19 months. No difference was observed in OS between SRT group and SRT + whole brain radiation therapy (WBRT) groups (p = 0.717). Statistically significant factors of better OS after univariable analysis were no extracranial metastases (p = 0.016), BED10-SRT≥50Gy (p = 0.049), oligometastases (1-3 brain metastases) (p < 0.001), GPA score≥2.5 (p = 0.003), RPA class I (p = 0.026), NSCLC tumor type (p = 0.006), targeted therapy (p < 0.001) and controlled extracranial disease (p = 0.011). Multivariate analysis indicated that higher BED10-SRT (≥50Gy, HR = 0.504, p = 0.027), controlled extracranial disease (HR = 0.658, p = 0.039) and targeted therapy (HR = 0.157, <0.001) were independent favorable predictors for OS. Besides that, we also find that the median overall survival (OS) was 22 months in NSCLC patients and controlled extracranial disease (HR = 0.512, p = 0.012) and targeted therapy (HR = 0.168, < 0.001) were independent favorable predictors for OS. Conclusion: For patients with brain metastases, stable extracranial disease, higher BED10-SRT (≥50Gy) and targeted therapy may predict a favorable prognosis.

Health-related quality of life for gemcitabine and nab-paclitaxel plus radiotherapy versus gemcitabine and S-1 plus radiotherapy in patients with metastatic pancreatic cancer.

PURPOSE: To compare the effects of gemcitabine and nab-paclitaxel (GT) plus stereotactic body radiation therapy (SBRT) or gemcitabine and S-1 (GS) plus SBRT on health-related quality of life (HRQOL) of metastatic pancreatic cancer. METHODS: Patients with biopsy-proven and radiographically metastatic pancreatic cancer were included. HRQOL was assessed using the Chinese version of Brief Pain Inventory (BPI) and 5-level European quality of life 5-dimensions (EQ-5D-5L). Data were analyzed with Spearman's rank correlation, ordinal regression, and propensity score-matched analysis. RESULTS: A total of 75 and 89 patients received GT and GS, respectively. The median biological effective dose of GT group and GS group was 59.5 Gy (range 48-85.5 Gy) and 64.4 Gy (range 52.48-85.5 Gy) in 5-8 fractions, respectively. More patients in the GS group had improvement in BPI and EQ-5D-5L compared with those in the GT group (n=38 vs n=15, P<0.001; n=42 vs n=20, P<0.001). No differences of BPI scores were found between pre- and post-treatment in each group, while only the post-treatment EQ-5D-5L score was higher than that at baseline in GS the group (P<0.001). Compared with GS group, it was unlikely for patients receiving GT to have better BPI and EQ-5D-5L. After propensity-matched analysis, more patients in GS group had improvement in BPI and EQ-5D-5L (n=24 vs n=12, P=0.002; n=28 vs n=16, P=0.002). Furthermore, patients with GS had a superior overall survival than those with GT (11.1 months [95% CI: 10.6-11.6 months] vs 9.9 months [95% CI: 8.8-11.0 months]; P=0.005). Both incidences of grade 3 hematological (P=0.024) and gastrointestinal (P=0.049) toxicities were higher in the GT group. CONCLUSION: GS may achieve better HRQOL than GT. Therefore, GS may be an alternative of GT for metastatic pancreatic cancer, especially for Asians.

Stereotactic body radiation therapy plus induction or adjuvant chemotherapy for early stage but medically inoperable pancreatic cancer: A propensity score-matched analysis of a prospectively collected database.

BACKGROUND: To evaluate and compare the efficacy and safety of stereotactic body radiation therapy (SBRT) plus induction chemotherapy and SBRT plus adjuvant therapy. METHODS: Patients with radiographically resectable, biopsy-proven pancreatic cancer were enrolled. Data were prospectively collected from 2012 to 2016. Cox proportional hazards regression was used to identify factors predictive of survival. Propensity score matching analysis was performed to assess the efficacy of SBRT combined with different timing of chemotherapy. RESULTS: One hundred patients were enrolled with 48 receiving induction chemotherapy and 52 undergoing adjuvant chemotherapy. The median overall survival (OS) and progression-free survival (PFS) were 17.5 months (95% CI: 15.8-19.2 months) and 13.7 months (95% CI: 12.3-15.1 months), respectively. Patients with adjuvant chemotherapy (P <0.001), CA19-9 response (P <0.001) and BED10 (biological effective dose, α/ß = 10) ≥ 60 Gy (P = 0.024) had a longer OS, while the former two correlated with PFS. Patients with more positive factors had a superior OS and PFS. After propensity score matching analysis, there were 23 patients from each group included in the analysis. Longer OS (23.1 months versus 15.6, P <0.001) and PFS (18.0 months versus 11.6 months, P <0.001) were found in patients with adjuvant chemotherapy compared with those with induction chemotherapy. CONCLUSION: SBRT was safe and effective in early stage pancreatic cancer. Combined with adjuvant chemotherapy, SBRT could be an alternative for patients with resectable pancreatic cancer but not eligible for surgical resection.

Prospective analysis of different combined regimens of stereotactic body radiation therapy and chemotherapy for locally advanced pancreatic cancer.

To identify impacts of different combined regimens of stereotactic body radiation therapy (SBRT) and chemotherapy on survival of patients with locally advanced pancreatic cancer (LAPC) and factors correlated with determinations of different combinations. Four hundred and nineteen patients with radiographically and biopsy-proven LAPC were prospectively enrolled. Factors associated with different strategies were analyzed with Chi-square test and contingency coefficients. Cox regression was used to identify factors predictive of survival. Prognostic values of different multimodality were further analyzed by propensity score-matched analysis. Median overall survival (OS) and progression-free survival (PFS) of all patients was 13.2 and 8.2 months, respectively. Baseline ECOG correlated with induction chemotherapy, while tumor stage, lymph node invasion, and toxicity after SBRT associated with adjuvant chemotherapy. Patients with induction chemotherapy alone (12.2 months), adjuvant chemotherapy alone (13.6 months), and induction and adjuvant chemotherapy (13.3 months) had longer OS than those without chemotherapy (11.2 months; P < .001), while adjuvant chemotherapy alone and induction and adjuvant chemotherapy increased PFS. An adjusted overall survival benefit was gained with adjuvant chemotherapy compared with induction and adjuvant chemotherapy (OS: 14.7 months [95% CI: 14.2-15.2 months] vs 13.1 months [95% CI: 12.3-13.9 months]; P < .001) (PFS: 8.8 months [95% CI: 8.4-9.2 months] vs 8.1 months [95% CI: 7.4-8.8 months]; P = .053). Induction and adjuvant chemotherapy, especially adjuvant chemotherapy, plus SBRT may improve OS and PFS. Baseline performance status, tumor stage, lymph node involvement, and toxicity after SBRT influenced determinations of upfront multimodality.

Prediction of overall survival after re-irradiation with stereotactic body radiation therapy for pancreatic cancer with a novel prognostic model (the SCAD score).

PURPOSE: To develop a predictive model for stratification of patients with pancreatic cancer who may achieve survival benefits from re-irradiation with stereotactic body radiation therapy (SBRT). METHODS: The score was developed based on clinical predictors of OS in 31 patients receiving two courses of SBRT with Cox proportional hazards model. Results were then validated in another cohort with 11 participants to assess the performance of the score. RESULTS: In the training cohort, the median BED10 of the first and second SBRT was 59.5 Gy (48-85.5 Gy) and 50.2 Gy (43.7-66.9 Gy) in 5-8 fractions, while in the validation cohort, the median BED10 of the first and second SBRT was 59.5 Gy (52.5-66.9 Gy) and 47.7 Gy (40.6-54.8 Gy) in 5-8 fractions. The interval between the first and second SBRT of the training cohort and validation cohort was 10.5 months (6.1-24.3 months) and 12.8 months (6.5-29.1 months), respectively. Multivariable analysis showed that tumor stage (P = 0.005), BED10 (P = 0.006) and CA19-9 response (P = 0.04) were significantly predictive of overall survival, which formed SCAD score (named after the initials of factors). Patients with the score < 3 points had a superior OS compared with those with the score ≥ 3 points in the validation cohort (median OS has not been reached vs. 15.9 months, P = 0.032). CONCLUSIONS: The SCAD score may have the potential to identify individuals benefiting from re-SBRT and be a step toward more personalized medicine.

Dose escalation of Stereotactic Body Radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer patients with CyberKnife: protocol of a phase I study.

BACKGROUND: Dose escalation of SBRT for locally advanced pancreatic cancer patients had been reported in several studies in one or three fractions, and phase I protocol was developed to investigate the maximum tolerated dose with CyberKnife for locally advanced unresectable pancreatic cancer patients in five fractions. METHODS: The study is designed as a mono-center phase I study. The primary endpoint is to determine the maximum tolerated dose by frequency of III/IV GI (gastrointestinal) toxicity. Adverse events (AE) according to Common Toxicity Criteria (CTC) version 4. Doses of 7 Gy, 7.5 Gy, 8 Gy, 8.5 Gy, 9 Gy, 9.5Gy x 5 respectively would be delivered while meeting with normal tissue constraints. A minimum of three patients will be included for each dosage level. And an interval is 4 weeks from the first patient treatment to the next patient treatment at each dose level. The maximal tolerated dose will be defined as the dose for which at least two patients in three, or at least three patients in nine, will present with a limiting toxicity. DISCUSSION: Since the dose and fractions of SBRT treatment for locally advanced pancreatic cancer patients are still unknown, we propose to conduct a Phase I study determining the maximum tolerated dose of CyberKnife SBRT for the treatment of locally advanced pancreatic tumor based on a 5 fractions treatment regimen. This trial protocol has been approved by the Ethics committee of Changhai hospital. The ethics number is 2016-030-01. TRIAL REGISTRATION: Clinical trials number: NCT02716207 . Date of registration: 20 March 2016.

Prognostic role of stereotactic body radiation therapy for elderly patients with advanced and medically inoperable pancreatic cancer.

The role of stereotactic body radiation therapy for the elderly with advanced or medically inoperable pancreatic cancer was still debated. Therefore, we evaluated the value of stereotactic body radiation therapy and its association with survival of those patients. A total of 417 elderly patients were retrospectively reviewed from 2012 to 2015. Overall survival (OS), progression-free survival (PFS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and toxicities were analyzed. Prescription doses ranged from 30-46.8 Gy in 5-8 fractions. Median age was 73 years old. Median OS, PFS, LRFS, and DMFS were 10, 8, 10, and 9.5 months, respectively. One-year OS, PFS, LRFS, and DMFS rate were 35.5%, 18.2%, 26.6%, and 27.1%, respectively. Tumor stage and tumor response at 6 months and CA19-9 levels normalization at 3 months after treatment were independent predictors of OS, PFS, LRFS, and DMFS. Patients with early-stage cancer, better tumor response, and normalization of CA19-9 levels had significantly longer OS, PFS, LRFS, and DMFS. Patients with the prodrug of 5-FU and radiotherapy had longer survival than those with gemcitabine-based chemotherapy and radiotherapy. Patients who received BED10  ≥ 60 Gy achieved better tumor response compared with those who received BED10  < 60 Gy. Two patients had grade 4 intestinal strictures. No grade 3 or higher hematologic toxicities occurred. Stereotactic body radiation therapy is safe and effective for elderly patients with advanced or medically inoperable pancreatic cancer. Early efficacy could be predictive of prognosis. Higher doses may be associated with efficacy but need further investigation.

Phosphorothioate­modified antisense oligonucleotides against human telomerase reverse transcriptase sensitize cancer cells to radiotherapy.

Emergence of resistance, unavoidable systemic toxicity and unsatisfactory efficacy arethe main obstacles for traditional cancer therapy. Combination with phosphorothioate modified antisense oligonucleotides (PS­ASODN) against human telomerase reverse transcriptase (hTERT) may enhance the therapeutic effect of irradiation. However, the effect of PS­ASODN against hTERT on the anti­tumor effects of irradiation in liver cancer remain unclear. In the current study, Walker 256 cells were transfected with hTERT PS­ASODN. Cell proliferation and cell viability were measured using the MTT assay and cell senescence was examined by SA­ß­gal staining. Telomerase activity was determined by telomeric repeat amplification protocol­polymerase chain reaction­ELISA. Cell apoptosis was assayed by flow cytometry and DNA damage was determined by the comet assay.The PS­ASODN was demonstrated to have an inhibitory effect on cell proliferation and accelerated effect on cell senescence by inhibiting telomerase activity. PS­ASODN promoted the irradiation­induced inhibition of cell viability and telomerase activity, and irradiation­induced DNA damage and cell apoptosis via the activation of apoptosis­associated proteins. Taken together, these results indicated that combined treatment of PS­ASODN with irradiation significantly enhanced tumor inhibition. Therefore, PS­ASODN provides an experimental foundation for gene therapy and is proposed for application in clinical treatment of liver cancer combined with radiotherapy.

Safety and efficacy of stereotactic body radiation therapy combined with S-1 simultaneously followed by sequential S-1 as an initial treatment for locally advanced pancreatic cancer (SILAPANC) trial: study design and rationale of a phase II clinical trial.

INTRODUCTION: Upfront surgeries are not beneficial to most patients with pancreatic cancer. Therefore, more emphasis has been placed chemoradiotherapy in locally advanced pancreatic cancer recently. Gemcitabine-based regimens or FOLFIRINOX (a chemotherapy regimen including leucovorin, 5-FU, irinotecan, oxaliplatin) has been proven as a standard chemotherapy in pancreatic cancer. However, severe toxicities may prevent the completion of chemotherapy. S-1 has showed better objective response rates, similar overall survival rates and progression-free survival rates compared with gemcitabine, revealing that S-1 may be a potential candidate in treating pancreatic cancer, especially for patients refractory to gemcitabine. Additionally, stereotactic body radiation therapy with Cyberknife could provide better efficacy than conventional radiotherapy in pancreatic cancer. Therefore, Cyberknife with S-1 simultaneously followed by sequential S-1 as an initial treatment may bring about favourable outcomes but needs further studies. METHODS AND ANALYSIS: The S-1 as an initial treatment for locally advanced pancreatic cancer (SILAPANC) trial is a prospective, single-centre, one armed ongoing study. 190 eligible patients are required to initially receive Cyberknife with 1 cycle of S-1 simultaneously. After the concurrent chemoradiotherapy, 2 or 3 cycles of S-1 are sequentially given. Doses and fractions depend on the locations and volumes of tumours and the adjacent organs at risk. S-1 is taken orally, 2 times a day, at a dose of 80 mg/m2 for 28 days, followed by a 14-day interval. The primary objectives are overall survival and 1-year, 2-year, 3-year, 4-year and 5-year overall survival rates. The secondary objectives are cancer-specific survival, progression-free survival, time to progression, local control rates, clinical benefit rates, radiation-induced acute and late toxicities, adverse effects of chemotherapy and quality of life of patients. Besides, variables most predictive of prognosis would be identified via multivariate methods. ETHICS AND DISSEMINATION: Approvals have been granted by the Changhai Hospital Ethics Committee (CHEC-2016-032-01). The results will be disseminated in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: NCT02704143; Pre-results.