Stereotactic body radiation therapy for the primary tumor and oligometastases versus the primary tumor alone in patients with metastatic pancreatic cancer.

BACKGROUND: Local therapies may benefit patients with oligometastatic cancer. However, there were limited data about pancreatic cancer. Here, we compared the efficacy and safety of stereotactic body radiation therapy (SBRT) to the primary tumor and all oligometastases with SBRT to the primary tumor alone in patients with metastatic pancreatic cancer. METHODS: A retrospective review of patients with synchronous oligometastatic pancreatic cancer (up to 5 lesions) receiving SBRT to all lesions (including all oligometastases and the primary tumor) were performed. Another comparable group of patients with similar baseline characteristics, including metastatic burden, SBRT doses, and chemotherapy regimens, receiving SBRT to the primary tumor alone were identified. The primary endpoint was overall survival (OS). The secondary endpoints were progression frees survival (PFS), polyprogression free survival (PPFS) and adverse events. RESULTS: There were 59 and 158 patients receiving SBRT to all lesions and to the primary tumor alone. The median OS of patients with SBRT to all lesions and the primary tumor alone was 10.9 months (95% CI 10.2-11.6 months) and 9.3 months (95% CI 8.8-9.8 months) (P < 0.001). The median PFS of two groups was 6.5 months (95% CI 5.6-7.4 months) and 4.1 months (95% CI 3.8-4.4 months) (P < 0.001). The median PPFS of two groups was 9.8 months (95% CI 8.9-10.7 months) and 7.8 months (95% CI 7.2-8.4 months) (P < 0.001). Additionally, 14 (23.7%) and 32 (20.2%) patients in two groups had grade 3 or 4 treatment-related toxicity. CONCLUSIONS: SBRT to all oligometastases and the primary tumor in patients with pancreatic cancer may improve survival, which needs prospective verification.

Immune profiling of pancreatic cancer for radiotherapy with immunotherapy and targeted therapy: Biomarker analysis of a randomized phase 2 trial.

PURPOSE: Immunotherapy alone offered limited survival benefits in pancreatic cancer, while the role of immunotherapy-centric combined therapy remains controversial. Therefore, it is required to develop biomarkers to precisely deliver immunotherapy-based multimodality for pancreatic cancer. METHODS: This is a secondary analysis of an open label, randomized, phase 2 trial, whereas patients with locally recurrent pancreatic cancer after surgery were enrolled. Eligible patients with mutant KRAS and positive immunohistochemical staining of PD-L1 were randomly assigned to receive stereotactic body radiation therapy (SBRT) plus pembrolizumab and trametinib (SBRT + K + M) or SBRT and gemcitabine (SBRT + G). Meanwhile, patients were classified into PD-L1+/tumor infiltrating lymphocytes [TIL(s)]- and PD-L1+/TIL + group for each arm. RESULTS: A total of 170 patients were enrolled and randomly assigned to receive SBRT + K + M (n = 85) or SBRT + G (n = 85). The improved outcomes have been reported in patients with SBRT + K + M in the previous study. In this secondary analysis, the median overall survival (OS) was 17.2 months (95% CI 14.6-19.8 months) in patients with PD-L1+/TIL + and 12.7 months (95% CI 10.8-14.6 months) in patients with PD-L1+/TIL- (HR 0.62, 95% CI 0.39-0.97, p = 0.036) receiving SBRT + K + M. In SBRT + G group, the median OS was 13.1 months (95% CI 10.9-15.3 months) in patients with PD-L1+/TIL- and 12.7 months (95% CI 9.2-16.2 months) in patients with PD-L1+/TIL+ (HR 0.97, 95% CI 0.62-1.52, p = 0.896). Grade 3 or 4 adverse events were found in 16 patients (30.8%) and 10 patients (30.3%) with PD-L1+/TIL- and PD-L1+/TIL + in SBRT + K + M group respectively; whereas 9 (16.7%) and 8 patients (25.8%) with PD-L1+/TIL- and PD-L1+/TIL + in SBRT + G group. CONCLUSION: PD-L1, TILs and mutant KRAS may be a biomarker to guide clinical practice of radiotherapy and immunotherapy-based regimens in pancreatic cancer if further combined with MEK inhibitors as targeted therapy.

Effect of stereotactic body radiotherapy dose escalation plus pembrolizumab and trametinib versus stereotactic body radiotherapy dose escalation plus gemcitabine for locally recurrent pancreatic cancer after surgical resection on survival outcomes: A secondary analysis of an open-label, randomised, controlled, phase 2 trial.

Background: There are a lack of studies about whether radiation dose escalation synergizes with immunotherapy and targeted therapy in pancreatic cancer. In this study, we performed a secondary analysis to investigate whether a high radiation dose rather than a low dose plus pembrolizumab and trametinib provided improved survival compared with gemcitabine in post-operative locally recurrent pancreatic cancer. Methods: In this open-label, randomised, controlled, phase 2 trial, eligible patients with pancreatic ductal adenocarcinoma characterized by mutant KRAS and positive immunohistochemical staining of PD-L1 and documented post-operative local recurrence were randomly assigned using an interactive voice or web response system, without stratification, to receive stereotactic body radiation therapy (SBRT) with doses ranging from 35 to 40Gy in five fractions, pembrolizumab 200 mg every three weeks and oral trametinib 2 mg once daily (SBRT + K + M) or SBRT and gemcitabine (1000 mg/m2) on day 1 and 8 of each 21-day cycle (SBRT + G) until disease progression in our hospital in China. Those had radiotherapy, immunotherapy or targeted therapy were excluded. Patients and investigators were not masked to the assignment. In each arm, patients were stratified based on biologically effective dose (BED10; α/ß = 10) of 60-65Gy and BED10 ≥65Gy. The primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). All patients received their assigned treatment and were included in the efficacy and safety analyses. This study is registered with ClinicalTrials.gov, NCT02704156. Findings: Between Oct 10, 2016, and Oct 28, 2017, 147 of 170 randomly assigned participants were eligible for inclusion in this analysis. In BED10 of 60-65Gy group, 34 and 29 patients had SBRT + G and SBRT + K + M, respectively. While there were 42 and 42 patients with SBRT + G and SBRT + K + M in BED10 ≥65Gy group. Patients in the SBRT + K + M group had longer OS compared with the SBRT + G group, but this did not reach statistical significance (median: 15.1 vs. 12.4 months, HR 0.67 [95%CI 0.43-1.04]; p = 0.071). For BED10 of 60-65Gy, OS was similar between patients in the SBRT + K + M and SBRT + G groups (median, 13.6 vs. 12.4 months; HR 0.69 [95% CI 0.41-1.16]; p = 0.16). For BED10 of ≥65Gy, PFS was prolonged with SBRT + K + M versus SBRT + G (median: 8.6 vs. 5.0 months, HR 0.48 [95% CI 0.31-0.77]; p = 0.0021). For BED10 of 60-65Gy, there was no significant difference in PFS between the two groups (PFS: median, 7.9 vs. 4.3 months; HR 0.69 [95% CI 0.42-1.15]; p = 0.16). In BED10 of 60-65Gy group, 7 (20.6%) and 8 patients (27.6%) with SBRT + G and SBRT + K + M had grade 3 or 4 adverse events (p = 0.52). In BED10 ≥65Gy group, 8 (19.0%) and 12 patients (28.6%) with SBRT + G and SBRT + K + M had grade 3 or 4 adverse events (p = 0.31). No treatment-related death occurred. Interpretation: Dose escalation of SBRT may improve PFS with pembrolizumab and trametnib versus gemcitabine for patients with post-operative locally recurrent pancreatic cancer. However, benefits of PFS did not translate into longer OS. This may be ascribed to small sample size and post-hoc analysis that was not powered to determine the significance. Therefore, synergy of high dose of SBRT with immunotherapy and targeted therapy required further investigations in phase 3 trials. Funding: Shanghai Shenkang Centre and Changhai Hospital.

Protocol of the integrated boost to the dominant intraprostatic nodule in stereotactic body radiation therapy for localized prostate cancer.

Aim: To explore the safety and efficacy of the integrated boost to the dominant intraprostatic nodule (DIN) based on 68Ga prostate-specific membrane antigen PET/MRI in stereotactic body radiation therapy (SBRT) for patients with localized prostate cancer. Methods: SBRT regimen is employed - namely, sequential integrated boost (SIB) to the DIN based on 68Ga prostate-specific membrane antigen PET/MRI. SIB prescription dose of 36.25 Gy in five fractions to fixed prophylactic tumoricidal region is delivered, followed by 7.25 Gy in one fraction added to the DIN every other day. The primary end point of the study will be toxicity assessed by the Common Terminology Criteria for Adverse Events 5.0 grading scale. Secondary end points include biochemical progression-free survival, local progression-free survival, distant metastasis-free survival and overall survival. Discussion: This trial is to prove the safety and efficacy of sequential integrated boost to the DIN in SBRT. Clinical Trial Registration: NCT04599699 (ClinicalTrials.gov).

Stereotactic body radiotherapy (SBRT) versus androgen deprivation therapy (ADT) for oligometastatic prostate cancer: protocol for a prospective randomised control clinical trial.

INTRODUCTION: The systemic therapy, especially androgen deprivation therapy (ADT), is currently recommended for patients with oligometastatic prostate cancer (PCa). However, the results have not been satisfactory including adverse reactions and castration resistance. Therefore, it is necessary to explore more effective treatment to prolong biochemical progression-free survival (bPFS) and delay the start of hormonal therapy for treating oligometastatic PCa. Stereotactic body radiotherapy (SBRT) is an emerging treatment alternative for patients with oligometastases with high local control rates and minimal toxic effects. This prospective trial aims to demonstrate whether SBRT for the oligometastases of hormone-sensitive PCa can delay the start of ADT and prolong the time from inception of the study to castration-resistant prostate cancer (CRPC). METHODS AND ANALYSIS: Patients with ≤3 oligometastatic recurrences, diagnosed on Ga-68 prostate-specific membrane antigen PET/CT, will be randomised in a 1:1 ratio between arm A (ADT only) and arm B (SBRT for oligometastases only). SBRT is conducted by CyberKnife with prescription dose 30-50 Gy in 3-5 fractions. One of the primary endpoints is ADT-free survival of arm B, the other is the time from inception of the study to CRPC. The secondary endpoints include radiotherapy-related toxicity, ADT-related toxicity, bPFS, local PFS and overall survival. Toxicity will be assessed using the National Cancer Institute Common Toxicity Criteria V.5.0. ETHICS AND DISSEMINATION: This protocol was approved by the institutional review board of Shanghai Changhai Hospital (CHEC2020-101). This is a randomised control clinical trial comparing SBRT to ADT for men with oligometastatic PCa. The study will be performed in compliance with applicable local legislation and in accordance with the ethical principles developed by the World Medical Association in the Declaration of Helsinki 2013. Study results will be disseminated through conferences and peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov identifier:NCT04599686.

Biologically effective doses of 60-70Gy versus >70Gy of stereotactic body radiotherapy (SBRT) combined with chemotherapy in locally advanced pancreatic cancer: protocol of a single-centre, phase II clinical trial.

INTRODUCTION: There is a paucity of studies about whether dose escalation of stereotactic body radiation therapy (SBRT) prolongs survival compared with de-escalation for patients with locally advanced pancreatic cancer (LAPC). Therefore, the aim of the study is to compare the survival benefits of biologically effective dose (BED10, α/ß=10) of 60-70 Gy with those of BED10 >70 Gy. METHODS AND ANALYSIS: This study is a single-centre, phase II trial. Patients with LAPC are randomly allocated to receive SBRT with BED10 of 60-70 Gy or >70 Gy in 5-6 fractions combined with gemcitabine plus albumin-bound paclitaxel. The primary outcome is progression-free survival. The secondary outcomes are adverse events, local control and overall survival. ETHICS AND DISSEMINATION: The trial protocol has been approved by the Ethics committee of Shanghai Changhai Hospital. The ethics number is CHEC2020-100. Study results will be disseminated through peer-reviewed journals and released in related medical conferences. TRIAL REGISTRATION NUMBERS: NCT04603586.

Safety and Efficacy Study of Neoadjuvant Radiohormonal Therapy for Oligometastatic Prostate Cancer: Protocol of an Open-Label, Dose-Escalation, Single-Centre Phase I/II Clinical Trial.

BACKGROUND: The optimal treatment for oligometastatic prostate cancer (OMPC) is still on its way. Accumulating evidence has proven the safety and feasibility of radical prostatectomy and local or metastasis-directed radiotherapy for oligometastatic patients. The aim of this trial is to demonstrate the safety and feasibility outcomes of metastasis-directed neoadjuvant radiotherapy (naRT) and neoadjuvant androgen deprivation therapy (naADT) followed by robotic-assisted radical prostatectomy (RARP) for treating OMPC. METHODS: The present study will be conducted as a prospective, open-label, dose-escalation, phase I/II clinical trial. The patients with oligometastatic PCa will receive 1 month of naADT, followed by metastasis-directed radiation and abdominal or pelvic radiotherapy. Then, radical prostatectomy will be performed at intervals of 4-8 weeks after radiotherapy, and ADT will be continued for 2 years. The primary endpoints of the study are safety profiles, assessed by the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 grading scale, and perioperativemorbidities, assessed by the Clavien-Dindo classification system. The secondary endpoints include positive surgical margin (pSM), biochemical recurrence-free survival (bPFS), radiological progression-free survival (RPFS), postoperative continence, and quality of life (QoL) parameters. DISCUSSION: The optimal treatment for OMPC is still on its way, prompting investigation for novel multimodality treatment protocol for this patient population. Traditionally, radical prostatectomy has been recommended as one of the standard therapies for localized prostate cancer, but indications have expanded over the years as recommended by NCCN and EAU guidelines. RP has been carried out in some centres for OMPC patients, but its value has been inconclusive, showing elevated complication risks and limited survival benefit. Neoadjuvant radiotherapy has been proven safe and effective in colorectal cancer, breast cancer and other various types of malignant tumors, showing potential advantages in terms of reducing metastatic stem-cell activity, providing clinical downstaging, and reducing potential intraoperative risks. Existing trials have shown that naRT is well tolerated for high-risk and locally-advanced prostate cancer. In this study, we hope to further determine the optimal irradiation dose and patient tolerance for genitourinary, gastrointestinal and systemic toxicities with the design of 3+3 dose escalation; also, final pathology can be obtained following RP to further determine treatment response and follow-up treatment plans. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900025743. http://www.chictr.org.cn/showprojen.aspx?proj=43065.

Short-Term Outcomes and Clinical Efficacy of Stereotactic Body Radiation Therapy (SBRT) for Oligometastases of Prostate Cancer in China.

Objective: To assess the efficacy and safety of stereotactic body radiation therapy (SBRT) in managing oligometastases of prostate cancer. Moreover, it is the largest-to-date study in China to report the safety and efficacy of SBRT by CyberKnife for oligometastases of prostate cancer. Methods: In this retrospective study, 75 patients with 108 oligometastases were treated by SBRT from May 2012 to February 2021. Among these patients, 43 patients were treated with the intention to control all known metastatic lesions and 32 were treated for palliative care. Patients received regular follow-up evaluations every 3 months. Efficacy was assessed based on local control (LC) rates, biochemical progression-free survival (bPFS), progression-free survival (PFS), and overall survival (OS). Safety was assessed based on clinical adverse events. Results: Median follow-up time was 23.2 months (1.2-106.9 months). The complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 63.0%, 10.2%, 21.3% and 5.6%, respectively. The 6-month, 1-, and 2-year LC rates were 100%, 97.5%, and 96.0% respectively while the 6-month, 1-, and 2-year bPFS rates were 74.6%, 53.3%, and 47.9%, respectively. Additionally, 6-month, 1-, and 2-year PFS rates were 77.5%, 50.8%, and 47.2%, respectively. The 6-month, 1-, and 2-year OS rates were 97.0%, 88.8%, and 87.0%, respectively. For the 15 metastatic castration-resistant prostate cancer (mCRPC) patients with 23 lesions, the 2-year LC rates were 93.8%, while for 60 metastatic hormone-sensitive prostate cancer (mHSPC) patients with 85 lesions, the 2-year LC rates were 96.7%. No predictors of LC were found after univariate analysis. In those not on androgen deprivation therapy (ADT; n = 27), the 2-year freedom from ADT was 44.0%. All of the 24 patients with oligmetastase-induced complications experienced varying degrees of alleviation after SBRT. The treatment was well tolerated. No grade 3 or higher toxicity was observed. Conclusion: SBRT is a safe and effective treatment modality in the management of oligometastases of mHSPC and mCRPC with high LC rates and acceptable toxicity. SBRT could provide a treatment choice for mCRPC, as well as an alternative to delay the start of ADT for mHSPC.

Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial.

BACKGROUND: There is paucity of investigations into immunotherapy or targeted therapy for postoperative locally recurrent pancreatic cancer. We aimed to assess the efficacy of stereotactic body radiotherapy (SBRT) plus pembrolizumab and trametinib in these patients. METHODS: In this open-label, randomised, controlled, phase 2 study, participants were recruited from Changhai Hospital affiliated to the Naval Medical University, Shanghai, China. Eligible patients were aged 18 years or older with histologically confirmed pancreatic ductal adenocarcinoma characterised by mutant KRAS and positive immunohistochemical staining of PD-L1, Eastern Cooperative Oncology Group performance status of 0 or 1, and documented local recurrence after surgery followed by chemotherapy (mFOLFIRINOX [ie, 5-fluorouracil, oxaliplatin, irinotecan, and folinic acid] or 5-fluorouracil). Eligible participants were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive SBRT with doses ranging from 35-40 Gy in five fractions, intravenous pembrolizumab 200 mg once every 3 weeks, and oral trametinib 2 mg once daily or SBRT (same regimen) and intravenous gemcitabine (1000 mg/m2) on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the as-treated population in all participants who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02704156, and is now complete. FINDINGS: Between Oct 10, 2016, and Oct 28, 2017, 198 patients were screened, of whom 170 patients were enrolled and randomly assigned to receive SBRT plus pembrolizumab and trametinib (n=85) or SBRT plus gemcitabine (n=85). As of the clinical cutoff date (Nov 30, 2020), median follow-up was 13·1 months (IQR 10·2-17·1). Median overall survival was 14·9 months (12·7-17·1) with SBRT plus pembrolizumab and trametinib and 12·8 months (95% CI 11·2-14·4) with SBRT plus gemcitabine (hazard ratio [HR] 0·69 [95% CI 0·51-0·95]; p=0·021). The most common grade 3 or 4 adverse effects were increased alanine aminotransferase or aspartate aminotransferase (ten [12%] of 85 in SBRT plus pembrolizumab and trametinib group vs six [7%] of 85 in SBRT plus gemcitabine group), increased blood bilirubin (four [5%] vs none), neutropenia (one [1%] vs nine [11%]), and thrombocytopenia (one [1%] vs four [5%]). Serious adverse events were reported by 19 (22%) participants in the SBRT plus pembrolizumab and trametinib group and 12 (14%) in the SBRT plus gemcitabine group. No treatment-related deaths occurred. INTERPRETATION: The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase 3 trials are needed to confirm our findings. FUNDING: Shanghai Shenkang Center and Changhai Hospital. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Five-year outcomes of stereotactic body radiation therapy (SBRT) for prostate cancer: the largest experience in China.

OBJECTIVE: To evaluate the efficacy and safety of SBRT for localized prostate cancer (PCa) with CyberKnife in China. Moreover, it is the largest-to-date pilot study to report 5-year outcomes of SBRT for localized PCa from China. METHODS: In this retrospective study, 133 PCa patients in our center were treated by SBRT with CyberKnife (Accuray Inc., Sunnyvale, USA) from October 2012 to July 2019. Follow-up was performed every 3 months for efficacy and toxicity evaluation. Biochemical progression-free survival (bPFS) and toxicities were assessed using the Phoenix definition and the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0, respectively. Factors predictive of bPFS were identified with COX regression analysis. RESULTS: 133 patients (10 low-, 21 favorable intermediate-, 31 unfavorable intermediate-, 45 high-, and 26 very high risk cases on the basis of NCCN risk classification) with a median age of 76 years (range 54-87 years) received SBRT. The median dose was 36.25 Gy (range 34-37.5 Gy) in 5 fractions. Median follow-up time was 57.7 months (3.5-97.2 months). The overall 5-year bPFS rate was 83.6% for all patients. The 5-year bPFS rate of patients with low-, favorable intermediate-, unfavorable intermediate-, high-, and very high risk PCa was 87.5%, 95.2%, 90.5%, 86.3%, and 61.6%, respectively. Urinary symptoms were all alleviated after SBRT. All patients tolerated SBRT with 1 (0.8%) patient reporting grade-3 acute and 1 (0.8%) patient reporting grade-3 late genitourinary (GU) toxicity, respectively. There were no grade 4 toxicities. Gleason score (P < 0.001, HR = 7.483, 95%CI: 2.686-20.846) was the independent predictor of bPFS rate after multivariate analysis. CONCLUSION: SBRT is an efficient and safe treatment modality for localized PCa with high 5-year bPFS rates and acceptable toxicities.

Stereotactic body radiation therapy with sequential S-1 for patients with locally advanced pancreatic cancer and poor performance status: An open-label, single-arm, phase 2 trial.

PURPOSE: The optimal treatment for a particularly neglected group of patients with locally advanced pancreatic cancer (LAPC) and poor performance status, who are usually excluded from most clinical trials, is required. Therefore, we aim to investigate the efficacy and safety of stereotactic body radiation therapy (SBRT) with sequential S-1 for those patients. METHODS: Eligible patients had histologically and radiographically confirmed LAPC and ECOG performance status of 2 or more points determined by two independent physicians. Radiation doses ranged from 35-40 Gy/5f. S-1 was taken orally, twice daily, at a dose of 80 mg/m2 for 28 days, followed by a 14-day interval, which repeated for 6 cycles and was initiated one month after SBRT. The primary endpoint was 1-year overall survival (OS). The secondary endpoints were OS, progression free survival (PFS), treatment-related toxicity and quality of life. The study was registered at ClinicalTrials.gov: NCT02704143. RESULTS: Sixty-three patients were enrolled. At the time of data cut-off, all patients died. No patients were lost to follow-up. Median follow-up was 15.8 months (95%CI 12.9-18.7 months). One-year OS was noted in 46 of 63 patients (73.0%, 95%CI 67.4%-78.6%). The median OS and PFS was 14.4 (95%CI 13.2-15.6 months) and 10.1 months (95%CI 9.7-10.5 months) respectively. Eighteen patients (28.6%) had grade 3 toxicity. According to Quality of Life Questionnaire-Core 30, significant improvements of abdominal pain were found, and patients with poorer baseline global health status had greater improvement of health status and pain relief after treatment. CONCLUSIONS: SBRT with sequential S-1 shows promising efficacy and acceptable toxicity in poor performance status patients with LAPC.

Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial.

BACKGROUND: There is paucity of investigations into immunotherapy or targeted therapy for postoperative locally recurrent pancreatic cancer. We aimed to assess the efficacy of stereotactic body radiotherapy (SBRT) plus pembrolizumab and trametinib in these patients. METHODS: In this open-label, randomised, controlled, phase 2 study, participants were recruited from Changhai Hospital affiliated to Naval Medical University, Shanghai, China. Eligible patients were aged 18 years or older with histologically confirmed pancreatic ductal adenocarcinoma characterised by mutant KRAS and positive immunohistochemical staining of PD-L1, Eastern Cooperative Oncology Group performance status of 0 or 1, and documented local recurrence after surgery followed by chemotherapy (mFOLFIRINOX or 5-fluorouracil). Eligible participants were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive SBRT with doses ranging from 35-40 Gy in five fractions, intravenous pembrolizumab 200 mg once every 3 weeks, and oral trametinib 2 mg once daily or SBRT (same regimen) and intravenous gemcitabine (1000 mg/m2) on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the as-treated population in all participants who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02704156, and is now complete. FINDINGS: Between Oct 10, 2016, and Oct 28, 2017, 198 patients were screen, of whom 170 patients were enrolled and randomly assigned to receive SBRT plus pembrolizumab and trametinib (n=85) or SBRT plus gemcitabine (n=85). As of the clinical cutoff date (Nov 30, 2020), median follow-up was 23·3 months (IQR 20·5-27·4). Median overall survival was 24·9 months (23·3-26·5) with SBRT plus pembrolizumab and trametinib and 22·4 months (95% CI 21·2-23·6) with SBRT plus gemcitabine (hazard ratio [HR] 0·60 [95% CI 0·44-0·82]; p=0·0012). The most common grade 3 or 4 adverse effects were increased alanine aminotransferase or aspartate aminotransferase (ten [12%] of 85 in SBRT plus pembrolizumab and trametinib group vs six [7%] of 85 in SBRT plus gemcitabine group), increased blood bilirubin (four [5%] vs none), neutropenia (one [1%] vs nine [11%]), and thrombocytopenia (one [1%] vs four [5%]). Serious adverse events were reported by 19 (22%) participants in the SBRT plus pembrolizumab and trametinib group and 12 (14%) in the SBRT plus gemcitabine group. No treatment-related deaths occurred. INTERPRETATION: The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase 3 trials are needed to confirm our findings. FUNDING: Shanghai Shenkang Center and Changhai Hospital. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Development and Validation of Multicenter Predictive Nomograms for Locally Advanced Pancreatic Cancer After Chemoradiotherapy.

OBJECTIVE: Due to common practice of hypofractionated radiotherapy in pancreatic cancer and heterogeneous chemotherapy regimens in previous studies, modified nomograms are required. Therefore, we aim to develop and validate prognostic nomograms for locally advanced pancreatic cancer (LAPC) after stereotactic body radiation therapy (SBRT) and chemotherapy. METHODS: The development cohort comprised 925 patients with LAPC receiving SBRT and gemcitabine-based chemotherapy in our center, while 297 patients from another two centers formed the validation cohort. Nomograms were created from COX models and internally validated by bootstrap. Model discriminations were evaluated by calibration plots and concordance index (C-index). A decision curve analysis (DCA) was performed to evaluate clinical benefits of nomograms. Additionally, recursive partitioning analysis (RPA) was used for stratifications of survival probability based on the total score of each patient calculated by nomograms. RESULTS: Weight loss, tumor diameter, radiation dose, CA19-9 kinetics after treatment and surgical resection were included in the nomogram for overall survival (OS), while the five factors plus performance status formed the nomogram for progression free survival (PFS). The corrected C-indexes for estimated 1-year and 2-year OS of the development cohort were 0.88 (95% CI: 0.85-0.91) and 0.86 (95% CI: 0.83-0.90). For those of the validation cohort, it was 0.88 (95% CI: 0.82-0.94) and 0.83 (95% CI: 0.74-0.91). Additionally, the corrected C-index for predicted 1-year PFS in the development and validation cohort was 0.83 (95% CI: 0.81-0.86) and 0.82 (95% CI: 0.78-0.87), respectively. The calibration plots showed good agreement of 1- and 2-year OS and 1-year PFS between the estimations and actual observations. Potential clinical benefits were demonstrated with DCA. Additionally, for 1- and 2-year OS and 1-year PFS, patients were stratified into four groups with different survival probability by RPA. CONCLUSION: The validated nomograms provided useful predictions of OS and PFS for LAPC with chemoradiotherapy.

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.

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.

Epigenetic knockdown of Notch1 inhibits hepatitis B virus X protein­induced hepatocarcinogenesis of L02/HBx cells.

The present study aimed to investigate the effects of Notch1 on the development of hepatitis B virus X protein (HBx)­induced hepatocarcinogenesis. The L02/HBx cells were transfected with a short hairpin RNA (shRNA) specially targeting Notch1 (Notch1­shRNA). The mRNA and protein expression levels of Notch1 signaling pathway­related molecules (Notch1, Hes1 and NICD) were detected after knockdown of Notch1. The effects of Notch1 knockdown on the proliferation was analyzed by Cell Counting Kit­8 assay, and cell cycle and apoptosis of L02/HBx cells in vitro were investigated by flow cytometry. The in vivo tumor xenograft model was established by subcutaneously injection of mice with Notch1­shRNA or sh­NC transfected cells. The effects of Notch1 knockdown on tumor progression in vivo were then explored by H&E staining and immunohistochemistry. The results showed that knockdown of Notch1 inhibited the activation of the Notch1 signaling pathway. In addition, decreased viability and colony formation ability of L02/HBx cells were detected along with downregulated protein expression levels of Ki­67 and PCNA (proliferating cell nuclear antigen). In addition, knockdown of Notch1 led to L02/HBx cell cycle arrest at G0/G1 phase by decreasing the expression of cyclin D1, CDK4, E2F1 and increasing the expression of p21 and retinoblastoma gene (Rb). Moreover, knockdown of Notch1 promoted the apoptosis of L02/HBx cells by activation of caspase­3 and caspase­9. In vivo experiments demonstrated that knockdown of Notch1 inhibited the tumorigenicity of L02/HBx cells. Our findings revealed that inhibition of the Notch1 signaling pathway may inhibit the development of HBx­induced hepatocellular carcinoma. Notch1 may serve as a promising therapeutic target for HCC.