Xiaofei Zhu

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.

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.

Combination of Pre-Treatment DWI-Signal Intensity and S-1 Treatment: A Predictor of Survival in Patients with Locally Advanced Pancreatic Cancer Receiving Stereotactic Body Radiation Therapy and Sequential S-1

OBJECTIVE: To identify whether the combination of pre-treatment radiological and clinical factors can predict the overall survival (OS) in patients with locally advanced pancreatic cancer (LAPC) treated with stereotactic body radiation and sequential S-1 (a prodrug of 5-FU combined with two modulators) therapy with improved accuracy compared with that of established clinical and radiologic risk models. METHODS: Patients admitted with LAPC underwent diffusion weighted imaging (DWI) scan at 3.0-T (b = 600 s/mm2). The mean signal intensity (SIb = 600) of region-of-interest (ROI) was measured. The Log-rank test was done for tumor location, biliary stent, S-1, and other treatments and the Cox regression analysis was done to identify independent prognostic factors for OS. Prediction error curves (PEC) were used to assess potential errors in prediction of survival. The accuracy of prediction was evaluated by Integrated Brier Score (IBS) and C index. RESULTS: 41 patients were included in this study. The median OS was 11.7 months (2.8-23.23 months). The 1-year OS was 46%. Multivariate analysis showed that pre-treatment SIb = 600 value and administration of S-1 were independent predictors for OS. The performance of pre-treatment SIb = 600 and S-1 treatment in combination was better than that of SIb = 600 or S-1 treatment alone. CONCLUSION: The combination of pre-treatment SIb = 600 and S-1 treatment could predict the OS in patients with LAPC undergoing SBRT and sequential S-1 therapy with improved accuracy compared with that of established clinical and radiologic risk models.

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/β = 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.

Phosphorothioate‑modified 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 (PS‑ASODN) against human telomerase reverse transcriptase (hTERT) may enhance the therapeutic effect of irradiation. However, the effect of PS‑ASODN against hTERT on the anti‑tumor effects of irradiation in liver cancer remain unclear. In the current study, Walker 256 cells were transfected with hTERT PS‑ASODN. Cell proliferation and cell viability were measured using the MTT assay and cell senescence was examined by SA‑β‑gal staining. Telomerase activity was determined by telomeric repeat amplification protocol‑polymerase chain reaction‑ELISA. Cell apoptosis was assayed by flow cytometry and DNA damage was determined by the comet assay.The PS‑ASODN was demonstrated to have an inhibitory effect on cell proliferation and accelerated effect on cell senescence by inhibiting telomerase activity. PS‑ASODN promoted the irradiation‑induced inhibition of cell viability and telomerase activity, and irradiation‑induced DNA damage and cell apoptosis via the activation of apoptosis‑associated proteins. Taken together, these results indicated that combined treatment of PS‑ASODN with irradiation significantly enhanced tumor inhibition. Therefore, PS‑ASODN provides an experimental foundation for gene therapy and is proposed for application in clinical treatment of liver cancer combined with radiotherapy.

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.

Optimization of dose distributions of target volumes and organs at risk during stereotactic body radiation therapy for pancreatic cancer with dose-limiting auto-shells

BackgroundTo identify optimization of dose distributions of target volumes and decrease of radiation doses to normal tissues during stereotactic body radiation therapy (SBRT) for pancreatic cancer with dose-limiting auto-shells.MethodsWith the same prescription dose, dose constraints of normal organs and calculation algorithm, treatment plans of each eligible patient were re-generated with 3 shells, 5 shells and 7 shells, respectively. The prescription isodose line and beam number of each patient in 3-shell, 5-shell and 7-shell plan remained the same. Hence, a triplet data set of dosimetric parameters was generated and analyzed.ResultsAs the increase of shell number, the conformal index, volumes encompassed by 100% prescription isodose line and 30% prescription isodose line significantly decreased. The new conformal index was higher in 3-shell group than that in 5-shell and 7-shell group. A sharper dose fall-off was found in 5-shell and 7-shell group compared to 3-shell group. And the tumor coverage in 7-shell was better than that of 3-shell and 5-shell. Lower D5cc of the intestine, D10cc of the stomach, Dmax of the spinal cord and smaller V10 of the spleen was confirmed in 7-shell group compared to 3-shell group.ConclusionsMore conformal dose distributions of target volumes and lower radiation doses to normal organs could be performed with the increase of dose-limiting auto-shells, which may be more beneficial to potential critical organs without established dose constraints.

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.

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.

A modified formula for dose calculations of stereotactic ablative body radiotherapy for non–small cell lung cancer

To provide a modified formula consistent with the Monte Carlo (MC) algorithm for dose calculations during stereotactic ablative body radiotherapy for non-small cell lung cancer. Seventy CyberKnife treatment plans were calculated and analyzed by MC and ray-tracing (RT) algorithms, separately. Parameters of treatment plans were compared, and those associated with differences of dose distributions were analyzed to establish a modified formula. Gross tumor volume and tumor tracking volume (TTV) were defined as the evident disease on the sequences of the window width and level of the lung and the mediastinum. Additionally, the formula was validated by another 20 plans. The prescription dose of the 90 patients was 60 Gy/5f. The RT algorithm overestimated the planning target volume (PTV) D95 by an average of 8.59 Gy and the gross tumor volume D99 by an average of 5.84 Gy. The homogeneity index of PTV was underestimated by 0.11 on average, whereas the conformity index and new conformity index was underestimated by 0.05. The RT algorithm overestimated the dose distribution to the spinal cord by 2.23 Gy, the esophagus by 1.96 Gy, the trachea by 1.89 Gy, the left-sided bronchus by 1.77 Gy, the right-sided bronchus by 1.64 Gy, and the heart by 2.16 Gy. The average whole-lung dose volumes of lung tissues and dose volumes of V5 were overestimated by 2.69 Gy and 7.52%, respectively. A power function distribution (R2 = 0.8626) was confirmed between PTV D95 and TTV volumes. PTV D95 calculated by the MC algorithm could be computed easily with TTV and PTV D95 calculated by the RT algorithm based on the formula. The modified equation was more consistent with MC algorithm than with other formula, which could be a reference to those not accessible to the MC algorithm.