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At least 523 records · Page 29

Carbon-Ion Irradiation Suppresses Migration and Invasiveness of Human Pancreatic Carcinoma Cells MIAPaCa-2 via Rac1 and RhoA Degradation

Purpose: To investigate the mechanisms underlying the inhibition of cancer cell migration and invasion by carbon (C)-ion irradiation. Methods and Materials: Human pancreatic cancer cells MIAPaCa-2, AsPC-1, and BxPC-3 were treated by x-ray (4 Gy) or C-ion (0.5, 1, 2, or 4 Gy) irradiation, and their migration and invasion were assessed 2 days later. The levels of guanosine triphosphate (GTP)-bound Rac1 and RhoA were determined by the active GTPase pull-down assay with or without a proteasome inhibitor, and the binding of E3 ubiquitin ligase to GTP-bound Rac1 was examined by immunoprecipitation. Results: Carbon-ion irradiation reduced the levels of GTP-bound Rac1 and RhoA, 2 major regulators of cell motility, in MIAPaCa-2 cells and GTP-bound Rac1 in AsPC-1 and BxPC-3 cells. Proteasome inhibition reversed the effect, indicating that C-ion irradiation induced Rac1 and RhoA degradation via the ubiquitin (Ub)-proteasome pathway. E3 Ub ligase X-linked inhibitor of apoptosis protein (XIAP), which directly targets Rac1, was selectively induced in C-ion–irradiated MIAPaCa-2 cells and coprecipitated with GTP-bound Rac1 in C-ion–irradiated cells, which was associated with Rac1 ubiquitination. Cell migration and invasion reduced by C-ion radiation were restored by short interfering RNA–mediated XIAP knockdown, indicating that XIAP is involved in C-ion–induced inhibition of cell motility. Conclusion: In contrast to x-ray irradiation, C-ion treatment inhibited the activity of Rac1 and RhoA in MIAPaCa-2 cells and Rac1 in AsPC-1 and BxPC-3 cells via Ub-mediated proteasomal degradation, thereby blocking the motility of these pancreatic cancer cells.

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RECQ1 A159C Polymorphism Is Associated With Overall Survival of Patients With Resected Pancreatic Cancer: A Replication Study in NRG Oncology Radiation Therapy Oncology Group 9704

Purpose: To confirm whether a previously observed association between RECQ1 A159C variant and clinical outcome of resectable pancreatic cancer patients treated with preoperative chemoradiation is reproducible in another patient population prospectively treated with postoperative chemoradiation. Methods and Materials: Patients were selected, according to tissue availability, from eligible patients with resected pancreatic cancer who were enrolled on the NRG Oncology Radiation Therapy Oncology Group 9704 trial of 5-fluorouacil (5-FU)-based chemoradiation preceded and followed by 5-FU or gemcitabine. Deoxyribonucleic acid was extracted from paraffin-embedded tissue sections, and genotype was determined using the Taqman method. The correlation between genotype and overall survival was analyzed using a Kaplan-Meier plot, log-rank test, and multivariate Cox proportional hazards models. Results: In the 154 of the study's 451 eligible patients with evaluable tissue, genotype distribution followed Hardy-Weinberg equilibrium (ie, 37% had genotype AA, 43% AC, and 20% CC). The RECQ1 variant AC/CC genotype carriers were associated with being node positive compared with the AA carrier (P=.03). The median survival times (95% confidence interval [CI]) for AA, AC, and CC carriers were 20.6 (16.3-26.1), 18.8 (14.2-21.6), and 14.2 (10.3-21.0) months, respectively. On multivariate analysis, patients with the AC/CC genotypes were associated with worse survival than patients with the AA genotype (hazard ratio [HR] 1.54, 95% CI 1.07-2.23, P=.022). This result seemed slightly stronger for patients on the 5-FU arm (n=82) (HR 1.64, 95% CI 0.99-2.70, P=.055) than for patients on the gemcitabine arm (n=72, HR 1.46, 95% CI 0.81-2.63, P=.21). Conclusions: Results of this study suggest that the RECQ1 A159C genotype may be a prognostic or predictive factor for resectable pancreatic cancer patients who are treated with adjuvant 5-FU before and after 5-FU-based chemoradiation. Further study is needed in patients treated with gemcitabine to determine whether an association exists.

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Predictors of Locoregional Failure and Impact on Overall Survival in Patients With Resected Exocrine Pancreatic Cancer

Purpose: Resection of exocrine pancreatic cancer is necessary for cure, but locoregional and distant relapse is common. We evaluated our institutional experience to better understand risk factors for locoregional failure (LRF) and its impact on overall survival (OS). Methods and Materials: We reviewed 1051 consecutive patients with nonmetastatic exocrine pancreatic cancer who underwent resection at our institution between March 1987 and January 2011. Among them, 458 had adequate follow-up and evaluation for study inclusion. All patients received adjuvant chemotherapy (n=80 [17.5%]) or chemoradiation therapy (n=378 [82.5%]). Chemotherapy and chemoradiation therapy most frequently consisted of 6 cycles of gemcitabine and 50.4 Gy in 28 fractions with concurrent 5-fluorouracil, respectively. Locoregional control (LRC) and OS were estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed with Cox proportional hazards regression models incorporating propensity score. Results: Median patient age was 64.5 years (range: 29-88 years). Median follow-up for living patients was 84 months (range: 6-300 months). Extent of resection was R0 (83.8%) or R1 (16.2%). Overall crude incidence of LRF was 17% (n=79). The 5-year LRC for patients with and without radiation therapy was 80% and 68%, respectively (P=.003; hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.28-0.76). Multivariate analysis, incorporating propensity score, indicated radiation therapy (P<.0001; HR: 0.23; 95% CI: 0.12-0.42) and positive lymph node ratio of ≥0.2 (P=.02; HR: 1.78; 95% CI: 1.10-2.9) were associated with LRC. In addition, LRF was associated with worse OS (P<.0001; HR: 5.0; 95% CI: 3.9-6.3). Conclusions: In our analysis of 458 patients with resected pancreatic cancer, positive lymph node ratio of ≥0.2 and no adjuvant chemoradiation therapy were associated with increased LRF risk. LRF was associated with poor OS. Radiation therapy should be considered as adjuvant locoregional treatment following pancreatic cancer resection.

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Lymphocyte-Sparing Effect of Stereotactic Body Radiation Therapy in Patients With Unresectable Pancreatic Cancer

Purpose: Radiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC). Methods and Materials: Serial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariate and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival. Results: Thirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm{sup 3}) than in CRT (344.6 cm{sup 3}; P<.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC <500 cells/mm{sup 3} vs 13.8% of SBRT patients; P<.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002). Conclusions: SBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

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Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation

Purpose: To review outcomes of locally advanced pancreatic cancer (LAPC) patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with curative intent. Methods and Materials: A total of 200 patients with LAPC were treated with induction chemotherapy followed by chemoradiation between 2006 and 2014. Of these, 47 (24%) having tumors >1 cm from the luminal organs were selected for dose-escalated IMRT (biologically effective dose [BED] >70 Gy) using a simultaneous integrated boost technique, inspiration breath hold, and computed tomographic image guidance. Fractionation was optimized for coverage of gross tumor and luminal organ sparing. A 2- to 5-mm margin around the gross tumor volume was treated using a simultaneous integrated boost with a microscopic dose. Overall survival (OS), recurrence-free survival (RFS), local-regional and distant RFS, and time to local-regional and distant recurrence, calculated from start of chemoradiation, were the outcomes of interest. Results: Median radiation dose was 50.4 Gy (BED = 59.47 Gy) with a concurrent capecitabine-based (86%) regimen. Patients who received BED >70 Gy had a superior OS (17.8 vs 15.0 months, P=.03), which was preserved throughout the follow-up period, with estimated OS rates at 2 years of 36% versus 19% and at 3 years of 31% versus 9% along with improved local-regional RFS (10.2 vs 6.2 months, P=.05) as compared with those receiving BED ≤70 Gy. Degree of gross tumor volume coverage did not seem to affect outcomes. No additional toxicity was observed in the high-dose group. Higher dose (BED) was the only predictor of improved OS on multivariate analysis. Conclusion: Radiation dose escalation during consolidative chemoradiation therapy after induction chemotherapy for LAPC patients improves OS and local-regional RFS.

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Carbon Ion Radiation Therapy With Concurrent Gemcitabine for Patients With Locally Advanced Pancreatic Cancer

Purpose: To determine, in the setting of locally advanced pancreatic cancer, the maximum tolerated dose of carbon ion radiation therapy (C-ion RT) and gemcitabine dose delivered concurrently and to estimate local effect and survival. Methods and Materials: Eligibility included pathologic confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent gemcitabine was administered on days 1, 8, and 15, and the dose levels were escalated from 400 to 1000 mg/m{sup 2} under the starting dose level (43.2 GyE) of C-ion RT. The dose levels of C-ion RT were escalated from 43.2 to 55.2 GyE at 12 fractions under the fixed recommended gemcitabine dose determined. Results: Seventy-six patients were enrolled. Among the 72 treated patients, dose-limiting toxicity was observed in 3 patients: grade 3 infection in 1 patient and grade 4 neutropenia in 2 patients. Only 1 patient experienced a late grade 3 gastric ulcer and bleeding 10 months after C-ion RT. The recommended dose of gemcitabine with C-ion RT was found to be 1000 mg/m{sup 2}. The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m{sup 2}) was safely increased to 55.2 GyE. The freedom from local progression rate was 83% at 2 years using the Response Evaluation Criteria in Solid Tumors. The 2-year overall survival rates in all patients and in the high-dose group with stage III (≥45.6 GyE) were 35% and 48%, respectively. Conclusions: Carbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer.

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Quantitative Analysis of {sup 18}F-Fluorodeoxyglucose Positron Emission Tomography Identifies Novel Prognostic Imaging Biomarkers in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy

Purpose: To identify prognostic biomarkers in pancreatic cancer using high-throughput quantitative image analysis. Methods and Materials: In this institutional review board–approved study, we retrospectively analyzed images and outcomes for 139 locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy (SBRT). The overall population was split into a training cohort (n=90) and a validation cohort (n=49) according to the time of treatment. We extracted quantitative imaging characteristics from pre-SBRT {sup 18}F-fluorodeoxyglucose positron emission tomography, including statistical, morphologic, and texture features. A Cox proportional hazard regression model was built to predict overall survival (OS) in the training cohort using 162 robust image features. To avoid over-fitting, we applied the elastic net to obtain a sparse set of image features, whose linear combination constitutes a prognostic imaging signature. Univariate and multivariate Cox regression analyses were used to evaluate the association with OS, and concordance index (CI) was used to evaluate the survival prediction accuracy. Results: The prognostic imaging signature included 7 features characterizing different tumor phenotypes, including shape, intensity, and texture. On the validation cohort, univariate analysis showed that this prognostic signature was significantly associated with OS (P=.002, hazard ratio 2.74), which improved upon conventional imaging predictors including tumor volume, maximum standardized uptake value, and total legion glycolysis (P=.018-.028, hazard ratio 1.51-1.57). On multivariate analysis, the proposed signature was the only significant prognostic index (P=.037, hazard ratio 3.72) when adjusted for conventional imaging and clinical factors (P=.123-.870, hazard ratio 0.53-1.30). In terms of CI, the proposed signature scored 0.66 and was significantly better than competing prognostic indices (CI 0.48-0.64, Wilcoxon rank sum test P<1e-6). Conclusion: Quantitative analysis identified novel {sup 18}F-fluorodeoxyglucose positron emission tomography image features that showed improved prognostic value over conventional imaging metrics. If validated in large, prospective cohorts, the new prognostic signature might be used to identify patients for individualized risk-adaptive therapy.

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A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

Purpose: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

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In Vivo Imaging Reveals Significant Tumor Vascular Dysfunction and Increased Tumor Hypoxia-Inducible Factor-1α Expression Induced by High Single-Dose Irradiation in a Pancreatic Tumor Model

Purpose: To investigate the effect of high-dose irradiation on pancreatic tumor vasculature and microenvironment using in vivo imaging techniques. Methods and Materials: A BxPC3 pancreatic tumor xenograft was established in a dorsal skinfold window chamber model and a subcutaneous hind leg model. Tumors were irradiated with a single dose of 4, 12, or 24 Gy. The dorsal skinfold window chamber model was used to assess tumor response, vascular function and permeability, platelet and leukocyte adhesion to the vascular endothelium, and tumor hypoxia for up to 14 days after 24-Gy irradiation. The hind leg model was used to monitor tumor size, hypoxia, and vascularity for up to 65 days after 24-Gy irradiation. Tumors were assessed histologically to validate in vivo observations. Results: In vivo fluorescence imaging revealed temporary vascular dysfunction in tumors irradiated with a single dose of 4 to 24 Gy, but most significantly with a single dose of 24 Gy. Vascular functional recovery was observed by 14 days after irradiation in a dose-dependent manner. Furthermore, irradiation with 24 Gy caused platelet and leukocyte adhesion to the vascular endothelium within hours to days after irradiation. Vascular permeability was significantly higher in irradiated tumors compared with nonirradiated controls 14 days after irradiation. This observation corresponded with increased expression of hypoxia-inducible factor-1α in irradiated tumors. In the hind leg model, irradiation with a single dose of 24 Gy led to tumor growth delay, followed by tumor regrowth. Conclusions: Irradiation of the BxPC3 tumors with a single dose of 24 Gy caused transient vascular dysfunction and increased expression of hypoxia-inducible factor-1α. Such biological changes may impact tumor response to high single-dose and hypofractionated irradiation, and further investigations are needed to better understand the clinical outcomes of stereotactic body radiation therapy.

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Stereotactic Body Radiation Therapy for Locally Advanced Pancreatic Cancer: A Systematic Review and Pooled Analysis of 19 Trials

Purpose: Although surgery is the standard of care for resectable pancreatic cancer (PC), standard-dose chemoradiation therapy and chemotherapy alone are suitable for patients with unresectable disease. Stereotactic body radiation therapy (SBRT) is an alternative, focused local therapy that delivers high radiation doses within a few fractions to the cancer, sparing the surrounding critical tissue. We performed a systematic review and pooled analysis of published trials to evaluate the efficacy and safety of this emerging treatment modality. Methods and Materials: We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, SCOPUS, the Web of Science, and CINAHL for publications regarding SBRT for locally advanced PC. The 1-year overall survival (OS) rate was the primary endpoint, and the median OS, 2-year OS rate, 1-year locoregional control (LRC) rate, and grade 3 to 4 toxicities were the secondary endpoints. A multivariate random-effects meta-analysis was performed to calculate the aggregated OS rates at 1 and 2 years and the 1-year LRC rate. Results: A total of 19 studies, encompassing 1009 patients, were included in the present analysis. The pooled 1-year OS was 51.6% in 13 trials with data available. The median OS ranged from 5.7 to 47 months (median 17). The LRC rate at 1 year was 72.3%. Overall, the occurrence of severe adverse events did not exceed 10%. LRC appeared to correlate with the total SBRT dose and the number of fractions. Conclusions: The advantages of SBRT in terms of treatment time, satisfactory OS, and LRC indicate that it is an effective option for inoperable PC. However, a definitive validation of this treatment modality in large randomized studies is required, owing to the nonrandomized nature of the included studies and the limitations of small single-center series that include mixed populations.

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Does Unintentional Splenic Radiation Predict Outcomes After Pancreatic Cancer Radiation Therapy?

Purpose: To determine whether severity of lymphopenia is dependent on radiation dose and fractional volume of spleen irradiated unintentionally during definitive chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC). Methods: 177 patients with LAPC received induction chemotherapy (mainly gemcitabine-based regimens) followed by CRT (median 50.4 Gy with concurrent capecitabine) from January 2006 to December 2012. Absolute lymphocyte count (ALC) was recorded at baseline, before CRT, and 2 to 10 weeks after CRT. Splenic dose-volume histogram (DVH) parameters were reported as mean splenic dose (MSD) and percentage of splenic volume receiving at least 5- (V5), 10- (V10), 15- (V15), and 20-Gy (V20) dose. Overall survival (OS) was analyzed with use of the Cox model, and development of post-CRT severe lymphopenia (ALC <0.5 K/UL) was assessed by multivariate logistic regression with use of baseline and treatment factors. Results: The median post-CRT ALC (0.68 K/UL; range, 0.13-2.72) was significantly lower than both baseline ALC (1.42 K/UL; range, 0.34-3.97; P<.0001) and pre-CRT ALC (1.32 K/UL, range 0.36-4.82; P<.0001). Post-CRT ALC <0.5 K/UL was associated with inferior OS on univariate analysis (median, 11.1 vs 15.3 months; P=.01) and multivariate analysis (hazard ratio = 1.66, P=.01). MSD (9.8 vs 6 Gy, P=.03), median V10 (32.6 vs 16%, P=.04), V15 (23.2 vs 9.5%, P=.03), and V20 (15.4 vs 4.6%, P=.02) were significantly higher in patients with severe lymphopenia than in those without. On multivariate analysis, postinduction lymphopenia (P<.001; odds ratio [OR] = 5.25) and MSD (P=.002; OR= 3.42) were independent predictors for the development of severe post-CRT lymphopenia. Conclusion: Severe post-CRT lymphopenia is an independent predictor of poor OS in LAPC patients receiving CRT. Higher splenic doses increase the risk for the development of severe post-CRT lymphopenia. When clinically indicated, assessment of splenic DVHs before the acceptance of treatment plans may minimize the risk of severe post-CRT lymphopenia.

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Management of Borderline Resectable Pancreatic Cancer

With the rapid development of imaging modalities and surgical techniques, the clinical entity representing tumors that are intermediate between resectable and unresectable pancreatic adenocarcinoma has been identified has been termed “borderline resectable” (BR). These tumors are generally amenable for resection but portend an increased risk for positive margins after surgery and commonly necessitate vascular resection and reconstruction. Although there is a lack of consensus regarding the appropriate definition of what constitutes a BR pancreatic tumor, it has been demonstrated that this intermediate category carries a particular prognosis that is in between resectable and unresectable disease. In order to downstage the tumor and increase the probability of clear surgical margins, neoadjuvant therapy is being increasingly utilized and studied. There is a lack of high-level evidence to establish the optimal treatment regimen for BR tumors. When resection with negative margins is achieved after neoadjuvant therapy, the prognosis for BR tumors approaches and even exceeds that for resectable disease. This review presents the current definitions, different treatment approaches, and the clinical outcomes of BR pancreatic cancer.

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Dose Prediction Model for Duodenum Sparing With a Biodegradable Hydrogel Spacer for Pancreatic Cancer Radiation Therapy

We previously have shown the feasibility of duodenum sparing using a biodegradable hydrogel spacer in pancreatic cancer radiation therapy. In this study, we propose an overlap volume histogram (OVH) prediction model to select patients who might benefit from hydrogel placement and to predict the hydrogel spacing required to achieve clinical constraints.

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Impact of Diabetes and Insulin Use on Prognosis in Patients With Resected Pancreatic Cancer: An Ancillary Analysis of NRG Oncology RTOG 9704

Diabetes mellitus (DM) has been proposed to be tumorigenic; however, prior studies of the association between DM and survival are conflicting. The goal of this ancillary analysis of RTOG 9704, a randomized controlled trial of adjuvant chemotherapy in pancreatic cancer, was to determine the prognostic effects of DM and insulin use on survival.

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A Phase 1 Dose Escalation Study of Neoadjuvant SBRT Plus Elective Nodal Radiation with Concurrent Capecitabine for Resectable Pancreatic Cancer

The role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach.

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