Chemoradiation For Pancreatic Cancer Research Articles

The effect of spleen dose-volume parameters on lymphopenia during chemoradiotherapy for pancreatic cancer

The effect of spleen dose-volume parameters on lymphopenia during chemoradiotherapy for pancreatic cancer

External Validity of the Multicenter Randomized PREOPANC Trial on Neoadjuvant Chemoradiotherapy in Pancreatic Cancer: Outcome of Eligible but Nonrandomized Patients.

To investigate the accrual proportion and patients' reasons for not participating in the PREOPANC trial on neoadjuvant chemoradiotherapy versus immediate surgery in resectable and borderline resectable pancreatic cancer, and to compare these patients' outcomes with those of patients who had been randomized in the trial. The external validity of multicenter randomized trials in cancer treatment has been criticized for suboptimal non-representative inclusion. In trials, it is unclear how outcomes compare between randomized and nonrandomized patients. At 8 of 16 participant centers, this multicenter observational study identified validation patients, who had been eligible but not randomized during recruitment for the PREOPANC trial. We assessed the accrual proportion, investigated their most common reasons for not participating in the trial, and compared resection rates, radical (R0) resection rates, and overall survival between the validation patients and PREOPANC patients, who had been randomized in the trial to immediate surgery. In total, 455 patients had been eligible during the recruitment period, 151 of whom (33%) had been randomized. Fifty-five percent of the 304 validation patients had refused to participate. Median overall survival in the validation group was 15.2 months, against 15.5 months in the PREOPANC group (P = 1.00). The respective resection rates (76% vs 73%) and R0 resection rates (51% vs 46%) did not differ between the groups. The PREOPANC trial included a reasonable percentage of 33% of eligible patients. In terms of the outcomes survival, resection rate, and R0 resection rate, this appeared to be a representative group.

Neoadjuvant chemoradiotherapy for pancreatic cancer is beneficial, but schedules should be improved

Neoadjuvant chemoradiotherapy for pancreatic cancer is beneficial, but schedules should be improved

A prospective observational study of the clinical and pathological impact of stereotactic body radiotherapy (SBRT) as a neoadjuvant strategy of chemoradiation in pancreatic cancer.

To improve the curative resection rates and prognoses, a variety of neoadjuvant (NA) strategies have been explored in PDAC. In our institution, non-metastatic PDACs have been treated with a NA intent with induction multiagent chemotherapy and SBRT. The primary endpoint was to increase R0 resection rate. The secondary endpoints were the analysis of the clinical tolerance, the pathological response, the local control (LC) and the OS. All consecutive patients with non-metastatic PDAC underwent SBRT as part of the NA strategy were included. A total dose of 40-62Gy were delivered in 5-10 fractions. Surgery was performed after SBRT and restaging. Since February 2014 to December 2018, 45 patients were enrolled. Thirty-two patients underwent surgery (71.1%), 10 out of 15 were initially unresectable disease patients (66.75%). R0 resection rate was 93% (30 patients) and pN0 status was achieved in 20 patients (60.6%). Tumour regression grade (TRG): 12 patients with complete response or marked response (TRG 0-1: 37.5%), 16 patients with moderate response (TRG 2: 50%) and four patients with poor response (TRG 3: 12.5%). The median follow-up was 16.2m (range 6.6-59.6m) since diagnosis. The LC rate achieved was very high (95.5%). Actuarial 12 and 24m OS was 67.4% and 35.9% respectively. No grade 3 or higher toxicity related to SBRT was observed. The results are encouraging, suggesting that SBRT has a significant role in the management of these patients and further studies will be necessary to prove these findings.

Supports and Barriers to Home-Based Physical Activity During Preoperative Treatment of Pancreatic Cancer: A Mixed-Methods Study.

Physical activity and exercise appear to benefit patients receiving preoperative treatment for cancer. Supports and barriers must be considered to increase compliance with home-based exercise prescriptions in this setting. Such influences have not been previously examined. The authors used quantitative and qualitative methods to examine potential physical activity influences among patients who were prescribed home-based aerobic and strengthening exercises concurrent with preoperative chemotherapy or chemoradiation for pancreatic cancer. Physical activity was measured using exercise logs and accelerometers. Social support for exercise and perceived neighborhood walkability were measured using validated surveys. Relationships between influences and physical activity were evaluated using linear regression analyses and qualitative interviews. Fifty patients received treatment for a mean of 16 (9) weeks prior to planned surgical resection. Social support from friends and neighborhood esthetics were positively associated with physical activity (P < .05). In interviews, patients confirmed the importance of these influences and cited encouragement from health care providers and desire to complete and recover from treatment as additional motivators. Interpersonal and environmental motivators of exercise and physical activity must be considered in the design of future home-based exercise interventions designed for patients receiving preoperative therapy for cancer.

A Prospective Observational Study of the Impact of Stereotactic Body Radiotherapy (SBRT) As a Neoadjuvant Strategy of Chemoradiation in Pancreatic Cancer

Pancreatic Adenocarcinoma (PA) is the fourth most common cause of cancer death in the world, with a very poor outcome despite of modern combined therapies. At diagnosis, only 15-20% of patients have resectable disease and the positive resection margin rates and overall survival after upfront surgery for borderline tumors are reported to be 36–64% and 13–15 months (m), respectively. To improve the curative resection rates and prognoses, a variety of neoadjuvant (NA) strategies have been explored. In our institution resectable (RE), borderline (BO) and initially unresectable (UR) PA have been treated with a neoadjuvant intent with induction multiagent chemotherapy and intensification of doses of radiation with SBRT, in order to improve the prognosis by treating micrometastases, increase the response rate, the probability of a tumor R0 resection and the local control rates. All consecutive patients with non-metastatic PA underwent SBRT as part of the NA strategy were included. Serum CA19-9 levels, computed tomography (CT) scan, 18-FDG PET-CT, and endoscopic ultrasound (EU) were performed at diagnosis, before chemotherapy, SBRT and surgery. Intrapancreatic internal fiducials were located guided by EU. SBRT was delivered sequentially 3-4 weeks after induction chemotherapy with IMRT or VMAT and IGRT with intrafraction control of tumor motion with a Gating or active breathing control system. SBRT total dose of 40-62 Gy were delivered in 5 to 10 fractions. Surgery was performed at least 6 weeks after SBRT in RE patients after restaging. Since February 2014 to December 2018, 45 patients (p), with a mean age of 65 years (range 43-84 years), were evaluated. Tumor resectability prior treatment: UR 15 p (33%), BO 25 p (56%) and RE 5 p (11%). Induction chemotherapy with Nab-paclitaxel plus gemcitabine was given to 36 p (80%), 6 p received FOLFIRINOX (13.3%) and capecitabine-based chemotherapy to 2 p (4.5%) and 1p unknown (2.2%). Thirty-two p underwent surgery (71.1%), 10 out of 15 initially UR p (66.75%). R0 margins were achieved in 30 p (91%) and 20 (60.6%) pN0 status. Tumor regression grade (TRG): 12 p complete response or marked response (TRG 0 - 1: 37.5%), 16 p moderate response (TRG 2: 50%) and 4 p poor response (TRG 3: 12.5%). The median follow-up was 16.2 m (range 6.6 – 59.6 m) since diagnosis. Actuarial 12 and 24 m OS was 67.4% and 35.9% respectively. For any kind of progression disease, the actuarial progression-free survival at 12 and 24 m were, 74.6% and 58.0% respectively. Only 2 p had local relapse. No grade 3 or higher toxicity related to SBRT was observed. In our experience, pancreatic SBRT is a feasible and well-tolerated treatment. As a NA treatment, can increase tumor regression, the probability of a tumor R0 resection and the local control rates. The benefit of survival will be evaluated with longer follow up.

Adjuvant chemoradiation in pancreatic cancer: impact of radiotherapy dose on survival

BackgroundTo evaluate the impact of radiation dose on overall survival (OS) in patients treated with adjuvant chemoradiation (CRT) for pancreatic ductal adenocarcinoma (PDAC).MethodsA multicenter retrospective analysis on 514 patients with PDAC (T1–4; N0–1; M0) treated with surgical resection with macroscopically negative margins (R0–1) followed by adjuvant CRT was performed. Patients were stratified into 4 groups based on radiotherapy doses (group 1: < 45 Gy, group 2: ≥ 45 and < 50 Gy, group 3: ≥ 50 and < 55 Gy, group 4: ≥ 55 Gy). Adjuvant chemotherapy was prescribed to 141 patients. Survival functions were plotted using the Kaplan-Meier method and compared through the log-rank test.ResultsMedian follow-up was 35 months (range: 3–120 months). At univariate analysis, a worse OS was recorded in patients with higher preoperative Ca 19.9 levels (≥ 90 U/ml; p < 0.001), higher tumor grade (G3–4, p = 0.004), R1 resection (p = 0.004), higher pT stage (pT3–4, p = 0.002) and positive nodes (p < 0.001). Furthermore, patients receiving increasing doses of CRT showed a significantly improved OS. In groups 1, 2, 3, and 4, median OS was 13.0 months, 21.0 months, 22.0 months, and 28.0 months, respectively (p = 0.004). The significant impact of higher dose was confirmed by multivariate analysis.ConclusionsIncreasing doses of CRT seems to favorably impact on OS in adjuvant setting. The conflicting results of randomized trials on adjuvant CRT in PDAC could be due to < 45 Gy dose generally used.

Immune landscape of neoadjuvant/preoperative chemoradiotherapy in pancreatic cancer.

e15709 Background: Neoadjuvant/preoperative chemoradiotherapy in pancreatic cancer has been implicated to induce a local anti-tumor immunity, however the molecular mechanism remains a conundrum. Methods: Two patients’ cohort samples with/without preoperative chemoradiotherapy were used (n = 26 and n = 20, respectively). The treatment-driven immune microenvironment changes were analyzed by stratified bioinformatic approaches i.e. heat map analysis of immune-related genes selected by Gene Ontology, GSEA with Immunologic Signature data base, and Ingenuity Pathway Analysis (IPA). The results were further validated by immunohistochemical approaches. Results: Preoperative treatment induced 212 genes including DC-SIGN (CD209) and 13 immune-associated pathways such as TCR signaling, with an increasing shift of CD8 T-cell population by upregulation of MAL (T-cell differentiation protein). Consistently, immunohistochemical findings showed that the accumulation of DC-SIGN (+) dendritic cells and MAL (+) lymphocytes were significantly increased in patients with preoperative therapy. Conclusions: Preoperative chemoradiotherapy induces a shift toward CD8 T-cell generation mediated by DC-SIGN (+) dendritic cells and MAL (+) lymphocytes, leading to enhance anti-tumor immunity.

Proposition of Splenic Dose-Volume Constraints to Prevent Severe Lymphopenia after Chemoradiation for Pancreatic Cancer

Proposition of Splenic Dose-Volume Constraints to Prevent Severe Lymphopenia after Chemoradiation for Pancreatic Cancer

PO-0886: Early changes of FDG-PET markers predict the outcome after chemo-radiotherapy for pancreatic cancer

PO-0886: Early changes of FDG-PET markers predict the outcome after chemo-radiotherapy for pancreatic cancer

Treatment outcomes of concurrent hyperthermia and chemoradiotherapy for pancreatic cancer: Insights into the significance of hyperthermia treatment.

Patients with locally advanced unresectable pancreatic cancer (LAUPC) have a poor prognosis. In addition their quality of life impaired by cancer pain and biliary tract infections. Therefore, multimodality therapy and selection of optimal treatment methods are essential for achieving prolonged survival. The present study investigated the significance of using hyperthermia concurrently with multimodality therapy to improve treatment outcomes in patients with LAUPC. In total, 13 patients receiving concurrent hyperthermia and chemoradiotherapy (HCR) or chemoradiotherapy (CR) alone for LAUPC between 2002 and 2013 were analyzed retrospectively. Of the 13 patients, 5 received concurrent HCR and 8 received CR. The chemotherapy regimens were 5-fluorouracil (5-FU) in 5 patients and gemcitabine hydrochloride (GEM) in the other 8. Patients who gave consent for hyperthermia treatment received GEM plus CR. The median overall survival period for all patients was 12 months and the 1-year survival rate was 55%; the corresponding values were 12 months and 57% in the GEM CR group, and 15 months and 80% in the HCR group. Univariate analyses was perfomed to identify factors predicting recurrence after treatment. The potential prognostic factors analyzed were: Age, sex, performance status, location, tumor size, the tumor marker CA 19-9, total radiation dose, chemotherapy and hyperthermia. Univariate analysis for factors associated with outcomes revealed a significant difference favoring the HCR group [relative risk=15.97 (95% confidence interval: 12.87-19.83) P=0.021]. In conclusion, hyperthermia merits active recommendation to pancreatic cancer patients who have a positive attitude toward this treatment and whose performance status is satisfactory.

Adjuvant therapy in stage II pancreatic cancer: A National Cancer Database analysis.

283 Background: Oldfield et al (2015) showed the conflicting evidence regarding the effect of adjuvant chemotherapy vs. chemoradiation in pancreatic cancer. Using patients identified by the National Cancer Database (NCDB), we are the largest study to compare survival in stage II pancreatic cancer patients who received adjuvant chemotherapy, chemoradiation, radiation, or no adjuvant therapy. Methods: We identified 65,091 patients with stage II pancreatic cancer who received surgery only or surgery in combination with chemotherapy, radiation, or chemoradiation. Between-therapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p &lt; .05 indicated statistical significance. Results: Patient characteristics were similar between groups; although, patients receiving chemoradiation were younger, had fewer comorbidities, and were more likely to have private insurance compared to all other therapy groups. Statistically significant survival differences were indicated between all therapy groups (all adjusted p&lt; 0.05), as patients receiving chemoradiation had the longest survival followed by patients receiving chemotherapy, patients receiving radiation therapy, and patients receiving no adjuvant therapy (median survival = 22.5, 19.6, 16.9, 14.8 months, respectively). When examining other variables, patients living in an area with a median income &lt; $43,000 were 14% more likely to die compared to patients in an area with a median income ≥ $63,000 (p &lt; 0.001) and those with no comorbidities were 19% less likely to die than patients with two or more comorbidities (p &lt; 0.001). Conclusions: Our data suggests that adjuvant therapy improves median and 3-year survival compared to no adjuvant therapy. Of all adjuvant therapies examined, adjuvant chemoradiation was associated with the greatest increase in survival, followed by adjuvant chemotherapy. Table 1: Median survival and survival rates of stage II pancreatic cancer [Table: see text]

Variation in target volume and position in concurrent chemoradiotherapy for pancreatic cancer

Objective To investigate the variation in target volume and position in radiotherapy for pancreatic cancer based on contrast-enhanced three-dimensional computed tomography (3DCT) images, and to investigate the influence of radiotherapy re-planning during the treatment on doses to organs at risk. Methods Thirty-one patients with pancreatic cancer received contrast-enhanced 3DCT scans before radiotherapy and at the 15th-18th fraction. gross tumor volume (GTV) was delineated on the two sets of images. The coordinates and volume of GTV were acquired after automatic registration in the treatment planning system. Radiotherapy plan-1 and plan-2 were made based on the initial target volume (CT-1) and the target volume after 15th-18th fraction (CT-2), respectively. Plan-3 was defined by copying plan-1 to the CT-2. The results were analyzed using one-way analysis of variance and Pearson correlation analysis. Results During the treatment, the center of GTV had a significant larger displacement in the superior-inferior direction than in the right-left or anterior-posterior direction ((0.7±0.2) vs. (0.4±0.1) cm, (0.7±0.2) vs. (0.4±0.1) cm, P=0.048); the volume of GTV was significantly reduced by (27.1±17.1)%(P=0.000). The degrees of inclusion (DI) of the two GTVs were 0.6±0.2 and 0.8±0.2(P=0.000). The matching index (MI) was 0.5±0.1.The three-dimensional vector of GTV was negatively correlated with DI and MI (P=0.000, 0.000, 0.000). Compared with plan-3, the Dmean values for the liver and right kidney in plan-2 were significantly reduced by 21.9% and 14.4%, respectively (P=0.025, 0.040). Conclusions The position and volume of GTV have significant changes during conventional fractionation radiotherapy combined with concurrent chemotherapy for pancreatic cancer. Re-planning during the treatment can significantly reduce doses to the liver and right kidney. Therefore, it is necessary to perform target correction and re-planning at an appropriate time during treatment. Key words: Pancreatic cancer/radiotherapy; Tomography, X ray computed, three dimentional; Concurrent radiochemotherapy; Target position; Target volume

306 - Preliminary Results of a Phase I Study of Pharmacological Ascorbate (P-AscH–) with Gemcitabine Chemoradiotherapy in Pancreatic Cancer

P-AscH– radiosensitizes pancreatic cancer (PDAC) in vitro and in vivo. The purpose of this Phase I trial is to determine the safety and tolerability of P-AscH- when combined with gemcitabine and radiation. Patients with locally advanced PDAC who were to undergo gemcitabine and radiotherapy were enrolled (Clinical Trials.gov NCT0152890). Patients were given P-AscH– (50-100 g/daily), 5 days/week and Gemcitabine as prescribed per standard of care guidelines. Intensity modulated radiation therapy was also administered at either 50.4 Gy in 28 fractions or 50 Gy in 25 fractions. The primary endpoints were safety and tolerability of P-AscH– other co-primary endpoints were dose-limiting toxicity and maximum tolerated dose. Since June, 2014, 14 patients have enrolled and 11 have completed therapy. Both 75 gram and 100 gram infusions achieved plasma ascorbate levels of 20 mM. The adverse event most commonly attributable to P-AscH– was dry mouth during infusion. No other adverse events were observed to be greater in intensity or frequency than with gemcitabine and radiation alone. Grade 3 or greater adverse events were hematologic in nature which occurred in all patients to varying severity. One P-AscH–-related toxicity was reported with non-cardiac chest pain which did not alter ongoing treatment. Common grade 1 and 2 adverse events included chills, abdominal pain, dry mouth, fatigue, nausea, vomiting, and thrombocytopenia, all in similar frequency and intensity to chemoradiotherapy alone. Progression Free and overall survival is 10.8 months and 13.1 months, respectively, compared to 6.0 months and 11.1 months, for historical controls. Our preliminary results demonstrate that P-AscH– in combination with gemcitabine/radiation is safe and tolerable.

Neoadjuvant Therapy for Pancreatic Cancer

The purpose of this review was to assess whether neoadjuvant chemotherapy and chemoradiotherapy (CRT) result in differential postoperative morbidity and mortality as compared with pancreatic tumor resection surgery alone. Using PRISMA guidelines and the PubMed search engine, we reviewed all prospective phase II trials of neoadjuvant chemotherapy and CRT for pancreatic cancer that examined postoperative morbidities and mortalities. A total of 30 articles were identified, collated, and analyzed. Risks of postoperative complications vary based on trial. With surgery alone, the most common postoperative complications included delayed gastric emptying (DGE) (17% to 24%), pancreatic fistula (10% to 20%), anastomotic leaks (0% to 15%), postoperative bleeding (2% to 13%), and infections/sepsis (17% to 20%). With surgery alone, the mortality was <5%. Neoadjuvant chemotherapy showed comparable fistula rates (3% to 4%), leaks (3% to 11%), infection (3% to 7%), with mortality 0% to 4% in all but 1 study. CRT for resectable/borderline resectable patients also showed comparable complication rates: DGE (6% to 15%), fistulas (2% to 3%), leaks (3% to 7%), bleeding/hemorrhage (2% to 13%), infections/sepsis (3% to 19%), with 9/13 studies showing a mortality of ≤4%. As compared with initially borderline/resectable tumors, CRT for initially unresectable tumors (despite less data) showed higher complication rates: DGE (13% to 33%), fistulas (3% to 25%), infections/sepsis (3% to 16%). However, the confounding factor of the potentially higher tumor burden as an associative agent remains. The only parameters slightly higher than historical surgery-only complication rates were leaks and bleeding/hemorrhage (13% to 20%). Mortality rates in these patients were consistently 0%, with 2 outliers. Hence, neoadjuvant chemotherapy/CRT is safe from a postoperative complication standpoint, without significant increases in complication rates compared with surgery alone. Resectable and borderline resectable patients have fewer complications as compared with unresectable patients, although data for the latter are lacking.

Pre-treatment neutrophil to lymphocyte ratio as a predictive marker for pathological response to preoperative chemoradiotherapy in pancreatic cancer

An elevated neutrophil to lymphocyte ratio (NLR) has been reported to be associated with the pathological response to neoadjuvant therapies in numerous types of cancer. The aim of the current study was to clarify the association between pre-treatment NLR and the pathological response to preoperative chemoradiotherapy in pancreatic cancer patients. This retrospective analysis included data from 56 consecutive patients whose tumors were completely surgically resected. All patients received preoperative therapy, consisting of gemcitabine-based chemotherapy (alone or in combination with S-1) combined with 40 or 50.4 Gy irradiation, prior to surgery. Predictive factors, including NLR, platelet to lymphocyte ratio (PLR), modified Glasgow prognostic score and prognostic nutrition index, were measured prior to treatment. A comparison was made between those who responded well pathologically (good response group, Evans classification IIb/III) and those with a poor response (Evans I/IIa). NLR was determined to be significantly higher in the poor response group. Multivariate analysis identified an elevated NLR as an independent risk factor for the poor pathological response [odds ratio (OR), 5.35; P=0.0257]. The pre-treatment NLR (≥2.2/<2.2) was found to be a statistically significant predictive indicator of pathological response (P=0.00699). The results demonstrate that pre-treatment NLR may be a useful predictive marker for the pathological response to preoperative therapy in pancreatic cancer patients.

C-Met and ERCC1 are Prognostic in Patients Receiving Neoadjuvant or Adjuvant Chemoradiation for Pancreatic Cancer

C-Met and ERCC1 are Prognostic in Patients Receiving Neoadjuvant or Adjuvant Chemoradiation for Pancreatic Cancer

Abstract B76: Targeting Mcl-1 for radiosensitization of pancreatic cancers

Abstract In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer and, thus, improve survival in patients with locally advanced pancreatic cancer, we conducted an siRNA library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to gemcitabine-radiation. Thus, we investigated Mcl-1 inhibition by genetic (siRNA) and pharmacological (small molecule) approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA radiosensitized BxPC-3, Panc-1, and MiaPaCa-2 cells with radiation enhancement ratios (RER) of 1.5±0.06, 1.4±0.03, and 1.3±0.01, respectively, and caused Caspase-3 activation and PARP cleavage. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI-77 (Abulwerdi F et al., Mol Cancer Ther, 2014), to inhibit the anti-apoptotic functions of Mcl-1 and radiosensitize in pancreatic cancer cells. Consistent with inhibition of Mcl-1 anti-apoptotic function, UMI-77 (1-5uM) caused dissociation of Mcl-1 from the pro-apoptotic protein Bak. Under these same conditions, UMI-77 produced significant radiosensitization in BxPC-3 and Panc-1 cells (RER: 1.5±0.1 and 1.3±0.04, respectively; P&amp;lt;0.05) with minimal radiosensitization of MiaPaCa-2 cells (1.2±0.07). Since Mcl-1 expression levels are highest in BxPC-3 and Panc-1 cells and lowest in MiaPaCa-2 cells, these results suggest that elevated Mcl-1 protein levels may be a biomarker for radiosensitization by Mcl-1 inhibition. In addition, radiosensitization by UMI-77 was associated with Caspase-3 activation, PARP cleavage, and increased sub-G1 DNA content. In contrast, ABT-737, a well-established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 in radiation survival. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the efficacy of small molecules which displace Mcl-1 from Bak/Bax as radiosensitizers in pancreatic cancer. Furthermore, these results support continued investigation of UMI-77 and its analogues in animal models and in combination with gemcitabine-radiation as a strategy for radiation and chemoradiation sensitization of pancreatic cancers. Citation Format: Qiang Zhang, Dongping Wei, Jason Schreiber, Tasneem Kausar, Theodore Lawrence, Yi Sun, Zaneta Nikolovska-Coleska, Meredith A. Morgan. Targeting Mcl-1 for radiosensitization of pancreatic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B76.

Lymph node status predicts the benefit of adjuvant chemoradiotherapy for patients with resected pancreatic cancer

BackgroundThe role of adjuvant chemoradiotherapy in pancreatic cancer remains limited. The primary aim of this study was to determine the prediction of lymph node (LN) status to the benefit of adjuvant chemoradiotherapy for patients with resected pancreatic adenocarcinoma. MethodsBetween December 2010 and December 2012, a total of 152 patients undergoing curative R0 resection for pancreatic adenocarcinoma from multi-institutions were retrospectively analyzed. ResultsOverall median survival was 16.3 months. Sixty-four patients (42.1%) received adjuvant chemoradiotherapy, whereas 88 (57.9%) did not receive adjuvant therapy after surgery. Patients who received chemoradiotherapy could achieve an improved median OS compared with surgery alone (20.3 versus 13.9 months, p=0.027). Stratified by different lymph node status, multivariate analysis demonstrated the benefit of adjuvant chemoradiotherapy was only seen among patients with lymphatic positive disease (HR = 0.54, 95% CI, 0.33–0.88; p=0.014), not lymphatic negative disease (HR = 0.80, 95% CI, 0.44–1.46; p=0. 468). ConclusionsThis study suggests adjuvant chemoradiotherapy is associated with a significant improvement of survival only in patients with LN-positive disease, while the effects of chemoradiotherapy on patients with LN-negative disease may be limited. This study may add incremental knowledge of the role of lymph node status in offering treatment with adjuvant chemoradiotherapy.

Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers

In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells.