Unresectable Pancreatic Cancer Patients Research Articles

Neoadjuvant FOLFIRINOX versus adjuvant gemcitabine in pancreatic cancer.

4123 Background: In the metastatic or adjuvant setting for pancreatic cancer, the combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) resulted in longer overall survival (OS) compared to gemcitabine therapy. We conducted an institutional study to compare the efficacy of neoadjuvant modified FOLFIRINOX (neo-mFOLFIRINOX) to adjuvant gemcitabine (adj-gem) for pancreatic cancer patients who completed resection. Methods: The study retrospectively enrolled patients from 2006 to 2017 from Ohio State University. While patients who received adjuvant gemcitabine were considered to be resectable upfront, patients who received neo-mFOLFIRINOX were either staged as borderline resectable (BR) or un-resectable (UR) by the institutional tumor board group. 111 patients received adj-gem (average cycles, 5.5) and 52 patients received neo-mFOLFIRINOX (average cycles, 3.5). The survival rates were determined by the Kaplan-Meier method and analyzed using Cox regression and log-rank test. Results: At a median follow up of 21.3 months, the median OS was 35.4 months in the neo-mFOLFIRINOX group and 21.8 months in the adj-gem group (hazard ratio, 0.56, 95% confidence interval (CI), 0.37-0.84 p = 0.005). The OS rate at 3 years was 46% in the neo-mFOLFIRINOX group and 22% in the adjuvant gemcitabine group (p = 0.001). The median disease free survival (DFS) was 18.6 months in the neo-mFOLFIRINOX group and 12.0 months in the adj-gem group (hazard ratio, 0.63, 95% CI, 0.43-0.93 p = 0.022). The DFS rate at 3 years was 17% in the neo-mFOLFIRINOX group and 11% in the adj-gem group (p = 0.02). On surgical pathological specimen review, the neo-mFOLFIRINOX group had statistically (p < 0.05) lower tumor grade, lower rates of perineural invasion and lymphovascular invasion, lower pathological T stage, lower pathological N stage, and lower number of nodes positive compared to the adj-gem group. Frequencies of obtaining R0 resections were higher in the neo-mFOLFIRINOX versus adj-gem groups but not statistically different (51.9% vs 40.4, p = 0.2). The average age and performance status were similar between the two groups. Conclusions: At our institution, BR and UR pancreatic cancer patients who received neo-mFOLFIRINOX and completed resection had longer OS, DFS, and more favorable pathological indicators compared to those patients who had upfront surgery and adjuvant gemcitabine. Randomized clinical trials comparing neoadjuvant versus adjuvant FOLFIRINOX are needed to validate these findings.

Effect of neoantigen reactive T cells combined with chemotherapy and radiation on survival in advanced pancreatic cancer.

e15756 Background: Pancreatic cancer (PC) is one of the most aggressive and death-relating malignancy. Gemcitabine (GEM) is the key agent in the first-line standard regimen for advanced PC, which is mostly diagnosed at advanced stage and unsuitable for curative resection. The objective responsive rate (ORR) and medium progression free survival (PFS) of various GEM-based regimens are still unsatisfied. Therefore, development of new therapeutic modalities, including immunotherapy, is needed. This study is to investigate the efficacy, safety and clinical beneficial of combination neoantigen based immunotherapy with GEM and radiotherapy in locally advanced and metastatic PC patients. Methods: Three locally advanced unresectable and seven metastatic PC patients received at least two cycles of GEM (1000mg/m2 on day 1 and day 6), radiotherapy combing with neoantigen induced DC vaccination on day 7 and cytotoxic T lymphocyte transfer from day 12 to 15 (repeated every 21 days). The locally advanced unresectable PC patients received stereotactic body radiotherapy (SBRT) with a total amount of 50-66Gy during the first cycle. For metastatic patients, their partial lesions received a low dose radiation (0.5Gy bid*2days ) on day 10 and 11 in each cycle. Results: Two cases were observed with partial remission (PR), five with stable disease (sd), and three with progressive disease (PD). The disease control rate (DCR) was 70%. Median progression free survival (PFS) was 6.4 months. After the first treatment cycle, the total effectiveness for pain easement and increasing appetite are 100% (8/8)and 66.7%, respectively. Haematotoxicities with a 40% incidence rate were the most common adverse drug reactions. Two patients had grade 1 to 2 neutropenia, two with grade 3 to 4 thrombocytopenia. Three patients suffered grade 1 to 2 gemcitabine-induced skin rash. No treatment-related mortality occurred. Conclusions: Neoantigen reactive T cells combined chemoradiotherapy demonstrated an acceptable response and safety in advanced pancreatic cancer patients.

Whole-exome sequencing in unresectable pancreatic cancer patients with long-term survival.

260 Background: Advances in technology of genomic sequencing have revealed the mutational landscape of pancreatic cancer. However, little is known with regard to molecular mechanisms underlying clinical diversity in “unresectable” advanced pancreatic cancer. Methods: We performed whole-exome sequencing using frozen cancer tissues prospectively obtained by EUS-FNA from primary tumors before chemotherapy in patients with metastatic or locally advanced pancreatic cancer (n = 35). All patients had pathological confirmation (adenocarcinoma, n = 34; carcinoma, n = 1). Somatic alterations in the cancer genome were compared with clinical outcomes. Results: Seventeen patients had metastatic disease and 18 had locally advanced disease. Thirty-four patients received chemotherapy with or without radiotherapy and one patient was treated with supportive care alone because of rapidly progressive disease. With a median follow-up time of 60.6 months (range 41.9–94.0) for censored cases, the median survival for all patients was 10.8 months. Nine patients survived more than 2 years ( > 6 years, n = 2; > 3 years, n = 3; > 2 years, n = 4), while 11 patients died within 4 months. We show mutational landscape of unresectable advanced pancreatic cancer and identified somatic mutations in known cancer related genes including KRAS (89%), TP53 (71%), SMAD4 (20%), CDKN2A (17%) and ARID1A (14%). We found that ARID1A mutation was mutually exclusive with TP53 mutation except for one tumor and had a significant correlation with survival outcomes. Among 9 patients who survived more than 2 years, 5 patients (56%) had ARID1A somatic mutation, whereas none (0%) had mutations in the remaining 26 patients who died within 2 years ( P = 0.0004). The median overall survival was 47.7 months for 5 patients with ARID1A-mutated tumors and 8.9 months for 30 patients with ARID1A wild-type tumors ( P = 0.0101). Conclusions: This is the first study to perform whole-exome sequencing in unresectable pancreatic cancer patients including very long-term survivors. We found that ARID1A mutations were associated with longer survival.

Dynamical changes of treatment patterns and outcomes of unresectable pancreatic cancer patients in real-life practice.

407 Background: Several new combination therapies, including GEM plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) has been developed for treating pancreatic ductal adenocarcinoma (PDAC) in these ten years. We investigated trends in characteristics, treatment patterns, and outcomes of unselected patients with unresectable PDAC in real-life practice in Japan. Methods: We retrospectively reviewed the medical records of 1917 patients diagnosed as having unresectable or recurrent PDAC in multiple centers in our local area between January 2009 and April 2018. Results: The median age was 74, and 53.1% were men; 27.2% had locally advanced and 67.2% metastatic disease, and 5.6% had recurrences. Oncological therapy was administered to 1295 patients (67.6%): chemotherapy (n = 1161), chemo-radiotherapy (n = 117), or radiotherapy (n = 17); the remaining patients were treated with best supportive care. Of 100 patients diagnosed in 2009, 62.0% received GEM as first-line chemotherapy; whereas 56.8% of the 266 patients diagnosed in 2017 or 2018 received GnP, 20.3% GEM, and 15.4% FFX. The objective response rates of patients treated with GnP, FFX and GEM were 16.8%, 17.6%, and 5.1%, respectively. The median time to treatment failures were 3.9, 3.6, and 2.8 months, and the overall survivals were 11.5, 11.7, and 6.5 months after GnP, FFX, and GEM, respectively. Grade 3 or greater any hematological toxicity occurred in 53.7%, 64.7%, and 34.6% of the patients treated with GnP, FFX, and GEM, respectively. The treatment discontinuation rates due to adverse events were 17.2%, 14.9% and 22.9% in the patients treated with GnP, FFX and GEM, respectively. Conclusions: Chemotherapeutic protocols changed dramatically between 2009 and 2018 in Japan. Both GnP and FFX are well-tolerable and effective in real-life practice despite high frequent adverse events.

Evaluation of Palliative Treatments in Unresectable Pancreatic Cancer Patients

Evaluation of Palliative Treatments in Unresectable Pancreatic Cancer Patients

Treatment patterns and outcomes of unresectable pancreatic cancer patients in real-life practice: a region-wide analysis.

FOLFIRINOX (FFX) and gemcitabine (GEM) plus nab-paclitaxel (GnP) have recently been available for treating pancreatic ductal adenocarcinoma (PDAC). We investigated trends in characteristics, treatment and outcomes of unselected patients with unresectable PDAC in real-life practice in Japan. We retrospectively reviewed the medical records of 1085 patients diagnosed as having unresectable or recurrent PDAC in multiple centers in the Hokuriku area between January 2009 and July 2015. The incidence of pathologically proven PDAC had increased from 18.7% in 2009 to 56.2% in 2015. Oncological therapy was administered to 779 patients (71.8%): chemotherapy (n = 675), chemo-radiotherapy (n = 92) or radiotherapy (n = 12); the remaining patients were treated with best supportive care. Of 100 patients diagnosed in 2009, 62.0% received GEM as first-line chemotherapy; whereas 30.7% of the 75 patients diagnosed in 2015 received FFX, 25.3% GnP, 22.7% GEM and 17.3% S-1. The objective response rates of patients treated with FFX, GnP and GEM were 14.9%, 35.0% and 5.5%, respectively and the OS 10.3, 9.9 and 7.5 months after FFX, GnP and GEM, respectively. Grade 3 or greater any hematological toxicity occurred in 70.2%, 70.0% and 18.8% of the patients treated with FFX, GnP and GEM, respectively. The reasons for treatment discontinuation were adverse events in 9.8%, 26.7% and 24.1% of the patients treated with FFX, GnP and GEM, respectively. Chemotherapeutic protocols changed dramatically between 2009 and 2015. Continuous collection and analysis for our cohort with longer follow-up provides useful information about treatment selection and prediction of outcome.

Association Between Opioid Use and Survival Time in Patients With Unresectable Pancreatic Cancer: 10 Years of Clinical Experience.

Patients with pancreatic cancer generally experience increasing pain as their disease progresses, making the titration of opioids difficult. This study aimed to determine a correlation between prescribed opioid doses and survival time in patients with unresectable pancreatic cancer. This retrospective observational cohort study in a tertiary care institution reviewed the medical records of patients diagnosed with unresectable pancreatic cancer and treated over a 10-year period. We screened 1152 patients with unresectable pancreatic cancer, and 566 were eligible for inclusion in this study. There was a statistically significant negative correlation between initial opioid dose and survival time from initial opioid dose (correlation coefficient, -0.184; P < 0.01) and survival time from initial pancreatic cancer diagnosis (correlation coefficient, -0.177; P < 0.01). In addition, there were 0.8% and 0.6% increases in initial opioid dosage (morphine equivalent daily dose) and rate of increasing opioid dose (morphine equivalent daily dose per month), respectively, associated with the risk of early death (≤180 days, P < 0.05). Correlations between patient survival, initial opioid dose, final opioid dose, and the rate of increase of opioid dosage could provide useful information for clinicians treating unresectable pancreatic cancer patients.

Lactic Dehydrogenase to Albumin Ratio in Prediction of Unresectable Pancreatic Cancer with Intervention Chemotherapy

To validate the prognostic value of lactic dehydrogenase to albumin ratio (LAR) in patients with unresectable pancreatic cancer treated by intervention chemotherapy. There were 139patients retrospectively analyzed in this study. The survival was depicted with Kaplan-Meier curves and calculated by log-rank test. We used Cox proportional hazards regression model with univariate and multivariate analyses, and integrated all independent risk factors to establish the nomogram. Patient with higher LAR group had poorer overall survival (OS). The Tumor, Node, Metastasis stage, carcinoembryonic antigen and LAR have been shown to be independent prognostic indicators for OS. The nomogram indicated superior predictive accuracy for OS. The preoperative LAR can be a prognostic indicator for unresectable pancreatic cancer patients with interventional therapy.

AB081. P053 Survival of unresectable pancreatic cancer patients after artery divestment combined pancreatectomy: a retrospective and propensity score-matched analysis

Background: For non-metastatic pancreatic patients, artery involvement is the major obstacle of curative operation. Here we present the oncologic effect of artery divestment in unresectable pancreatic cancer patients.

Phase I study of third-line palliative chemotherapy with low dose paclitaxel for pancreatic cancer.

The prognosis of patients with unresectable or recurrent pancreatic cancers is very poor. Prior to development of nab-paclitaxel (PTX) plus gemcitabine (GEM) therapy and FOLFIRINOX therapy, there was no recommended third-line chemotherapy after 5-fluorouracil (5-FU) and GEM-based regimens. The present study conducted a Phase I clinical trial of weekly low-dose PTX as a third-line palliative chemotherapy for patients with pancreatic cancer. PTX was administered on days 1, 8, 15, and 22 of each cycle, repeated twice as follows: Level 1, 40 mg/m2 (n=6); Level 2, 50 mg/m2 (n=4). During the two cycles, three patients developed Grade 3 neutropenia in level 2; thus, the recommended dose was defined as 40 mg/m2. The disease control rate was 40.0% (stable disease, n=4). Median time to treatment failure of the four patients with stable disease was 5.5 months. In conclusion, palliative chemotherapy with low-dose PTX after failure of GEM and 5-FU is well tolerated and safe for unresectable or recurrent pancreatic cancer patients. The unique ID issues by UMIN: 000008148.

The role of soluble TGF-beta and its dynamics for predicting the prognosis in unresectable pancreatic cancer patients treated with chemotherapy.

288 Background: Transforming growth factor-beta (TGF-β) is a multifunctional regulatory factor. Here, we measured serum soluble TGF-β (sTGF-β) levels and evaluated its dynamics and prognostic capabilities during chemotherapy in unresectable pancreatic cancer patients. Methods: Sixty patients treated with FOLFIRINOX as the first-line palliative chemotherapy were prospectively enrolled. We prospectively collected blood samples at the time of diagnosis, first response assessment, and disease progression and measured serum sTGF-β using an enzyme-linked immunosorbent assay. Results: The patients’ median overall survival (OS) and progression free survival (PFS) were 10.3 (95% confidence interval [CI], 8.5–12.1) and 6.5 (95% CI, 4.9–8.1) months, respectively. Patients with low sTGF-β at diagnosis ( &lt; 31.2ng/mL) had better OS and PFS than patients with high sTGF-β, respectively (OS, 13.7 vs. 9.2 months; hazard ratio [HR], 2.602; P =0.004; PFS, 9.0 vs. 5.8 months; HR, 2.010; P =0.034). At the time of disease progression, sTGF-β was increased compared with that of diagnosis (mean 26.4 vs. 23.9ng/mL). Especially, in patients with a partial response, sTGF-β was significantly increased at disease progression (mean 25.7 vs. 31.0ng/mL; P =0.049). Conclusions: Pre-treatment sTGF-β levels serve as a prognostic indicator in unresectable pancreatic cancer patients treated with FOLFIRINOX chemotherapy. Likewise, the dynamics of sTGF-β during chemotherapy have prognostic value.

A Real-World Comparison of FOLFIRINOX, Gemcitabine Plus nab-Paclitaxel, and Gemcitabine in Advanced Pancreatic Cancers.

FOLFIRINOX (FFN), nab-paclitaxel plus gemcitabine (GN), and gemcitabine are three systemic therapies that provide clinically meaningful benefit to patients with unresectable pancreatic cancer (UPC). There are no clinical trials that directly compare the efficacy of all three regimens. In this study, we aim to examine and compare the real-world effectiveness of these treatments. Patients diagnosed with UPC who initiated palliative chemotherapy from August 2014 to January 2016 at any one of six cancer centers in British Columbia were identified from the provincial pharmacy. Clinical, pathological, treatment, and outcome characteristics were compared. Two hundred twenty-five patients were included: 55% men, 68% Eastern Cooperative Oncology Group 0/1, 58% metastatic disease. Patients who received FFN were younger (p < 0.001) and in better performance status (p < 0.001). Patients treated with FFN or GN experienced significantly longer median overall survival (OS) when compared to those treated with gemcitabine (14.1 vs 10.5 vs 4.2months, respectively, p < 0.001). Progression-free survival (PFS) was also longer among patients on FFN or GN in comparison to gemcitabine (FFN, HR 0.44, 95% CI 0.24 to 0.814, p = 0.008; GN, HR 0.30, 95% CI 0.19 to 0.47, p < 0.001). A significantly higher proportion of patients require two or more dose modifications on FFN (40%) compared to GN (14%) or gemcitabine (9%) (p < 0.001). Receipt of modified FFN and GN portends a better prognosis than gemcitabine alone. In the absence of a randomized comparison of all three regimens, our population-based study reveals that the introduction of modified FFN and GN confers real-world effectiveness for UPC patients.

Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio as Prognostic Factors for Locally Advanced Pancreatic Cancer Patients

It is well known that locally advanced pancreatic cancer patients have a poor prognosis. Outcomes of these patients are not only determined by tumor characteristics but also by host-related factors. Recently, hematologic markers showing systemic inflammatory status such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have aroused much attention due to its potential to predict patient survival. In this study, we investigated whether pre-treatment NLR and PLR independently and combination of NLR and PLR would be significant prognostic factors for survival in locally advanced pancreatic cancer patients. A total of 497 locally advanced (borderline resectable and unresectable) pancreatic cancer patients who received neoadjuvant or definitive chemoradiotherapy (CCRT) between January 2005 and December 2015 were included in this study. NLR and PLR prior to the start of treatment within 2 weeks were defined as pre-treatment NLR and PLR. We divided the patients with the median values of pre-treatment NLR and PLR; NLR < 2.44 group (n = 248), NLR ≥ 2.44 group (n = 249), PLR < 149 group (n = 248) and PLR ≥ 149 (n = 249) group. Overall survival (OS) and progression-free survival (PFS) were compared between each group for NLR and PLR. Additionally, we grouped the patients into 3 groups concerning both factors. Patients with NLR < 2.44 and PLR < 149 (n = 175), either NLR ≥ 2.44 or PLR ≥ 149 (n = 146), and NLR ≥ 2.44 and PLR ≥ 149 (n = 176) were evaluated for OS and PFS. Median overall survival was 15.7 months (range, 2.3-128.5 months). For NLR, the OS, PFS rates were significantly lower in the NLR ≥ 2.44 group, with 1-year OS rates of 67.9% and 61.5% (p = 0.003) and 1-year PFS rates of 38.1% and 32.4% (p = 0.003), for NLR < 2.44 and ≥ 2.44 group, respectively. The PLR ≥ 149 group also showed significantly poorer OS and PFS than PLR < 149 group. The 1-year OS rates were 68.1% and 61.3% (p = 0.029) and 1-year PFS rates were 37.9% and 32.5% (p = 0.027), for PLR < 149 and ≥ 149 group, respectively. When multivariate analysis was performed, NLR ≥ 2.44 remained as a significant adverse factor for OS (p=0.007) and PFS (p=0.026). PLR > 149 also proved to be a significant factor for poorer OS (p=0.03) and PFS (0.007). When both NLR and PLR were taken into account, NLR ≥ 2.44 and PLR ≥ 149 group showed the worst OS (p=0.008) and PFS (p=0.002) compared to the other two groups and remained significant after multivariate analysis for both OS (p=0.003) and PFS (p=0.003). Elevated pre-treatment NLR and PLR independently and in combination significantly predicted poor OS and PFS. The NLR or PLR can be easily measured using peripheral blood samples. Pre-treatment NLR and PLR could be useful prognostic factors for OS and PFS in locally advanced pancreatic cancer patients.

Effect of advanced age, elevated bilirubin, and disease extent on outcomes of unresectable pancreatic cancer (UPC) patients receiving first-line chemotherapy: A population-based study.

325 Background: Superiority of FOLFIRINOX (FFN) and nab-paclitaxel plus gemcitabine (NG) over standard gemcitabine (GEM) monotherapy for UPC was shown in the PRODIGE and MPACT trials, respectively. However, both trials either excluded or limited enrollment of patients with locally advanced disease, elevated bilirubin and advanced age. We sought to determine the impact of age, bilirubin and disease extent on treatment outcomes in the real-world setting. Methods: We identified all patients newly diagnosed with UPC who received palliative chemotherapy at any 1 of 6 British Columbia Cancer Centers and the Cross Cancer Institute in Alberta from January 2014 to April 2016. Receipt of at least one cycle of chemotherapy represented treatment with group assignment based on the initial regimen delivered. Outcomes were compared while adjusting for age, bilirubin, extent of disease, and other measured confounders. Results: A total of 292 consecutive patients were identified of whom 161 (55%) were aged &gt; = 65 years, 164 (56%) were male, 74 (25%) had elevated bilirubin, and 205 (70%) had metastatic disease at the time of presentation. Patients who received FFN or NG had a longer median overall survival (OS) than those treated with GEM alone after adjusting for age, ECOG, bilirubin and extent of metastatic disease (11 vs 10 vs 4 months, respectively; FFN: HR 0.297, 95% CI 0.199-0.445, p &lt; 0.0001, and NG: HR 0.338, 95% CI 0.236 – 0.485, p &lt; 0.0001). Similarly, FFN and NG patients also had longer progression-free survival (PFS) in comparison to GEM alone (8.8 vs 6.9 vs 2.9 months, respectively; FFN: HR 0.33, 95% CI 0.22-0.499, p &lt; 0.0001, and NG: HR 0.47, 95% CI 0.33 – 0.67, p &lt; 0.0001). Advanced age and elevated bilirubin were not significantly associated with OS and PFS (p &gt; 0.05). Conclusions: The efficacy of FFN and NG were superior when compared to GEM alone for patients with UPC in the real-world setting. This population-based study showed that the benefits of FFN and NG persisted regardless of advanced age and hyperbilirubinemia.

Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as prognostic factors for locally advanced pancreatic cancer patients.

326 Background: It is well known that locally advanced pancreatic cancer patients have a poor prognosis. Recently, hematologic markers showing systemic inflammatory status such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have aroused much attention due to its potential to predict patient survival. In this study, we investigated whether pre-treatment NLR and PLR independently and in combination would be significant prognostic factors for survival in locally advanced pancreatic cancer patients. Methods: A total of 497 locally advanced (borderline resectable and unresectable) pancreatic cancer patients who received neoadjuvant or definitive chemoradiotherapy (CCRT) between January 2005 and December 2015 were included in this study. NLR and PLR prior to the start of treatment within 2 weeks were defined as pre-treatment NLR and PLR. We divided the patients with the median values of pre-treatment NLR and PLR; NLR &lt; 2.44 group (n = 248), NLR ≥ 2.44 group (n = 249), PLR &lt; 149 group (n = 248) and PLR ≥ 149 (n = 249) group. Overall survival (OS) and progression-free survival (PFS) were compared between each group for NLR and PLR. Results: Median overall survival was 15.7 months (range, 2.3-128.5 months). For NLR, the OS, PFS rates were significantly lower in the NLR ≥ 2.44 group, with 1-year OS rates of 67.9% and 61.5% (p = 0.003) and 1-year PFS rates of 38.1% and 32.4% (p = 0.003), for NLR &lt; 2.44 and ≥ 2.44 group, respectively. The PLR ≥ 149 group also showed significantly poorer OS and PFS than PLR &lt; 149 group. The 1-year OS rates were 68.1% and 61.3% (p = 0.029) and 1-year PFS rates were 37.9% and 32.5% (p = 0.027), for PLR &lt; 149 and ≥ 149 group, respectively. When multivariate analysis was performed, NLR ≥ 2.44 remained as a significant adverse factor for OS (p = 0.011) and PFS (p = 0.026). PLR &gt; 149 also proved to be a significant factor for poorer OS (p = 0.003) and PFS (p = 0.021). Conclusions: Elevated pre-treatment NLR and PLR independently and in combination significantly predicted poor OS and PFS. Pre-treatment NLR and PLR are useful prognostic factors for OS and PFS in locally advanced pancreatic cancer patients.

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

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

Abstract A19: Fundamental significance of specific KRAS mutant types for prognosis of unresectable pancreatic cancer patients

Abstract Introduction: The overall survival prognosis of patients in advanced unresectable stages of pancreatic ductal adenocarcinoma is poor, typically ranging from days to months from diagnosis. A prognostic marker would be useful in management of the disease guiding rational decisions between systemic or palliative therapy ensuring longest survival at an adequate quality of life. Due to its frequent occurrence in PDAC, prognostic value of KRAS mutation status has traditionally been studied. The results, however, were often contradictory. In the present work, we explore the role of individual KRAS mutant types in the assessment of prognosis. In addition, we explore KRAS mutation analysis from circulating tumor DNA (ctDNA) as a source material to eliminate biopsy-associated burden to the patient. Experimental: A total of 118 patients with PDAC clinically confirmed by EUS-FNAC were included in the study. DNA was extracted from FNA slides following a standard cytology evaluation to ensure adequacy (viability, quantity) and to mark tumor cell fraction. CtDNA was extracted from plasma samples of patients in Stage IV of the disease. KRAS mutations were detected by denaturing capillary electrophoresis (DCE) revealing minute presence of mutation specific hetero-duplexes. Kaplan-Meier survival curves were calculated for individual KRAS mutation types. Data Summary: KRAS mutation was detected in 90% of tissue (106/118) and in 39 % of plasma (16/41) samples. All mutations were localized at exon 2, codon 12 with Gly12Asp (GGT&amp;gt;GAT) as the most frequent at 45% (48/106) and 68% (11/16), followed by other types including Gly12Val (GGT&amp;gt;GTT) at 31% (33/106) and 13% (2/16), Gly12Arg (GGT&amp;gt;CGT) at 17% (18/106) and 6% (1/16), Gly12Cys (GGT/TGT) at 5% (5/106) and 0% (0/16) and Gly12Ser (GGT/AGT) at 1% (1/106) and 13% (2/16) in tissue and plasma samples respectively. Survival of patients with the Gly12Asp was less than a half when compared to all of the other mutation types combined (107 days vs. 218 days, P=0.002, long-rank test) in tissues. In plasma samples it was less than four times (27 days vs. 146 days, P=0,03). Conclusions: FNA-biopsy followed by cytology evaluation and molecular testing of KRAS is feasible in routine management of pancreatic cancer patients. Differentiation of specific KRAS mutation types (above all the crucial Gly12Asp) is imperative for assessment of prognosis in the rational therapy decision process. Supported by the IGA grant no. 13638 Citation Format: Lucie Benesova, Tereza Halkova, Barbora Belsanova, Bohus Bunganic, Eva Traboulsi, Miroslav Zavoral, Marek Minarik.{Authors}. Fundamental significance of specific KRAS mutant types for prognosis of unresectable pancreatic cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A19.

683P - Impact of age, bilirubin, and disease burden in unresectable pancreatic cancer patients receiving first-line chemotherapy: A population-based analysis

FOLFIRINOX (FFN), nab-paclitaxel plus gemcitabine (NG), and gemcitabine (gem) are 3 systemic therapies that provide clinically meaningful benefit to patients with unresectable pancreatic cancer (UPC). Clinical trials have previously excluded patients with advanced age, elevated bilirubin, or locally advanced disease. Our aim was to examine whether age, bilirubin, and disease extent affected treatment outcomes. Patients diagnosed with UPC who initiated palliative chemotherapy from August 2014 to August 2015 at any 1 of 5 cancer centers in British Columbia were identified from the provincial pharmacy. Clinical, pathological, treatment, and outcome characteristics were compared. 150 patients were included: 53% men, 78% ECOG 0/1, and 71% with metastatic disease. Patients who received FFN and NG were younger (p < 0.001), in better performance status (p < 0.001), and exhibited fewer metastases at presentation (p = 0.032) (Table). Bilirubin did not alter treatment selection (p = 0.502). Patients treated with FFN or NG also experienced significantly longer median overall survival (OS) when compared to those treated with gem after adjusting for confounders (11.2 vs 11.6 vs 4.1 months, respectively; FFN: HR 0.391, 95%CI 0.192-0.796, p = 0.009, and NG: HR 0.239, 95%CI 0.132-0.430, p < 0.001). Likewise, progression-free survival (PFS) was longer among patients on FFN or NG in comparison to gem. Neither advanced age nor elevated bilirubin at presentation affected OS (p >0.05). Having metastatic instead of locally advanced disease significantly impacted OS (p <0.001), especially for those on gem (p = 0.020).Tabled 1FFNNGGemP valueAge ≥6537%58%78%0.002Bilirubin >1819%19%28%0.502Metastatic disease59%78%80%0.032 Open table in a new tab Receipt of FFN and NG portended a better prognosis than gem alone. In the absence of a randomized comparison of all 3 regimens, our population-based study revealed that the introduction of modified FFN and NG confers real world effectiveness for UPC patients regardless of age and bilirubin at presentation.

Second-line chemotherapy by FOLFIRINOX with unresectable pancreatic cancer (phase I, II study).

297 Background: The purpose of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and efficacy of the second-line chemotherapy (after gemcitabine based chemotherapy) by FOLFIRINOX with unresectable pancreatic cancer. Methods: The subjects were histopathologically proven unresectable pancreatic cancer patients. The schedule was oxaliplatin 85mg/m2 on day1, irinotecan on day1, leucovorin 400mg/m2 on day 1 followed by FU 400mg/m2 as a bolus on day 1 and 2400mg/m2 as 46-hour continuous infusion biweekly. We were planned the dose of oxaliplatin, leucovorin and FU were fixed and the dose of irinotecan was defined as follows: level 0: 100mg/m2, level 1: 125mg/m2, level 2: 150mg/m2, and level 3: 180mg/m2. We started level 1 and at least three patients were enrolled at same dose two cycles. If DLT was observed two patients in six or three patients, we suspected the level was MTD. We also evaluated this study as phase II. Primary end point was response rate (RR). We also evaluated progression free survival (PFS), overall survival (OS) and adverse event (AE). Results: Eighteen patients were enrolled in this study (man: n = 11, woman: n = 7). We evaluated initial eight patients as phase I study. One patient had neutropenia and another one patient had hyperglycemia and severe infection. We decided level 1 was MTD and recommended dose was level 0. According to phase II study, RR was 22.2% (CR: n = 0, PR: n = 4, SD: n = 7, PD: n = 7) and disease control rate (DCR) was 61.1%. PFS was 2.8 (0.7-11.7) months and OS was 9.8 (2.4-14.4) months. The most common severe AE was neutropenia (66.7%). Fibril neutropenia was occurred one (5.6%) case. Conclusions: Recommended dose was oxaliplatin 85mg/m2 on day1, irinotecan 100mg/m2 on day1, leucovorin 400mg/m2 on day 1 followed by FU 400mg/m2 as a bolus on day 1 and 2400mg/m2 as 46-hour continuous infusion. RR was 22.2% and major AE was neutropenia but FN was rare. Second-line FOLFIRINOX is marginally effective treatment for gemcitabine-base chemotherapy failure cases.

Concomitant Statin Use Has a Favorable Effect on Gemcitabine-Erlotinib Combination Chemotherapy for Advanced Pancreatic Cancer

PurposeErlotinib-gemcitabine combined chemotherapy is considered as the standard treatment for unresectable pancreatic cancer. This study aimed to determine the clinical factors associated with response to this treatment.Materials and MethodsThis retrospective study included 180 patients with unresectable pancreatic cancer who received ≥2 cycles of gemcitabine-erlotinib combination therapy as first-line palliative chemotherapy between 2006 and 2014. "Long-term response" was defined as tumor stabilization after >6 chemotherapy cycles.ResultsThe median progression-free survival (PFS) and overall survival (OS) were 3.9 and 8.1 months, respectively. On univariate analysis, liver metastasis (p=0.023) was negatively correlated with long-term response. Locally advanced stage (p=0.017), a history of statin treatment (p=0.01), and carcinoembryonic antigen levels <4.5 (p=0.029) had a favorable effect on long-term response. On multivariate analysis, a history of statin treatment was the only independent favorable factor for long-term response (p=0.017). Prognostic factors for OS and PFS were significantly correlated with liver metastasis (p=0.031 and 0.013, respectively). A history of statin treatment was also significantly associated with OS after adjusting for all potential confounders (hazard ratio, 0.48; 95% confidence interval, 0.26–0.92; p=0.026).ConclusionThese results suggest that statins have a favorable effect on "long-term response" to gemcitabine-erlotinib chemotherapy in unresectable pancreatic cancer patients. Statins may have a chemoadjuvant role in stabilizing long-term tumor growth.