Search

B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m 2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 10 7 /m 2 ) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 10 7 /m 2 ). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7-10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Patients with pancreatic neuroendocrine tumors (PNET) commonly develop advanced disease and require systemic therapy. However, treatment options remain limited, in part, because experimental models that reliably emulate PNET disease are lacking. We therefore developed a patient-derived xenograft model of PNET (PDX-PNET), which we then used to evaluate two mTOR inhibitor drugs: FDA-approved everolimus and the investigational new drug sapanisertib. PDX-PNETs maintained a PNET morphology and PNET-specific gene expression signature with serial passage. PDX-PNETs also harbored mutations in genes previously associated with PNETs (such as MEN1 and PTEN ), displayed activation of the mTOR pathway, and could be detected by Gallium-68 DOTATATE PET-CT. Treatment of PDX-PNETs with either everolimus or sapanisertib strongly inhibited growth. As seen in patients, some PDX-PNETs developed resistance to everolimus. However, sapanisertib, a more potent inhibitor of the mTOR pathway, caused tumor shrinkage in most everolimus-resistant tumors. Our PDX-PNET model is the first available, validated PDX model for PNET, and preclinical data from the use of this model suggest that sapanisertib may be an effective new treatment option for patients with PNET or everolimus-resistant PNET., (©2018 American Association for Cancer Research.)

Purpose: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis., Patients and Methods: Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines., Results: The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70-0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63-0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor., Conclusion: Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients., Competing Interests: The authors have declared that no competing interests exist.

Importance: Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported., Objective: To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting., Design, Setting, and Participants: A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014., Interventions: Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy., Main Outcomes and Measures: Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate., Results: The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration., Conclusions and Relevance: The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients., Trial Registration: clinicaltrials.gov Identifier: NCT01821612., Competing Interests: Disclosures: None reported.

Objectives: In mouse models of pancreatic cancer, IPI-926, an oral Hedgehog inhibitor, increases chemotherapy delivery by depleting tumor-associated stroma. This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic cancer., Methods: Patients were treated with once-daily IPI-926 plus FOLFIRINOX. A 3 + 3 dose escalation design was used, with cohort expansion at the maximum tolerated dose. A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion., Results: The maximum tolerated dose was identified 1 dose level below standard FOLFIRINOX. Common treatment-related adverse events included liver function test abnormalities, neuropathy, nausea/vomiting, and diarrhea. Objective response rate was high (67%), and patients receiving IPI-926 maintenance showed further declines in CA19-9 levels even after FOLFIRINOX discontinuation. Treatment did not result in consistent increases in tumor perfusion. The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination., Conclusions: This is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design. Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen, future development of Hedgehog inhibitors in pancreatic cancer seems unlikely.

Purpose: On the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors in pancreatic ductal adenocarcinoma (PDAC), we evaluated the safety and efficacy of selumetinib, a MEK1/2 inhibitor, plus erlotinib in patients with previously treated advanced PDAC., Experimental Design: In this single-arm phase II trial, eligible patients received the combination of erlotinib 100 mg plus selumetinib 100 mg daily in 3-week cycles. Study assessments included measurement of clinical outcomes, with a primary endpoint of overall survival, and exploration of potential molecular predictors of treatment benefit., Results: Forty-six patients were enrolled and received a median of two cycles (range, 1-7). Although no objective responses were observed, 19 patients (41%) showed evidence of stable disease for ≥6 weeks, and 13 of 34 patients (38%) had a CA19-9 decline ≥50%. Median progression-free survival was 1.9 months [95% confidence interval (CI), 1.4-3.3 months], with a median overall survival of 7.3 months (95% CI, 5.2-8.0 months). Common adverse events included rash, diarrhea, and nausea/vomiting. Patients with tumors exhibiting an epithelial phenotype (demonstrated by a high level of E-cadherin expression) were more likely to be sensitive to study treatment. Tumor-derived DNA was detectable in plasma from the majority of patients using next-generation digital DNA sequencing, and its relative abundance correlated with tumor burden., Conclusions: A therapeutic strategy of dual targeted inhibition of the MEK and EGFR pathways shows modest antitumor activity in pancreatic cancer. Specific molecular subtypes may derive greatest benefit from this combination. Further exploration, both with more potent MEK inhibitors and in molecularly enriched patient subsets, is warranted., (©2015 American Association for Cancer Research.)

Background: Data from animal and cell-line models suggest that vitamin D metabolism plays an important role in pancreatic tumor behavior. Although vitamin D deficiency has been implicated in numerous cancers, the vitamin D status of patients with advanced pancreatic cancer and the effect of baseline vitamin D levels on survival are unknown., Methods: Participants in this correlative study (CALGB 151006) were enrolled in CALGB 80303, which was a randomized trial of patients with advanced pancreatic cancer that demonstrated no difference in overall survival (OS) among patients treated with gemcitabine plus placebo vs gemcitabine plus bevacizumab. We measured baseline serum 25-hydroxyvitamin D (25[OH]D) levels and examined associations between baseline 25(OH)D levels and progression-free survival and OS using the Cox rank score test. All statistical tests were two-sided., Results: Of 256 patients with available serum, the median 25(OH)D level was 21.7ng/mL (range 4 to 77). 44.5% of patients were vitamin D deficient (25[OH]D <20ng/mL), and 32.4% were insufficient (25[OH]D ≥20 and <30ng/mL). 25(OH)D levels were lower in black patients compared with white patients, and patients of other/undisclosed race (10.7 vs 22.4 vs 20.9ng/mL, P < .001). Baseline 25(OH)D levels were not associated with PFS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .60) or OS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .95)., Conclusion: Vitamin D deficiency was highly prevalent among patients with a new diagnosis of advanced pancreatic cancer. Black patients had statistically significantly lower 25(OH)D levels than white patients. In this cohort of patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: CALGB80303 was a phase III trial of 602 patients with locally advanced or metastatic pancreatic cancer comparing gemcitabine/bevacizumab versus gemcitabine/placebo. The study found no benefit in any outcome from the addition of bevacizumab to gemcitabine. Blood samples were collected and multiple angiogenic factors were evaluated and then correlated with clinical outcome in general (prognostic markers) and with benefit specifically from bevacizumab treatment (predictive markers)., Experimental Design: Plasma samples were analyzed via a novel multiplex ELISA platform for 31 factors related to tumor growth, angiogenesis, and inflammation. Baseline values for these factors were correlated with overall survival (OS) using univariate Cox proportional hazard regression models and multivariable Cox regression models with leave-one-out cross validation. Predictive markers were identified using a treatment by marker interaction term in the Cox model., Results: Baseline plasma was available from 328 patients. Univariate prognostic markers for OS were identified including: Ang2, CRP, ICAM-1, IGFBP-1, TSP-2 (all P < 0.001). These prognostic factors were found to be highly significant, even after adjustment for known clinical factors. Additional modeling approaches yielded prognostic signatures from multivariable Cox regression. The gemcitabine/bevacizumab signature consisted of IGFBP-1, interleukin-6, PDGF-AA, PDGF-BB, TSP-2; whereas the gemcitabine/placebo signature consisted of CRP, IGFBP-1, PAI-1, PDGF-AA, P-selectin (both P < 0.0001). Finally, three potential predictive markers of bevacizumab efficacy were identified: VEGF-D (P < 0.01), SDF1 (P < 0.05), and Ang2 (P < 0.05)., Conclusion: This study identified strong prognostic markers for pancreatic cancer patients. Predictive marker analysis indicated that plasma levels of VEGF-D, Ang2, and SDF1 significantly predicted for benefit or lack of benefit from bevacizumab in this population., (©2013 AACR.)

Background: Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included an absence of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy., Methods: In this manuscript, we review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A021101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed., Results: We identified twenty-three studies published since 2001 which report outcomes of patients with tumors labeled as borderline resectable and who were treated with neoadjuvant therapy prior to planned pancreatectomy. These studies were heterogeneous in terms of the populations studied, the metrics used to characterize therapeutic response, and the indications used to select patients for surgery. Mechanisms used to standardize these and other issues that are incorporated into Alliance A021101 are reviewed., Conclusions: Rigorous standards of clinical trial design incorporated into trials of other disease stages must be adopted in all future studies of borderline resectable pancreatic cancer. The Intergroup trial should serve as a paradigm for such investigations.

Objectives: This multisite study sought to optimize the dosing, schedule, and administration of fixed-dose rate (FDR) gemcitabine plus capecitabine for advanced pancreatic and biliary tract cancers using an alternating-week dose schedule of both agents., Methods: Patients with previously untreated advanced pancreatic and biliary tract cancers with Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. For the dose-finding portion, a standard 3+3 dose-escalation schema was used, with the gemcitabine dose kept at 1000 mg/m(2) administered by FDR (10 mg/m(2)/min) on day 1 of each 14-day cycle, and capecitabine given on days 1 to 7 at doses ranging from 800 to 1500 mg/m(2) twice daily. Primary study objective was determination of maximum tolerated dose (MTD). The cohort at MTD was expanded for further efficacy assessment., Results: A total of 45 patients (median age 61 y; 93% pancreatic/7% biliary; 84% with metastatic disease) were enrolled. Median number of cycles received was 11.5. The MTD using this dose schedule was FDR gemcitabine 1000 mg/m(2) plus capecitabine 1000 mg/m(2) bid, due to a high incidence of late hand-foot syndrome observed at the next higher dose level. Most common nonhematologic adverse events related to treatment included nausea/vomiting (overall rate, 64%; all grade 1/2) and hand-foot syndrome (overall rate, 60%; grade 3, 22%). The incidence of grade 3/4 hematologic adverse events was 24%. Six of 41 evaluable patients (14.6%) had a partial response; 18 of 31 patients (58%) with elevated baseline CA 19-9 level had ≥50% biomarker decline during treatment. Estimated median time to tumor progression and overall survival were 5.5 and 9.8 months, respectively (5.5 and 10.1 mo in the metastatic pancreatic cancer cohort)., Conclusions: This dosing schedule of FDR gemcitabine plus capecitabine is active in patients with advanced pancreatobiliary cancers. Given its favorable toxicity profile and convenience, this regimen represents an appropriate front-line option for this patient population and may serve as the foundation on which new investigational agents are added in future trial design.

Objectives: The decision to perform pancreas-preserving procedures or standard resections for pancreatic neuroendocrine tumors (PNETs) is often based on the perceived risk of malignancy, including potential nodal involvement. We sought to identify clinicopathological factors that predict nodal disease., Methods: This is a retrospective review of pathology database for PNET resections from January 1, 1988, to March 15, 2010. Univariate analysis and multivariate logistic regression were used to identify predictors of nodal metastasis., Results: A total of 149 patients were identified. Enucleations had lower lymph node sampling rates compared to major resections. Excluding enucleations, 23% of patients had no lymph nodes sampled. For patients who did have lymph nodes evaluated, a median of 5 lymph nodes were examined. On multivariate analysis, only distant disease predicted nodal metastasis (odds ratio = 3.80, P = 0.02); tumor size did not (P = 0.48). One third of patients with lymph node metastasis had tumors less than 3 cm., Conclusions: Lymph nodes are not evaluated in many major pancreatic resections for PNET, and preoperative prediction of nodal metastasis is difficult, even when tumor size is considered. Consequently, many patients may be understaged and undergo potentially inadequate resection. Inconsistent lymph node sampling may explain conflicting conclusions in the literature regarding the prognostic value of lymph node involvement in PNET patients.

Background: Patients with advanced stage adenocarcinoma of the pancreas have a poor prognosis. The identification of prognostic and/or predictive biomarkers may help stratify patients so that therapy can be individualized., Methods: Serum samples from patients enrolled in the Cancer and Leukemia Group B 80303 phase 3 trial, "Randomized Study of Gemcitabine With Versus Without Bevacizumab in Patients With Locally Advanced or Metastatic Adenocarcinoma of the Pancreas" were used to discover novel biomarkers. For the discovery phase, 40 sera were selected based on length of survival and type of therapy, and subjected to liquid chromatography coupled to tandem mass spectrometry analysis (LC-MS-MS). The top features (proteins) were then further selected for validation by enzyme-linked immunosorbent assay (ELISA)., Results: Quantification by nano-LC-MS-MS resulted in 1452 peptides mapping to 156 proteins across all 40 samples, 92 of which had 2 or more peptides. After curation of the data, the authors selected 1 putative prognostic protein, alpha 1-antichymotrypsin (AACT), and 2 putative predictive proteins, histidine-rich glycoprotein (HRG) and complement factor H (CFH), for validation by ELISA. AACT was found to be negatively correlated with overall survival (τ = -0.30 [-0.38, -0.22]; P < .00001). There was no evidence for interaction with bevacizumab and HRG, but there was some evidence for a weak positive correlation of HRG with overall survival (τ = 0.11 [0.03, 0.19]; P < .01). CFH was found to be neither a predictive nor a prognostic factor for overall survival., Conclusions: AACT may be a useful prognostic marker in patients with advanced stage pancreatic carcinoma, although additional validation studies are needed., (Copyright © 2011 American Cancer Society.)

Purpose: No standard of care exists for patients with metastatic pancreatic cancer following progression on first-line chemotherapy. Based on potential for additive or synergistic activity by concurrent inhibition of VEGF and EGFR, we conducted a phase II study evaluating the combination of bevacizumab plus erlotinib in this patient population., Methods: Patients with metastatic pancreatic adenocarcinoma, ECOG performance status 0-1, and previous exposure to 1-3 systemic therapies (at least one gemcitabine-based) were eligible. Treatment consisted of bevacizumab 15 mg/kg every 21 days plus erlotinib 150 mg daily., Results: Thirty-six patients were enrolled, including eight who had previously received VEGF-targeted therapy and nine prior erlotinib. Median number of treatment cycles was 2 (range, 1-7). Common toxicities included rash (72%), diarrhea (25%), venous thromboembolic events (15%), and hypertension (11%). One patient demonstrated partial response and seven others stable disease for >2 cycles. CA19-9 decline ≥25% was observed in 4/26 patients with baseline levels >2x ULN. Estimated median time to progression was 40 days (95% CI, 35-41 days) and median survival 102 days (95% CI, 74-117 days), with a 6-month survival rate of 22%. Baseline concentration of circulating endothelial cells (CD45(-)/CD34(+)/CD31(+)) was inversely associated with overall survival., Conclusions: The combination of bevacizumab and erlotinib is safe but relatively ineffective in patients with gemcitabine-refractory metastatic pancreatic cancer. Future studies should focus on refining subsets of patients in this challenging population likely to benefit from treatment beyond first-line.

Objective: Serum carbohydrate antigen 19-9 (CA19-9) has never been compared to radiographic objective response as a surrogate for clinical outcomes in patients receiving chemotherapy for metastatic pancreatic cancer., Methods: We compared CA19-9 decline to objective response as surrogate end points for both time to progression (TTP) and overall survival (OS) in patients with metastatic pancreatic cancer receiving fixed-dose rate gemcitabine., Results: A total of 75 patients from 2 studies were eligible for analysis. Significant correlations were observed between maximum CA19-9 decline and both TTP (P < 0.0001) and OS (P < 0.0001). Median OS was 12.2 months for patients with more than a 75% decline in CA19-9, 7.5 months for those with 0% to 75% decline, and 3.5 months for those with no decline. Correlations between best radiographic response and both TTP (P < 0.0001) and OS (P=0.0013) were also observed. Median OS was 12.8 months for patients with partial or complete response, 8.0 months for those with stable disease, and 4.6 months for those with progressive disease., Conclusions: CA19-9 decline compares favorably with objective response as a strong predictor of TTP and OS. CA19-9 could represent amore cost-effective tool for the evaluation of new therapies and guidance of clinical management in patients with metastatic pancreatic cancer.

Background: The role of bevacizumab, a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor, in the treatment of pancreatic cancer remains unclear. The objectives of this study were to determine safety and efficacy in chemotherapy-naive patients with metastatic pancreatic cancer receiving bevacizumab in combination with fixed-dose rate (FDR) gemcitabine and low-dose cisplatin., Methods: Eligible patients received gemcitabine 1,000 mg/m2 at FDR infusion (10 mg/m(2) per minute), cisplatin 20 mg/m(2), and bevacizumab 10 mg/kg, on days 1 and 15 of a 28-day cycle. Patients were monitored by computed tomography scans every two cycles and monthly serum CA19-9 measurements., Results: Of 52 patients eligible for analysis, ten (19.2%) had an unconfirmed response and 30 (57.7%) had stable disease. Of 35 patients with elevated baseline CA19-9 levels, 20 (57.1%) had > or = 50% biomarker decline during treatment. Median time to tumor progression was 6.6 months and median survival was 8.2 months (estimated 1-year survival, 36%). Grade 3/4 toxicities possibly related to bevacizumab included thromboembolic events (15.1%), hypertension (13.2%), gastrointestinal bleeding (9.4%), cardiac events (7.5%), and bowel perforation (5.7%). Plasma vascular endothelial growth factor and basic fibroblast growth factor levels and circulating tumor cell concentration did not correlate with overall survival, either at baseline or after 2 months of therapy., Conclusions: This bevacizumab-containing study regimen is modestly effective in patients with metastatic pancreatic cancer, although occasional serious complications may occur. Given the negative results of CALGB 80303, future efforts should be focused on identifying those specific patients who are most likely to benefit from bevacizumab-based therapy.

Background: No therapeutic standard of care exists for patients with advanced pancreatic cancer who progress following first-line treatment with a gemcitabine-based regimen. There is evidence of synergistic activity between docetaxel and irinotecan, and the combination of these two agents has shown promising efficacy in the first-line setting for advanced pancreatic cancer. We, therefore, evaluated this regimen in patients with gemcitabine-refractory disease., Methods: Eligible patients with metastatic pancreatic adenocarcinoma were required to have an elevated serum CA19-9 (> 2x ULN) and exposure to one or two prior chemotherapy regimens, including one gemcitabine-based. Treatment consisted of docetaxel 65 mg/m2 and irinotecan 160 mg/m2, both administered every 21 days. Serum CA19-9 levels were measured at the start of each treatment cycle and CT scans performed after every two cycles., Results: Fourteen patients were enrolled before the study was closed due to excess toxicity. The most common grade 3/4 toxicities included neutropenia/leukopenia, nausea and vomiting, and diarrhea. Fully half of patients received only 1 treatment cycle, with a median time to treatment failure of 36 days. No objective responses were observed, although 3 patients had stable disease for at least 6 cycles. Overall survival for the entire cohort was 134 days, with a 6-month survival rate of 36%., Conclusions: The combination of docetaxel and irinotecan given on a 21-day cycle is associated with excess toxicity in gemcitabine-refractory patients with advanced pancreatic cancer. Although select patients may benefit from treatment, the overall risk:benefit ratio is unfavorable, and other dosing regimens and therapeutic options should be explored in this setting.

Purpose: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population., Methods and Materials: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m(2) at 10 mg/m(2)/min) plus cisplatin 20 mg/m(2) on Days 1 and 15 of a 28-day cycle. Those without evidence of extrapancreatic metastases after six cycles of chemotherapy received radiation (5,040 cGy over 28 fractions) with concurrent capecitabine (800 mg/m(2) orally twice daily on the day of radiation) as a radiosensitizer., Results: A total of 25 patients were enrolled with a median follow-up time of 656 days. Twelve patients (48%) successfully received all six cycles of chemotherapy plus chemoradiation. Eight patients (32%) progressed during chemotherapy, including 7 with extrapancreatic metastases. Grade 3/4 hematologic toxicities were uncommon. Two patients sustained myocardial infarctions during chemotherapy, and 4 were hospitalized for infectious complications, although none in the setting of neutropenia. Median time to progression was 10.5 months and median survival was 13.5 months, with an estimated 1-year survival rate of 62%. Patients receiving all components of therapy had a median survival of 17.0 months., Conclusions: A strategy of initial fixed-dose rate gemcitabine-based chemotherapy, followed by chemoradiation, shows promising efficacy for treatment of locally advanced disease. A substantial proportion of patients will be identified early on as having extrapancreatic disease and spared the potential toxicities associated with radiation.

Purpose: Although gemcitabine remains the standard of care for patients with advanced pancreatic cancer, additional improvements may be realized by combining therapeutic agents with synergistic activity, and optimizing drug delivery using pharmacokinetic principles such as fixed dose rate (FDR) infusion. The objectives of this study were to determine safety and efficacy in patients with metastatic pancreatic cancer treated with FDR gemcitabine in combination with low-dose cisplatin., Patients and Methods: Chemotherapy-naive patients with metastatic pancreatic adenocarcinoma were treated with a combination of gemcitabine 1,000 mg/m2 at 10 mg/m2/min together with cisplatin 20 mg/m2 on days 1 and 8 of a 21-day cycle. Patient follow-up was performed using computerized tomographic scans and serial CA 19-9 measurements., Results: A total of 51 patients were enrolled onto the study, with a median follow-up time of 215 days. Twenty-two of 40 patients (55.0%) with a baseline serum CA 19-9 level > or = 2x the upper limit of normal demonstrated a > or = 50% biomarker decline during treatment. Nine of 47 patients (19.1%) with measurable disease achieved a partial response, and 28 patients (59.6%) had disease stabilization for at least two treatment cycles. Median time to progression was 3.9 months and median survival was 7.1 months, with an estimated 1-year survival rate of 29%. The most frequently reported grade 3 or 4 adverse events were neutropenia (52.9%) and thrombocytopenia (15.7%). Most patients were switched to an every-other-week dosing schedule., Conclusion: The combination of FDR gemcitabine and cisplatin is well tolerated and appears to be an acceptable, albeit not clearly superior, alternative to other gemcitabine/platinum regimens for the treatment of metastatic pancreatic cancer.

The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (> 75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P < 0.001). Using specific thresholds, patients with > or = 25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P < 0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.