Reduction In CA19-9 Research Articles

Circulating tumor-associated antigen-specific IFNγ+4-1BB+ CD8+ T cells as peripheral biomarkers of treatment outcomes in patients with pancreatic cancer.

CD8+ T cells affect the outcomes of pancreatic ductal adenocarcinoma (PDAC). Using tissue samples at pre-treatment to monitor the immune response is challenging, while blood samples are beneficial in overcoming this limitation. In this study, we measured peripheral antigen-specific CD8+ T cell responses against four different tumor-associated antigens (TAAs) in PDAC using flow cytometry and investigated their relationships with clinical features. We analyzed the optimal timing within the treatment course for effective immune checkpoint inhibition in vitro. We demonstrated that the frequency of TAA-specific IFNγ+4-1BB+ CD8+ T cells was correlated with a fold reduction in CA19-9 before and after neoadjuvant therapy. Moreover, patients with TAA-specific IFNγ+4-1BB+ CD8+ T cells after surgery exhibited a significantly improved disease-free survival. Anti-PD-1 treatment in vitro increased the frequency of TAA-specific IFNγ+4-1BB+ CD8+ T cells before neoadjuvant therapy in patients, suggesting the importance of the timing of anti-PD-1 inhibition during the treatment regimen. Our results indicate that peripheral immunophenotyping, combined with highly sensitive identification of TAA-specific responses in vitro as well as detailed CD8+ T cell subset profiling via ex vivo analysis, may serve as peripheral biomarkers to predict treatment outcomes and therapeutic efficacy of immunotherapy plus neoadjuvant chemotherapy.

HPB P12 Do Chemotherapy Factors or Treatment Intervals Influence Pathological Tumour Response during Neoadjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma? A Bi-Institutional Study

Abstract Background Pathological response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant chemotherapy (NAT) can be assessed using grading systems such as the College of American Pathologists (CAP) system, with favourable regression being associated with improved oncological outcomes. The aim of the study was to investigate factors associated with favourable tumour regression in patients undergoing pancreatoduodenectomy (PD) for PDAC. Methods Patients who received NAT before undergoing PDAC resection at two institutions in the United Kingdom between 2013 and 2021 were reviewed. Interactions between chemotherapy regimens, tumour staging, carbohydrate antigen 19-9 (Ca19-9) levels, perioperative factors and tumour regression grading (TRG) were explored. Results 54 patients were identified who were suitable for inclusion. 12 (22%) patients had a favourable response to NAT according to the CAP grading system. A significantly greater reduction in Ca19-9 observed in the favourable TRG group [mean -2359 U/mL] compared to the unfavourable TRG group [mean -569 U/mL (p<0.001). The type of chemotherapy agent received, the number of cycles or whether the patient had a dose reduction during their NAT course did not differ significantly between the groups. The time from diagnosis to chemotherapy and time from end of chemotherapy to surgery were also similar between the groups. Conclusions In this bi-institutional retrospective study, neither chemotherapy factors nor treatment intervals were not found to be significantly related to pathological tumour response to NAT in PDAC patients undergoing resection. Given that a favourable pathological response has been related to improved oncological outcomes, future research should concentrate on further mechanisms that may influence the response of PDAC tumours to NAT, such as gene expression and the tumour microbiome. Given that NAT is also a relatively new approach, further multicentre collaboration should be encouraged to increase numbers of patients for study.

Letter to the Editor Re: Yamamoto R, Sugiura T, Ashida R, Ohgi K, Yamada M, Otsuka S, and Uesaka K. Prognostic value of carbohydrate antigen 19-9 and the surgical margin in extrahepatic cholangiocarcinoma. Ann Gastroenterol Surg. 2022; 6:307-315.

We have read with great interest a manuscript that demonstrated margin status having a significant impact on OS in the group of patients with the lowest preoperative Ca19-9 value.1 In contrast, in two other groups with increased preoperative Ca19-9, the OS rate of the R0 and R1 resection did not differ. Here we would like to comment on the hidden message of this interesting paper referring to the data which is shown exceptionally in tables and figures but is not remarked on in the article. In the presence of minimal margins, R1 dramatically worsened the survival chances in the best prognosis group and did not have an impact on medium (B) or high-risk (C) groups. Paradoxically, R1-exhibiting patients in the low-risk A group were exhibiting not only inferior OS as compared to R0 patients of their own normal group (fig. 3A) but also as compared to R1 patients in normalization (fig. 3B) or non-normalization (fig. 3C) groups. It seems that the authors initially aimed for an ambitious and difficult objective: to explore tumor marker Ca19-9 reduction achieved during the surgical intervention to evaluate the completeness of resection and to predict the prognosis of EHCC. An analysis of Table 1 reveals interesting findings. The degree of Ca19-9 reduction as a result of tumor debulking surgery was more pronounced in two higher-risk groups (also designated as “B” and “C” in some tables) as compared to the low-risk (A) group. The postoperative decline of the Ca19-9 value in the normal group can be calculated as 1.6 times reduction (from 16 to 10 U/mL); whereas it exhibited a significantly better reduction—4.1 times in the highest risk group (C). Finally, the highest reduction of Ca19-9 was seen in the B group—it exhibited 8 times decline. Nevertheless, patients in the B and C groups exhibited inferior overall survival regardless of margin status. Obviously occult distant metastasis at a time of surgical intervention in groups B and C resulted in inferior survival outcomes. The distant recurrence parameters later in time are remarkably worse in groups B and C (table 2). We would like to offer the rate of change of Ca19-9 in the early postoperative period to evaluate the completeness of surgical intervention. A specific growth rate (SGR) with negative values at the early postoperative period requires only two time points. Interestingly SGR can be compared between patients with no exact time points of blood sampling. The rate of tumor marker decline during an early postoperative period can signal the presence of positive margins or occult metastasis.2, 4 Similarly, SGR calculation following surgical resection for patients in remission3, 4 can be helpful in finding patients at risk of recurrence early. The monitoring of completeness of resection in oncology has been a point of debate over the past several decades.5 The absolute value of Ca19-9 should be less specific and less sensitive in identifying recurrence as compared to SGR, at least in theory. We are grateful for the authors providing us with many takeaways and ideas. The authors claim no conflict of interest. All the comments of this letter are in accordance with the Helsinki Declaration of 1964 and later versions.

A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma

Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor. Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P0=0.15, P1=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling. Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5-1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7-not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression. The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.

Improving Outcomes Prediction Using a Combination of MRI Wavelet Delta-Radiomic Textures and Clinical Biomarkers for MR-Guided Adaptive Radiation Therapy of Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> We have previously reported that wavelet delta radiomic features (WDRF) extracted from daily MRIs can predict treatment response of MRI-guided adaptive radiation therapy (MRgART) for pancreatic cancer. This study aims to investigate whether combining available clinical biomarkers with the WDRF would improve outcome prediction for pancreatic cancer treated with pre-operative MRgART. <h3>Materials/Methods</h3> This method was developed and demonstrated using 90 daily motion averaged MRI sets derived from 4D MRIs acquired during MRgART with concurrent chemotherapy for 18 pancreatic cancer patients treated in 5 SBRT fractions on a 1.5T MR-Linac, along with their CA19-9, CEA, metastatic status, and follow up data. For each daily MRI set, wavelet decompositions were applied a programming environment to provide a robust way for feature extraction and to overcome challenges with inter- and intra-patient MRI intensity variations. 438 WDRF were calculated from different decomposition levels. Good or bad response groups were defined based on pathological response or distant metastasis free progression, and 50% reduction in CA19-9. The time between the end of treatment and end points of death or presence of distant metastasis within 2 years were used to build progression free survival (PFS) model. Spearman correlations were applied to rule out redundant features. T-test and regression models were used to identify independent WDRFs with significant changes that correlate to response and to examine the effect of combining CA19-9, CEA, and WDRFs on response prediction. Concordance statistics was used to measure model effectiveness. A Cox analysis was performed to identify predictors of PFS and test the association of the combinations on PFS correlations. The effect of a decrease in CA19-9 or CEA levels during treatment versus failure of CA19-9 or CEA levels to normalize on PFS was examined. <h3>Results</h3> Spearman correlation showed that 67 WDRFs from different wavelet decomposition were not redundant and can be used for the analysis. 30 WDRF demonstrated opposite trends correlating to response. Of these, 8 WDRFs passed the t-test showing significant changes correlating to response by the 3rd or 4th fraction. CA199 and CEA were each correlated to 2 WDRFs. Increasing CA19-9, CEA levels during treatment were correlated to bad response. Incorporating CEA, CA19-9 with the significant WDRFs increased the concordance statistics from 0.65 to 0.96. The Cox multivariate analysis showed that a treatment related decrease in CA19-9 levels (p=0.0017), and 3 WDRFs (p=0.004-0.013) were independent predictors of PFS. The hazard ratio was reduced from 0.57, p=0.03 for using CA19-9 only to 0.163, p=0.004 for the combination of WDRFs and CA19-9. <h3>Conclusion</h3> Combining wavelet delta-radiomics features extracted from daily treatment MRIs with common clinical biomarkers improves outcome prediction for chemoradiation therapy of pancreatic cancer and may ultimately enable intensification of additional treatment to improve outcomes.

Use of Deep Learning to Predict Tumor Response to Neoadjuvant Therapy in Pancreatic Adenocarcinoma: Pure and Hybrid Modelling

Introduction: Neoadjuvant chemotherapy (NAC) is a growing treatment of pancreatic adenocarcinoma (PDAC) however, determining response to NAC is difficult from preoperative imaging. Our hypothesis is that a deep learning model can be used to predict tumor response to neoadjuvant therapy. Method: Patients with PDAC that received NAC before pancreaticoduodenectomy between November 2009 and February 2019 were identified. Computed tomography (CT) images of the entire pancreas with 5mm width were obtained. Patients were grouped by CAP-TRG grade (0-2 good response vs 3 poor response). Images were used to train a convolutional neural network (CNN) deep learning model (LeNet-type). Image augmentation was used to increase the number of images available for model creation and validation. Results: 81 patients were identified, 35 patients with good response (333 images) and 46 patients with poor response (443 images). A "training set” of 80% of patient images (n=65) was used to create the deep learning model. The model had good internal validity (100%) with loss function < 0.02. The "testing set” of 20% of patient images (n=16) was analyzed with the trained model. The AOC was 0.7383 (p< 0.0001) with Brier statistic of 0.2347. The same procedure was used to analyze patients with >10% reduction in CA19-9 after NAC (n=51). This improved the model with AOC of 0.7846 (p< 0.0001) and Brier statistic of 0.1735. Conclusion: Deep learning can be used to predict response to NAC for patients with PDAC from imaging or CA19-9 response. Further model improvements are needed before widespread clinical application.

Treatment Response Prediction Using Extracellular Volume Fraction Based on Dual Source DECT for Chemoradiation Therapy of Pancreatic Cancer

Pancreatic cancer is expected to become the 2nd leading cause of cancer-related death in the United States by 2020. Discovering reliable and accessible biomarkers for the prediction of treatment response would aid clinicians in choosing the best course of treatment. Dual-source dual energy CT (DECT) is an emerging technology which enables the derivation of Iodine density maps when a patient is simulated with contrast. From these Iodine maps and the hematocrit measured on the day of simulation, it is possible to calculate the extracellular volume (ECV) fraction, which has been correlated with patient outcome. We seek to find a correlation between the ECV fraction and change in Carbohydrate Antigen (CA) 19-9 as a surrogate for treatment response. DECT study sets acquired in the standard CT simulation on a dual source simulator for 12 pancreatic cancer patients at the late arterial contrast phase were used. Each patient was to receive a dose of 50.4 Gy in 28 fractions. The study patients were chosen based on the presence of a solid tumor in the pancreas which could be clearly delineated on the imaging sets. A region of interest was placed in the tumor and in the aorta. From the ratio of the I density calculated from the DECT in the ROI and the hematocrit taken at the time of simulation, the ECV fraction was calculated. The ECV fraction was then compared to the change in CA19-9 as calculated from a few days before and a few days after chemoradiation therapy. Distant metastases as the cause of CA 19-9 elevation was ruled out on subsequent restaging prior to surgery. The average hematocrit, ECV fraction, and change in Ca19-9 during treatment for the 12 patients was 35.9 ± 5.4%, 37.29 ± 17.3% and -5.625 ± 32.0 respectively. We found a linear correlation between the ECV fraction and the change in CA19-9 with an R2 of 0.94: ΔCA19-9 = 1.7932 × ECVfraction – 72.487 Thus, with increased ECV fraction in the tumor, the CA19-9 concentration also increased during treatment. Similarly, a reduction in CA19-9 during treatment correlated with a smaller ECV fraction. It has been shown that with a neoadjuvant treatment approach, failure to normalize CA19-9 prior to surgery is associated with reduced survival. Hence for the 12 patients, a reduced ECV fraction is correlated with treatment resistance. Therefore, ECV fraction, as calculated from Iodine maps derived from dual source DECT, may be useful as a predictor of treatment response for pancreatic cancer patients as measured by a change in the CA19-9.

Combining irreversible electroporation with a biliary composite stent implantation in treatment of unresectable hilar cholangiocarcinoma

Objective To evaluate the clinical value of combining irreversible electroporation (IRE) with a biliary composite stent implantation in the treatment of unresectable hilar cholangiocarcinoma. Methods A total of sixteen patients with unresectable hilar cholangiocarcinoma were treated in the Fifth Affiliated Hospital of Zhengzhou University, from April 2016 to July 2018 with combined IRE ablation with a 125I particle biliary composite stent implantation. A comparative analysis was conducted on the clinical data including total bilirubin, ALT, AST, myocardial enzymes before and after surgery. Results All patients underwent successful operation and the hemodynamics were stable during the operations. In 16 patients, the myocardial enzymes increased on the first day after surgery and fell to normal within 5 days. A total of thirteen patients had a progressive reduction of CA19-9, 1 patient had no significant change in CA19-9, and 2 patients had CA19-9 in the normal range before and after treatment. Total bilirubin, AST, and ALT decreased gradually after surgery in all the patients. Postoperative complications included biliary bleeding (1 patient), and ascites (1 patient). All patients were able to have the PTCD tube removed after treatment. The median time to PTCD removal was 46 days (range 11~123 days), and the median catheter-free time before requiring another PTCD tube replacement was 184 days (range 43~365 days). Conclusions IRE ablation combined with a biliary composite stent in the treatment of unresectable hilar cholangiocarcinoma was safe. The treatment had good short-term outcomes and it significantly improved the quality of life of the patients. Key words: Klatskin tumor; Bile duct neoplasms; Electroporation; Biliary stent

Comprehensive genomic analysis of metastatic pancreatic ductal adenocarcinoma (mPDAC) reveals a significant proportion of clinical actionable aberrations.

273 Background: Substantial progress has been made in the understanding of the genomic landscape of PDAC, but the clinical utility of these data remains uncertain. Methods: As part of the BC Cancer Personalized Oncogenomics (POG) and PanGen studies, whole genome analysis and transcriptome sequencing were performed on fresh biopsy and blood sample from 47 mPDAC patients. Genomic findings informed therapy choices including potential eligibility for the CCTG PM.1 molecular basket trial. Results: Cohort consists of 53% male, average age 57.8, 34/47 had ≥2 lines of treatment. 37/47 biopsies were from liver and 26/47 were collected pre-treatment. 8/47 (17%) patients had aberrations with strong evidence of clinical actionability. These include 2 germline BRCA2, 1 germline BRCA1, 1 somatic XRCC2 homozygous deletion with strong COSMIC signature 3, all predictive of platinum sensitivity. Patients with XRCC2 deletion and BRCA1 had over 2 years on FOLFIRINOX. Fusions affecting the NRG1 gene were identified in 3 patients, all with KRAS wildtype tumours, which may confer ERRB inhibitor sensitivity. 1/3 NRG1 fusion patients had thus far been treated with the ERBB inhibitor afatinib, with reduction of CA19-9 from &gt;120,000 to 7246 and dramatic response noted on PET CT imaging one month post treatment. One patient had mismatch repair deficiency, and a high mutational burden, suggestive of immune checkpoint inhibitor sensitivity. In total 85% (40/47) sequenced mPDAC patients had potentially actionable mutations which includes CCTG PM.1 trial eligibility: 24/47 with cell cycle dysregulation (CDK4/6 inhibitor arm), 4/47 with high homologous recombination defects (PARP inhibitor arm), 1/47 ERBB2 amplification (anti-HER2 arm), 2/47 high expression of FGFR1 (Sunitinib arm) and 1/47 with high FLT4 and IGF1R expression (Axitinib arm). Conclusions: More routine use of comprehensive genomic analysis should be considered in mPDAC given finding of high degree of actionability. Importantly, a significant proportion (17%) had findings with strong evidence of clinical impact.(NCT02155621, NCT02869802, NCT03297606)

Conversion surgery with gemcitabine plus nab-paclitaxel for locally advanced unresectable pancreatic cancer: A case report.

The standard treatment for locally advanced unresectable (UR-LA) pancreatic ductal adenocarcinoma (PDAC) is chemo-radiotherapy. Surgery following chemo-radiotherapy (conversion surgery), has been considered a useful strategy and has been used for UR-LA PDAC. The current study presents the case of a 43-year-old woman who complained of back pain. A radiological examination revealed a pancreatic tumor in contact with >270 degrees of the superior mesenteric artery (SMA) perimeter, with invasion extending from the superior mesenteric vein (SMV) to the portal vein (PV). An endoscopic ultrasonography-guided fine needle aspiration biopsy revealed adenocarcinoma as the pathological diagnosis and the patient was diagnosed with UR-LA PDAC. Following 12 courses of combined gemcitabine plus nab-paclitaxel (GnP) for 9 months, the extent of tumor invasion to the SMA and SMV was improved and the level of cancer antigen (CA) 19-9 decreased. A pancreatoduodenectomy with PV resection and reconstruction using a left renal vein graft were performed. Pathological examination revealed that the operative outcome was R0 (no residual tumor) resection and the patient was alive 19 months after the initial treatment (9 months post surgery), however, there was local tumor recurrence. Between March 2015 and February 2016 a total of 10 cases of UR-LA PDAC were encountered at the Department of General Surgery, Chiba University Hospital (Chiba, Japan), in which GnP therapy was performed. Including the present case, 6 of the 11 cases (55%) underwent conversion surgery with curative resection. Kaplan-Meier analysis revealed that patients treated with conversion surgery presented significantly longer overall survival (OS) than those treated with no conversion surgery (median OS, 22.5 vs. 11 months; P=0.047, Wilcoxon test). The minimum reduction of CA19-9 was 67%. In conclusion, conversion surgery following GnP therapy is a desirable option for UR-LA PDAC. A significant reduction in the CA19-9 levels may be useful in determining the timing of changeover from medicine to surgery in patients with UR-LA PDAC in whom conversion surgery is being considered.

18F-fluorodeoxyglucose positron emission tomography to indicate conversion surgery in patients with initially unresectable locally advanced pancreatic cancer.

Advances in chemotherapy and chemoradiotherapy have enabled conversion of initially unresectable locally advanced (UR-LA) pancreatic adenocarcinoma (PDAC) to a resectable disease. However, definitive criteria for conversion surgery have not been established. We evaluated the potential of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to indicate conversion surgery in patients with primary UR-LA PDAC. Twenty consecutive patients with UR-LA PDAC underwent chemoradiation or chemotherapy followed by assessment with FDG-PET. We defined PET responders (standardized uptake value <3.0) with marked reduction (>80%) of carbohydrate antigen 19-9 as potential candidates for conversion surgery. Outcomes were compared with those of the patients with resectable (R; n = 94) and borderline resectable (BR; n = 37) PDAC. Eight of the 20 patients (40%) were considered PET responders with marked reduction of CA19-9 and received conversion surgery (UR-LAR) 3-9 months (median, 5 months) after the initiation of therapy. Complete resection (R0) was achieved in 7 of 8 patients (87.5%) with UR-LAR. There was no significant difference in R0 rates, morbidity, or mortality among the UR-LAR, R and BR groups. The overall survival (OS) curve was better in the UR-LAR group than in the group that did not receive surgery. There was no significant difference in OS between the UR-LAR and the R or BR groups. FDG-PET could be a potential indicator for conversion surgery in patients with primary UR-LA PDAC and may help in selecting patients who qualify for complete surgical resection and have a promising prognosis.

Nab-paclitaxel plus S-1 as first-line treatment in patients with advanced pancreatic adenocarcinoma.

e15788 Background: Nab-paclitaxel plus gemcitabine and FOLFIRINOX showed survival advantage comparing to gemcitabine monotherapy in metastatic pancreatic cancer (PAC). However, the objective response rates (ORR) were about 30% and still unmet clinical expectation. S-1 is an oral fluoropyrimidine derivative showed comparable and superior clinical benefit in treatment of unresectable and postoperative PAC comparing to gemcitabine. Since nab-paclitaxel and S-1 provided additional clinical benefits in PAC, we conducted a single-arm, phase II trial to investigate the efficacy and safety of nab-paclitaxel plus S-1 as first-line treatment in patients with locally advanced and metastatic PAC. Methods: Nab-paclitaxel was given at 120 mg/m2 intravenously on day 1 and 8, in combination with S-1 which was orally administered (80-120 mg/d according to the body surface area) on day 1-14 of each 21-day cycle, for 6 cycles. The primary endpoint was ORR, secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: Sixty patients including 5 locally advanced and 55 metastatic PAC received a median of 4 cycles (range from 2 to 6). The ORR by either blinded independent review or investigator assessment was 50.0% (Table). Median PFS and OS were 5.7 months (95%CI, 4.9 to 6.6 m) and 9.3 months (95%CI, 8.3 to 10.3 m), respectively. The most common adverse events were neutropenia, sensory neuropathy, and nausea/vomiting. Grade 3 and 4 neutropenia were 22.3% and 11.7%, grade 3 sensory neuropathy was 5%. The patients with grade 3 and 4 neutropenia, and those with biochemical response (50% reduction of CA19-9) achieved better ORR (75% and 76.7%, respectively). Of 52 patients with elevated CA19-9 at baseline, 32 patients (61.5%) had biochemical response showed a better median OS than those without the biochemical response (15.9 m versus 5.7 m, P=0.029). Conclusions: Nab-paclitaxel plus S-1 showed encouraging ORR and being tolerated. Future phase III randomized clinical trial in advanced PAC is warranted. Clinical trial information: NCT02124317. [Table: see text]

Biweekly gemcitabine plus S-1 for locally advanced and metastatic pancreatic cancer: a preliminary feasibility study

Chemotherapy for unresectable pancreatic cancer should not only prolong survival but maintain quality of life, considering its limited life expectancy. To achieve these goals, biweekly gemcitabine plus S-1 was assessed in the clinical practice setting. Fifty-two patients with either locally advanced or metastatic pancreatic cancer who received biweekly gemcitabine plus S-1 as a first-line anti-cancer treatment were included in this study. Treatment delivery, toxicity, response, and survival were reviewed to assess the feasibility and efficacy. The completion rate of treatment delivery was 95.1%, with relative dose intensity of 97.1% for gemcitabine and 97.3% for S-1. Overall, grade 3 or worse adverse events were rare, with hematologic toxicities occurring in 5.8%. The objective response rate was 30.8%, and more than a 50% reduction of CA19-9 was observed in 77.1%. Surgical conversion was completed with a margin-negative resection in four patients whose tumor had shrunk for at least 6 months. The median progression-free and overall survivals were 10.4 and 18.2 months, respectively. Reduction of CA19-9 was associated with longer survival. Biweekly gemcitabine plus S-1 may be a good alternative to current standard chemotherapies for unresectable pancreatic cancer with less toxicity and less treatment burden without losing efficacy.

Phase II Trial of Gemcitabine, Irinotecan, and Celecoxib in Patients With Advanced Pancreatic Cancer

Cyclooxygenase-2 (COX-2) has been shown to be expressed in a variety of tumors including pancreatic cancer. The combination of gemcitabine and irinotecan is active in pancreatic cancer. The purpose of this study is to determine the toxicity and response rate to the addition of the selective oral COX-2 inhibitor, celecoxib, to gemcitabine and irinotecan in patients with inoperable pancreatic cancer. Twenty-one patients with previously untreated inoperable pancreatic cancer were entered on this trial. Seven patients had localized disease, 8 had metastatic disease, and 6 patients were inevaluable. Twenty percent of the patients had a partial response and 80% of the patients had a stable response with a median response rate of 9 months. The median overall survival was 18 months with 80% of the patients achieving 1-year survival and 20% achieving 2-year survival. Using the FACT-PA scale to measure the quality of life (QOL), 13 of the 15 patients reported an improvement in their QOL and 2 patients reported no change. The median CA19-9 levels for the 13 patients with measurable CA19-9 values, decreased by 71% by cycle 2. Adverse events were acceptable and included neutropenia, thrombocytopenia, nausea, fatigue, and anemia. The combination of gemcitabine, irinotecan, and celecoxib is an active therapy for inoperable pancreatic cancer. A marked reduction in CA19-9 is observed in all evaluable patients by cycle 2. Toxicity is tolerable and a majority of patients reported a decrease in pain and a significant improvement in their QOL.

Are serial measurements of CA19-9 useful in predicting response to chemotherapy in patients with inoperable adenocarcinoma of the pancreas?

Thirty-nine patients with inoperable adenocarcinoma of the pancreas were studied (27 male, 12 female; median age 60 years, range 39-75 years). All patients received chemotherapy with continuous infusion 5-fluorouracil with intravenous bolus epirubicin followed by cisplatin, repeated every 21 days for a total of six cycles and were evaluable for response. Serum CA19-9 concentrations were obtained at baseline and before each cycle. A rise or fall in the tumour marker was defined as a greater than 15% increase or decrease in the marker on two consecutive occasions 3 weeks apart. A plateau in the tumour marker was defined as a less than 15% decrease or increase on two occasions. Changes in marker expression were compared with serial computerized tomography scanning before treatment and after the third and sixth cycle of chemotherapy. Thirty-five of 39 patients had an elevated CA19-9 (87.9%). Thirteen (36.2%) exhibited a decrease, seven (19.4%) a plateau and 16 (44.4%) patients had a progressive rise in serum CA19-9. The sensitivity of CA19-9 was 67% for predicting a partial response and 86% for progressive disease. The median survival for the 13 patients exhibiting a reduction was 333 days, for the seven patients exhibiting a plateau 253 days and for those who had a progressive rise 185 days. The difference in median survival between the group of patients with > 15% decrease and those with > 15% increase of CA19-9 was significant (P = 0.001). In the cohort of patients who exhibited a reduction in CA19-9, no tumour progression was seen, and the reduction occurred during the first three cycles of treatment. Thus, interval scanning may be avoided in this group of patients.