Inoperable Pancreatic Cancer Research Articles

Combined modality therapy for pancreatic carcinoma: An Australian Pancreatic Cancer Group study of the addition of gemcitabine (G) to concurrent infusional 5-fluorouracil (CI 5FU) and 3D conformal radiotherapy (RT)—Final outcomes

4104 Background: This open-label Phase II study (B9E-AY-S168) examined whether CI 5FU plus 3D conformal planning RT is well tolerated and may be combined with G pre and post chemoradiotherapy in patients (pts) with pancreatic cancer (PC). Methods: Eligible pts were enrolled in two strata: (1) inoperable PC in head or body without metastases (LAD) or (2) resected PC at high risk of relapse (Surg). G was given at 1000 mg/m2 weekly for 3 wks followed by 1 wk rest and a 5–6 wk period of RT and concurrent CI 5FU (200 mg/m2/day). The defined target volume was treated to 54Gy in 30# of 1.8Gy (LAD) or 45Gy in 25# (Surg). After 4 wks rest, G was given for 12 wks. Results: 63 pts were enrolled: 39 females, 24 males; mean age 61 yr, range 31–79; 43% ECOG PS 0, 51% PS 1, 5% PS 2. Follow-up was 2 yr. 1- and 2-yr survival (KM) were 46% and 10% (LAD) and 59% and 27% (Surg). 1- and 2-yr local control (KM) were 48% and 21% (LAD) and 80% and 80% (Surg). The % planned dose delivered was (i) G pre RT: 87.6% (LAD)/94.6% (Surg); (ii) 5FU: 100.7%/96.4%; (iii) RT: 96.2%/99.5%; (iv) G post RT: 67.4%/65.3%. The baseline CA 19.9 level was significantly associated with a shorter TTPD (p=0.0002) and a shorter survival time (p=0.0071). Using Time Dependent Covariate analysis, CA 19.9 levels were strongly associated with TTPD and survival (both p < 0.0001); a person with a 10-fold higher level has a 1.95-fold higher risk of death over the next time period than their counterpart (95% CI: 1.53–2.49-fold). In 22 pts we found no statistically significant associations between outcome and mutations in K-RAS or TP53 or with microsatellite instability. Grade 3/4 hematological and non-hematological toxicity was reported by 29 (46%) and 42 pts (67%), respectively. There was one treatment-related death. Conclusions: This approach to treatment is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomized trial. [Table: see text] [Table: see text]

Phase II study evaluating trimodal therapy with cetuximab intensity modulated radiotherapy (IMRT) and gemcitabine for patients with locally advanced pancreatic cancer [ISRCTN56652283

4100 Background: The induction of EGFR targeting with cetuximab in radiation based therapy of solid tumors has yielded promising results. Thus, we initiated a prospective Phase II trial designed to analyze the feasibility and effectivity of trimodal therapy with gemcitabine-based chemoradiation and cetuximab in locally advanced inoperable pancreatic cancer. Methods: In this phase 2 study, pts with locally advanced pancreatic cancer without prior cytotoxic therapy were treated with radiotherapy (RT), gemcitabine weekly (300 mg/m2), and cetuximab weekly (loading dose 400 mg/m2 day 1, and concomitant with radiation day 8,15,22,29,36 250 mg/m2). RT was delivered by using an integrated IMRT boost concept (54 Gy GTV, 45 Gy CTV) over 5 weeks. RT was followed by gemcitabine (1000 mg/m2) weekly × 3 in 4 weeks. Response evaluation using computed tomography followed at week 12. All amenable patients were intended for surgical treatment between week 12–15. Results: 24 pts were enrolled until now. Preliminary results are presented on 20 pts with the following characteristics: pancreatic adenocarcinoma c2 T4 N1 20/20, median age = 63.5 (range 51–79); M/F = 13/7; ECOG PS 0/1/2 = 2/12/6; median days on treatment: 90 (range 70–100). Treatment-related toxicities were observed in 16 pts. Grade 3 toxicities included diarrhea (n = 4), fatigue (n = 2), nausea (n = 3), neutropenia (n = 6), thrombocytopenia (n = 2), and vomiting (n = 2). 18/20 pts developed some acneiforme rush during therapy. No omittance of cetuximab therapy was necessary. 1 patient died during RT due to tumor bleeding. Median follow-up at present is 6 month, median survival has not been reached. Partial remissions 8/20, stable disease 9/20, progressive disease 3/20. 12/20 patients were amenable for secondary potentially curative resection. 4 patients could be resected, while 3 patients were found to have abdominal metastatic spread. Conclusions: Early data from trimodal therapy in pancreatic adenocarcinoma with chemoradiation (IMRT), gemcitabine, and cetuximab indicate feasibility without increased toxicity profile. The local response appears to be very promising in pancreatic cancer, potentially allowing neoadjuvant treatment. [Table: see text]

A Prospective Study of Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis Combined with Local Chemotherapy for Pancreatic Cancer Pain

Objective: Since the general condition of patients in advanced stage pancreatic cancer is usually too poor to tolerate traditional intravenous chemotherapy, a EUS guide local chemotherapy was developed in order to get long-term control of abdominal pain. The aim of this study was to evaluate the long-term effect of EUS-guided celiac plexus neurolysis combined with local chemotherapy on abdominal pain associated with pancreatic cancer. Methods: Twenty-three patients with painful and inoperable pancreatic cancer were evaluated at before and 20 weeks after EUS celiac plexus neurolysis combined with local chemotherapy. EUS CPN was performed with a linear array echoendoscope (Pentax EG3630U, Pentax Precision Instruments) Under direct EUS visualization, After injecting 2 mL of saline solution to clear the needle adjacent and anterior to the lateral aspect of the aorta at the level of the celiac trunk, 10 mL of dehydrated 98% absolute alcohol was injected. The process was then repeated on the opposite side of the aorta. EUS guide local chemotherapy was performed with the same echoendoscope and aspiration needle. Under direct EUS visualization, 1 mg/ml Cisplatin (DDP) solution was injected into tumor tissues directly. The total dose of DDP was about 15 mg for tumors which diameters were less than 40 millimeter, while for tumors larger than 40 millimeter, the total dose increased to 20 mg. Pain scores were assessed with a standardized 11-point continuous visual analog pain scale. Results: The study population consisted of 18 men and 5 women (mean age 57 years; range 48 to 67 years). Of the 23 patients enrolled, 7 had the tumor located in the head of the pancreas, 13 in the body or the tail, and 3 patients had diffuse pancreatic involvement. There were no major complications in both the EUS CPN and EUS guide local chemotherapy. Five patients had transient abdominal pain after the procedure, which persisted less than 48 hours and was relieved by an increase in the dosage of pain medication. 10 patients suffered with male nausea and vomiting after chemotherapy, no bone marrow depression was founded. Overall pain scores decreased significantly after EUS CPN combined with EUS guide local chemotherapy. There were no statistically significant changes of the diameters of the tumors before and after the treatment procedure. Conclusion EUS-guided celiac plexus neurolysis combined with local chemotherapy is effective and safe in long-term control of abdominal pain associated with pancreatic cancer. Potential benefits of this procedure require further investigation to identify advantages of this approach over conventional general intravenous chemotherapy.

Aged Garlic Extract Prevents a Decline of NK Cell Number and Activity in Patients with Advanced Cancer

Aged garlic extract (AGE) has manifold biological activities including immunomodulative and antioxidative effects. It is used as a major component of nonprescription tonics and cold-prevention medicines or dietary supplements. Advanced-cancer patients decline in immune functions and quality of life (QOL). The study's subjects were patients with inoperable colorectal, liver, or pancreatic cancer. In a randomized double-blind trial, AGE was administered to one group and a placebo was administered to another for 6 mo. The primary endpoint was a QOL questionnaire based on the Functional Assessment of Cancer Therapy (FACT). The subendpoints were changes in the natural-killer (NK) cell activity the salivary cortisol level from before and after administering AGE. Out of 55 patients invited to participate in the trial, 50 (91%) consented to enroll. They consisted of 42 patients with liver cancer (84%), 7 patients with pancreatic cancer (14%), and 1 patient with colon cancer (2%). Drug compliance was relatively good in both the AGE and placebo groups. Although no difference was observed in QOL, both the number of NK cells and the NK cell activity increased significantly in the AGE group. No adverse effect was observed in either group. The study showed that administering AGE to patients with advanced cancer of the digestive system improved NK cell activity, but caused no improvement in QOL.

CA 19-9 as a Prognostic Factor in Inoperable Pancreatic Cancer: The Implication for Clinical Trials

CA 19-9 as a Prognostic Factor in Inoperable Pancreatic Cancer: The Implication for Clinical Trials

Gemcitabine-related radiation recall in a patient with pancreatic cancer

Radiation recall refers to inflammatory reactions triggered by chemotherapeutic agents and develops cutaneously in the previously irradiated areas. Such agents include anthracyclines, taxanes and capecitabine. Radiation recall related to gemcitabine has been reported in lung and breast cancer. Similar phenomenon associated with gemcitabine, the only FDA-approved drug for pancreatic cancer, is rarely reported. We report a patient with inoperable pancreatic cancer who developed gastrointestinal bleeding secondary to radiation-recall related to gemcitabine and review literature. A 57-year-old white male with unresectable pancreatic cancer received capecitabine in combination with radiation therapy followed by capecitabine alone given over approximately a 3-month time period. Computed tomography re-evaluation demonstrated a new liver lesion. The patient was then treated with gemcitabine and irinotecan. On day 15 of cycle 1, he reported progressive worsening of weakness and fatigue, and melena. Physical examination revealed hypotension (84/47 mmHg) and heme-positive stool on rectal examination. He denied aspirin or non-steroidal anti-inflammatory drug use. Chemotherapy was held. Hematocrit was 20% (previously 33%). He was transfused with 3 units of packed red blood cells. An esophago-gastro-duodenal examination was performed which showed antritis and duodenitis consistent with radiation therapy. A single site of oozing was injected with epinephrine. The diffuse gastritis was aggressively treated with proton pump inhibitors. The patient's hematocrit eventually stabilized and was 30% at discharge. Gemcitabine was not resumed. Radiation recall from gemcitabine is rare, but can potentially arise in any site that has been previously irradiated. Gemcitabine should be added to the list of drugs known to cause radiation recall. Treating physicians must be aware of this potential toxicity from gemcitabine either given concomitantly or followed by radiation. We suggest discontinuing gemcitabine if radiation recall is observed. Further studies are warranted into the pathogenesis of this unique phenomenon.

Use of cell therapy as a means of targeting chemotherapy to inoperable pancreatic cancer.

Although approved for the treatment of pancreatic cancer, the chemotherapeutic agent ifosfamide is not an effective therapy for this type of tumour. Ifosfamide must be activated by cytochrome P450 (P450) enzymes in the liver, initially to a short lived intermediate and then to toxic metabolites that are subsequently distributed by the circulatory system. Particularly for pancreatic cancer, this liver-mediated conversion results in relatively high systemic toxicities and poor therapeutic concentrations at the liver-distant site of the tumour. Activation of ifosfamide at the site of the tumour may allow lower doses to be used, while increasing the therapeutic index due to the resultant active concentrations generated locally. A cell-based therapy has been conceived where encapsulated, 293-derived cells genetically modified to overexpress a cytochrome P450 enzyme, are implanted near solid tumours. The cells are encapsulated in polymers of cellulose sulphate in order to provide a means of immunoprotection in vivo as well as to physically constrain them to the vicinity of the tumour. A major advantage of this strategy is that it allows one standard cell line to be applied to all patients and this approach can be extended to the treatment of other tumour types. After proof of principle studies in animal models, a phase I/II clinical trial was initiated in patients with stage III/IV nonresectable pancreatic cancer. Encapsulated cells were angiographically placed into the tumour vasculature of 14 patients and followed by systemic low dose ifosfamide treatment. Angiographic delivery of encapsulated cells proved feasible in all but one patient, and was well tolerated with no capsule or ifosfamide treatment-related adverse events. Four of the treated patients showed tumour regressions after capsule delivery and ifosfamide treatment in computer-tomography scans. The other 10 patients showed no further tumour growth (i.e. stable disease) during 20 weeks observation period. The median life expectancy of the patient collective was extended two fold as compared to age and status matched historical controls, with a 3-fold improvement in one year survival being attained. Evidence for a clinical benefit of the treatment was also obtained on the basis of standard parameters for quality of life. This approach has been evaluated by the European Medicines Evaluation Agency (EMEA) and orphan drug status has been granted. A pivotal clinical trial is now being planned with the help of the EMEA. Taken together, the data from this clinical trial suggest that encapsulated cytochrome P450-expressing cells combined with chemotherapy may be useful for the local treatment of a number of solid tumours and support the performance of further clinical studies of this new treatment.

CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials

In a multivariate analysis of 154 patients receiving chemotherapy, baseline CA19-9 was an independent prognostic factor for overall survival (OS) (HR 1.8; 95% CI: 1.3–2.5, P=0.0004). The 1-year OS was 19 and 46%, respectively, for patients with a baseline CA19-9 above or below the median value. A fall of 20% in CA19-9 level from baseline was an independent prognostic factor for OS (HR 1.9; 95% CI: 1.1–3.4, P=0.019).

Comparing gemcitabine-based combination chemotherapy with gemcitabine alone in inoperable pancreatic cancer: A meta-analysis

4110 Background: In inoperable pancreatic cancer, many randomized controlled trials documented that gemcitabine-based chemotherapy had higher objective remission rate, but no more survival than gem...

A randomised, prospective, multicenter, phase III trial of adjuvant chemotherapy with gemcitabine vs. observation in patients with resected pancreatic cancer

LBA4013 Background: Chemotherapy with Gemcitabine 1 g/m2 given on d 1, 8, 15 every four weeks is standard therapy in inoperable pancreatic cancer. The value of adjuvant therapy has not been clearly defined and no data on randomised trials with Gemcitabine in the adjuvant setting is available. Methods: This study was designed to evaluate the efficacy and toxicity of Gemcitabine in patients with resectable pancreatic cancer. Within 6 weeks after operation, patients were randomised to receive Gemcitabine or observation after stratification for positive or negative resection margins, nodal tumor involvement and tumor stage. Gemcitabine was administered at a dosage of 1g/m2 days 1, 8 and 15 every 4 weeks for 6 months. Patients in the observation arm received no specific postoperative treatment. Primary endpoint was disease free survival (DFS), secondary endpoints included overall survival (OS) and side effects in both groups. The study was powered to detect a significant difference with 90% probability at a significance level of 0.05. Results: Between 07/98 and 12/2004, 368 patients were randomised after a safety only interim analysis confirmed feasibility of adjuvant Gemcitabine therapy without excessive toxicity. At the meeting, data on time-to-event endpoints and toxicity data will be available and be presented. Conclusion: Will be made after final analysis of the results is completed. The results will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Oncology Lilly Oncology

Gemcitabine-based chemotherapy in advanced-metastatic and/or unresectable pancreatic cancer

4274 Introduction: Advanced and/or unresectable pancreatic cancer is a lethal disease with a median survival lasting no longer than two months. Many chemotherapeutic regimens are investigated with newer drug-combinations, in order to improve responses and quality of life. Materials and Methods: 16 men and 8 women with histologically proved inoperable or metastatic adenocarcinoma of the pancreas were eligible for the study. The median age was 65 (range 35–81) years old. 14 out of 24 patients (pts) had performance status (PS): 0, 6 pts had PS: 1, and 4 pts had PS: 2. 11 patients received docetaxel: 75mg/m2 day 1 in combination with gemcitabine 1100mg/ m2 d1+d8 in a 3 week cycle (group A). 8 pts received gemcitabine 1100mg/ m2 d1+d8 in combination with paraplatine AUC: 5, d1 in a 3 week cycle (group B). 5 patients received monotherapy with gemcitabine 1100mg/ m2 d1+d8+d15 in 4 week cycle (group C). Patients received in total 112 chemotherapeutic cycles, 51 cycles in group A (median: 4.6, range: 1–9), 38 cycles in group B (median: 4.7, range: 2–6), 23 cycles in group C (median: 4.6, range 1–8). Results: 3 out of 11 patients (27%) had stable disease (SD) (group A), 4 out of 8 patients (50%) had SD (group B), and 3 out of 5 patients (60%) had SD (group C). The rest of the patients progressed. In total we observed 10 (41.6%) patients with stable disease with a median time to progression of 6 (range: 1–18) months. Toxicity grade III included: anemia in 2 patients (8.3%), granulocytopenia in 1 patient (4%) and thrombocytopenia in 1 patient (4%). Grade I-II toxicities reported in 5 (21.1%) patients with anemia, 3 (12.5%) patients with granulocytopenia, one patient (4%) had fever and 3 (12.5%) patients had alopecia. No toxic death was reported. Patients’ survival lasted until 36 months with a median survival of 7.89 (range: 1–36) months in all the three group-arms. Many patients reported amelioration in their pain-scale and performance status. Conclusion: Gemcitabine based chemotherapy offered a stability of their disease in 41% of the patients with a median time to progression of 6 months (range: 1–8) and a median survival of 8 months (range: 1–36) respectively. Also, it improves the quality of life in patients with inoperable and/or metastatic pancreatic cancer. No significant financial relationships to disclose.

Phase II trial of gemcitabine and irinotecan plus celecoxib in advanced adenocarcinoma of the pancreas

4155 Background: Over expression of the cyclooxygenase-2 (COX-2) enzyme has been reported in 90% of patients (pts) with pancreatic cancer. COX-2 derived prostaglandins contribute to tumor growth through angiogenesis and COX-2 inhibitors have been shown to arrest the growth of pancreatic cell lines in vitro. Gemcitabine (Gem) and irinotecan (I) is an active regimen in pancreatic cancer. The aim of this study is to evaluate the efficacy and toxicity of Gem + I + celecoxib in advanced pancreatic cancer. Methods: Study eligibility included chemotherapy naïve pts with locally advanced inoperable or metastatic pancreatic cancer, measurable disease, and performance status 0–2. Tumor response was assessed by RECIST criteria with CT imaging every 3 cycles. CEA, CA 19–9, pain assessment and QOL assessment with the FACT-pa were performed with each cycle. Patients received Gem 1000mg/m2 and I 100mg/m2 days 1 and 8 of a 21 day cycle. Celecoxib was given at a dose of 400mg BID throughout the entire study. Toxicity was graded according to the NCI common toxicity criteria. Results: A total of 20 pts (median age 57) were enrolled of which 17 (8 local, 9 metastatic) were evaluable for response and 18 for toxicity. The most common Grade 3/4 toxicities included 9 neutropenia (50%), 7 anemia (39%), 3 diarrhea (17%), 3 fatigue (17%), 2 nausea (11%), 1 edema (6%), 1 thrombocytopenia (6%) and 1 UGI bleed (6%). There was one treatment related death due to neutropenic sepsis. To date there have been 3 PR (18%), 12 SD (70%), and 2 PD (12%). 9/13 pts (69%) who reported pain prior to beginning treatment had a significant improvement. A marked decrease in elevated baseline CA 19–9 and CEA was observed in 12/14 and 8/10 pts respectively. 13 pts (76%) reported an improvement in quality of life. The overall median TTP was 8 months (m) (10.5 m for local, 6 m for metastatic). Median OS was 13 m (>16 m for local, 9 m for metastatic) with a 1 year OS of 64%. 31% of the pts are approaching a two year survival. Conclusion: Gem + I + celecoxib is an active regimen with both objective responses and clinical benefit demonstrated by improvement in pain and quality of life, reduction in tumor markers, and a 1 year OS of 64%. Toxicities are manageable and include neutropenia, anemia, and diarrhea. No significant financial relationships to disclose.

A comparison of two invasive techniques in the management of intractable pain due to inoperable pancreatic cancer: neurolytic celiac plexus block and videothoracoscopic splanchnicectomy

Background and aimsPancreatic cancer is characterized by a constant deterioration in quality of life, excruciating pain and progressive cachexia. The aim of this study was to compare the effectiveness of two invasive methods of pain treatment in these patients: neurolytic coeliac plexus block (NCPB) and videothoracoscopic splanchnicectomy (VSPL) to a conservatively treated control group concerning pain, quality of life and opiates' consumption. Patients and methodsFifty nine patients suffering from pain due to inoperable pancreatic cancer were treated invasively with NCPB (N=35) or VSPL (N=24) in two non-randomised, prospective, case-controlled protocols. Intensity of pain (VAS-pain), quality of life (FACIT and QLQ C30) and opioid intake were compared between the groups and to a control group of patients treated conservatively before the procedure and after 2 and 8 weeks of follow-up. The analysis was performed retrospectively using meta-analysis statistics. ResultsBoth methods of invasive pain treatment resulted in significant reduction of pain (VSPL effect size=11.27, NCPB effect size=7.29) and fatigue (effect sizes, respectively, 1.23 and 3.37). NCPB improved also significantly physical, emotional and social well-being (effect sizes, respectively, 2.37, 4.13 and 7.51) which was not observed after VSPL. No influence on ailments characteristic for the disease was demonstrated. Mean daily opioid consumption was significantly decreased after both procedures. There was no perioperative mortality and no major morbidity. ConclusionBoth NCPB and VSPL provide significant reduction of pain and improvement of quality of life in inoperable pancreatic cancer patients. They present rather similar efficacy, but lower invasiveness of NCPB, in combination with its more positive effect on quality of life, pre-disposes it as being the preferred method.

Carboplatin plus gemcitabine in patients with inoperable or metastatic pancreatic cancer: a phase II multicenter study by the Hellenic Cooperative Oncology Group

In the present phase II multicenter study, we assessed the efficacy and tolerability of the combination of gemcitabine and carboplatin in patients with advanced pancreatic cancer. Patients with previously untreated, locally advanced or metastatic pancreatic cancer were treated with gemcitabine 800 mg/m(2) on days 1 and 8 and carboplatin at an AUC of 4 on day 8 of a 3-week cycle, for a total of six cycles. Primary end points were response rate and clinical benefit; secondary end points were, survival, time to progression (TTP) and toxicity. A total of 50 patients were enrolled in the study, 47 of whom were eligible for treatment. The median age was 63 years (range 34-76) and the median Karnofsky performance status (PS) was 80%. Patients received a median of six cycles (range 1-11). Among 35 patients evaluable for response, eight (17%) achieved partial response; 15 (32%) and 12 (25%) patients had stable and progressive disease, respectively. The median overall survival was 7.4 months; the median TTP was 4.4 months and the 1-year survival was 28%. The observed clinical benefit response was remarkable. After the second cycle of chemotherapy, 21 of 31 (68%) patients experienced pain improvement and reduced analgesic consumption. At the same time, 35% and 56% of our patients significantly improved their Karnofsky PS and weight, respectively. Overall, the treatment was well tolerated. The most common grade 3-4 toxicities were hematological, including 8% anemia, 6% neutropenia and 13% thrombocytopenia. The combination of gemcitabine plus carboplatin is a moderately active treatment for patients with locally advanced and metastatic pancreatic cancer. This regimen has an acceptable toxicity profile and provides a significant clinical benefit, and hence warrants further investigation.

Effect of Chemoradiotherapy with Gemcitabine and Cisplatin on Locoregional Control in Patients with Primary Inoperable Pancreatic Cancer

Gemcitabine sensitizes tumor cells to radiation and cisplatin and thereby enhances the cytotoxic effect of gemcitabine. Here we report the efficacy and toxicity of concurrent chemoradiation with gemcitabine and cisplatin in the treatment of patients with locally advanced, unresectable pancreatic cancer. A total of 47 patients (29 men, 18 women; median age 61 years) with histologically proven advanced pancreatic carcinoma were included in the study. They underwent chemotherapy with gemcitabine 300 mg/m2 and cisplatin 30 mg/m2 on days 1, 8, 22, and 29; concurrent radiation (45-50 Gy) was applied to the tumor and regional lymph nodes (1.8-2.0 Gy/fraction 5 days per week). Subsequent to chemoradiotherapy, treatment was continued with more two cycles of gemcitabine (1000 mg/m2) and cisplatin (50 mg/m2) applied on days 1 and 15 of a 4-week cycle. After completion of chemoradiotherapy, 9 patients (19.1%) achieved a complete response and 23 patients (48.9%) a partial response, for an overall response rate of 68%. The lesions were considered resectable in 27 patients, and 25 of the 27 patients underwent laparotomy. The other 20 patients underwent a definitive pancreatic resection. Altogether, 13 patients had negative surgical margins. With a median follow-up of 25.7 months (range 12.7-38.7 months) after completion of chemoradiation, distant metastasis had occurred in 23 patients and local recurrence in only 4 of 44 patients (8.5%). the median progression-free survival was 7.8 months (range 6.2-9.4 months). The median survival amounted to 10.7 months (range 8.4-13.0 months) for all patients, whereas it was prolonged to 24.2 months (range 6.8-41.7 months) for those undergoing R0 resection. The main toxicities associated with chemoradiation included grade 3/4 leukopenia (68% of patients) and thrombocytopenia (61%). Episodes of cholangitis were observed in 11 patients. We concluded that gemcitabine and cisplatin can safely be combined with external beam radiation. This preoperative treatment approach is highly effective and appears to improve survival in patients whose tumors are rendered completely resectable.

Combined modality therapy for pancreatic carcinoma - An Australian Pancreatic Cancer Group study of the addition of gemcitabine to concurrent infusional 5-fluorouracil and 3D conformal radiotherapy

4100 Background: There is no consensus on the optimal management of locally advanced pancreatic cancer. This open-label phase II study examined whether continuous infusion 5-fluorouracil (CI 5FU) plus 3D conformal planning radiotherapy (RT) is well tolerated and may be combined with gemcitabine (G) pre and post chemoradiotherapy. Methods: Eligible patients (pts) were enrolled in 2 strata: (1) inoperable pancreatic cancer in head or body without metastases (LAD) or (2) resected pancreas cancer at high risk of relapse (Surg). G was given at 1000 mg/m2 weekly for 3 wks followed by 1 wk rest then a 5–6 wk period of RT and concurrent CI 5FU (200 mg/m2/day). The defined target volume was treated to 54Gy in 30# of 1.8Gy in the LAD and 45Gy in 25# in the Surg arm. After a 4-wk rest period, G was reinitiated for 12 wks. Results: 64 pts are on study and results for the first 40 pts are reported (26 females, 14 males; mean age 60 yr, range 39–79; 48% PS 0, 50% PS 1, 3% PS 2). Treatment was well tolerated: 3 pts are still on treatment after 2 cycles of G post RT, 19 completed all planned treatment, 13 discontinued due to disease progression, 4 withdrew and there was 1 treatment-related death. 75% of pts reported CTC grade 3/4 toxicities. 38/40 pts completed the initial G treatment; of these, 36/38 completed RT. 5/38 pts required reduction in 5FU, 10/40 in G pre RT and 32/36 in G post RT. In the LAD arm, 4.8% of pts responded and median TTPD was 6.9 mo (interquartile range (IQR) 5.9–10.3). In the 23 pts who progressed, 6 progressed locally, 14 systemically and 5 site unknown. More recent data shows 61% of LAD (median 13.4 mo, IQR 10.3–18.3) and 65% of Surg pts were alive at 1 yr (median 14.2 mo, IQR 9.5–23). The change in CA 19–9 levels (but not the baseline level) was predictive of outcome. In 17 pts we found no association of outcome with fluorescent-SSCP analysis of K-RAS, 4 p53 mutations or MSI status. Conclusions: This approach to treatment of locally advanced disease is safe and promising with good local control for a substantial proportion of patients and merits testing in a randomized trial against chemotherapy alone. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Amgen; Sanofi Sanofi; Eli Lilly; Oncomethylome Sciences Novartis

Combined modality therapy for pancreatic carcinoma - An Australian Pancreatic Cancer Group study of the addition of gemcitabine to concurrent infusional 5-fluorouracil and 3D conformal radiotherapy

4100 Background: There is no consensus on the optimal management of locally advanced pancreatic cancer. This open-label phase II study examined whether continuous infusion 5-fluorouracil (CI 5FU) plus 3D conformal planning radiotherapy (RT) is well tolerated and may be combined with gemcitabine (G) pre and post chemoradiotherapy. Methods: Eligible patients (pts) were enrolled in 2 strata: (1) inoperable pancreatic cancer in head or body without metastases (LAD) or (2) resected pancreas cancer at high risk of relapse (Surg). G was given at 1000 mg/m2 weekly for 3 wks followed by 1 wk rest then a 5–6 wk period of RT and concurrent CI 5FU (200 mg/m2/day). The defined target volume was treated to 54Gy in 30# of 1.8Gy in the LAD and 45Gy in 25# in the Surg arm. After a 4-wk rest period, G was reinitiated for 12 wks. Results: 64 pts are on study and results for the first 40 pts are reported (26 females, 14 males; mean age 60 yr, range 39–79; 48% PS 0, 50% PS 1, 3% PS 2). Treatment was well tolerated: 3 pts are still on treatment after 2 cycles of G post RT, 19 completed all planned treatment, 13 discontinued due to disease progression, 4 withdrew and there was 1 treatment-related death. 75% of pts reported CTC grade 3/4 toxicities. 38/40 pts completed the initial G treatment; of these, 36/38 completed RT. 5/38 pts required reduction in 5FU, 10/40 in G pre RT and 32/36 in G post RT. In the LAD arm, 4.8% of pts responded and median TTPD was 6.9 mo (interquartile range (IQR) 5.9–10.3). In the 23 pts who progressed, 6 progressed locally, 14 systemically and 5 site unknown. More recent data shows 61% of LAD (median 13.4 mo, IQR 10.3–18.3) and 65% of Surg pts were alive at 1 yr (median 14.2 mo, IQR 9.5–23). The change in CA 19–9 levels (but not the baseline level) was predictive of outcome. In 17 pts we found no association of outcome with fluorescent-SSCP analysis of K-RAS, 4 p53 mutations or MSI status. Conclusions: This approach to treatment of locally advanced disease is safe and promising with good local control for a substantial proportion of patients and merits testing in a randomized trial against chemotherapy alone. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Amgen; Sanofi Sanofi; Eli Lilly; Oncomethylome Sciences Novartis

A non-intensive gemcitabine-cisplatin regimen in pancreatic cancer significantly improves quality of life and pharmacoeconomics with high response rates

8155 AIM: This Prospective Phase II study was undertaken to determine whether a dose-modified gemcitabine-cisplatin regimen improved QOL, reduced toxicity, increased compliance and improved delivered dose-intensity, with lowered costs, while preserving response rates. METHODS: 34 Chemotherapy naive patients with inoperable, locally advanced or metastatic pancreatic cancer were enrolled. Quality of life, clinical benefit response, albumin and CA19.9 were assessed cyclically: Patients received gemcitabine 1000mg/m2 day 1 and 8 and Cisplatin 60mg/m2 day 1 only (Q=21 days), all on an out-patient basis, with an intended minimum of 6 cycles. Objective response and toxicity were evaluated with WHO & CTC criteria. RESULTS: A total of 28 patients (19 male 9 female) are assessable currently. 89% (25 patients) had no increase in their analgesia. 77% (21 patients) had at least a 10% increase in dry weight or stabilization. Of the 13 patients with low serum albumin, 8 patients (29% of the total) had an increase or stabilization. This improvement in quality of life was mirrored in the tumor markers and objective disease response.12 patients (43%) had a decrease in their CA19.9 of >50%, and 9 patients had a partial or complete response with a further12 patients having stable disease. Critically, we were able to downstage 3/28 patients to successful pancreatectomies. This regimen caused little clinical toxicity ( 3 patients grade 3 nausea/lethargy). There was mild hematological toxicity with mainly anemia (26 patients (93%) grade 1+2, 2 patients (7%) grade 3+4) and neutropenia (13 patients (46%) grade 1+2, 5 patient (17%) grade 3+4). This regime produced cost savings of up to 1/3 when compared to other standard published regimens of either gemcitabine alone (+/− cisplatin), and more convenient with significantly fewer visits to hospital. CONCLUSION: By adding cisplatin to gemcitabine, at a reduced dose and frequency, we have been able to significantly improve patients quality of life, maintain responses and save on health costs. Currently the projected median survival for patients in this cohort is greater than 11 months. No significant financial relationships to disclose.

Cancer therapy with unloaded monocyte-derived dendritic cells in patients with inoperable pancreatic and gall bladder cancer

2569 Background: Several studies could show that immunotherapy with monocyte-derived dendritic cells (MoDC) loaded with tumor-cell-lysate or known peptides induce clinical antitumor response in certain patients with various types of solid tumors. Given that tumor proteins in the serum of cancer patients may be sufficient to internalize and presented by immature dendritic cells, we investigated whether immature dendritic cells incubated with the serum of cancer patients could induce an antitumor response in vivo. Methods: After isolating monocytes from peripheral blood of patients with pancreatic (n=17) and gall bladder cancer (n=6), dendritic cells were generated ex vivo in the presence of recombinant cytokines (IL-4;GMC-SF) and autologous serum. After 7 days of culture, the autologous MoDC were administered to the cancer patients (intradermal or intratumoral). Results: Flow cytometric analysis of the surface markers revealed that the generated MoDC were of immature type with expression of CD1a and MHC-II but not monocyte specific marker CD14. The generated MoDC could induce an antigen specific lymphocyte proliferation in vitro. Using a phagocytosis assay it could be demonstrated by flow cytometry and electron microscopy that immature dendritic cells are in general able to phagocytose different sized particles. The vaccination induced a clinical response in n=5 patients with pancreatic cancer including 2 stable diseases, 2 minor remissions and 1 mixed response (overall survival 4–32 months; 2 patients died of their disease after 10 and 21 months, respectively) as well as in n=1 patient with gall bladder cancer (stable disease after 18 months using intratumoral administration). A biopsy taken from the patient with the gall bladder cancer within the treatment period demonstrated unusually low proliferative activity. Conclusions: The results suggest that immature dendritic cells could be loaded by soluble tumor antigens in the serum of cancer patients as well as able to uptake tumor antigens in vivo. No significant financial relationships to disclose.

Cancer therapy with unloaded monocyte-derived dendritic cells in patients with inoperable pancreatic and gall bladder cancer

2569 Background: Several studies could show that immunotherapy with monocyte-derived dendritic cells (MoDC) loaded with tumor-cell-lysate or known peptides induce clinical antitumor response in certain patients with various types of solid tumors. Given that tumor proteins in the serum of cancer patients may be sufficient to internalize and presented by immature dendritic cells, we investigated whether immature dendritic cells incubated with the serum of cancer patients could induce an antitumor response in vivo. Methods: After isolating monocytes from peripheral blood of patients with pancreatic (n=17) and gall bladder cancer (n=6), dendritic cells were generated ex vivo in the presence of recombinant cytokines (IL-4;GMC-SF) and autologous serum. After 7 days of culture, the autologous MoDC were administered to the cancer patients (intradermal or intratumoral). Results: Flow cytometric analysis of the surface markers revealed that the generated MoDC were of immature type with expression of CD1a and MHC-II but not monocyte specific marker CD14. The generated MoDC could induce an antigen specific lymphocyte proliferation in vitro. Using a phagocytosis assay it could be demonstrated by flow cytometry and electron microscopy that immature dendritic cells are in general able to phagocytose different sized particles. The vaccination induced a clinical response in n=5 patients with pancreatic cancer including 2 stable diseases, 2 minor remissions and 1 mixed response (overall survival 4–32 months; 2 patients died of their disease after 10 and 21 months, respectively) as well as in n=1 patient with gall bladder cancer (stable disease after 18 months using intratumoral administration). A biopsy taken from the patient with the gall bladder cancer within the treatment period demonstrated unusually low proliferative activity. Conclusions: The results suggest that immature dendritic cells could be loaded by soluble tumor antigens in the serum of cancer patients as well as able to uptake tumor antigens in vivo. No significant financial relationships to disclose.