Chemotherapy For Advanced Pancreatic Cancer Research Articles

Pancreatic cancer – ASCO 2009

The publication of practice changing clinical data is a rare event in the field of pancreatic cancer. In line with this general statement, oncologists attending or following the ASCO Annual Meeting 2009 were not surprised by being confronted with the study results mainly confirming the already existing evidence. The following conference report will therefore in its first part cover the results of the most important clinical phase III-trials presented. The ESPAC 3(v2)-study established 5-Fluorouracil (5-FU) as an equally effective but more toxic alternative to gemcitabine in the adjuvant treatment of patients with resected pancreatic cancer. Concerning the palliative treatment of advanced disease the Italian GIP-1-study provided us with another set of data comparing gemcitabine with a gemcitabine/platinum-duplet, once again failing to document a survival benefit. The CONKO-004-study investigated the prophylactic application of a low-molecular-weight heparin (enoxaparin) in patients treated with chemotherapy for advanced pancreatic cancer. As one would expect, the rate of symptomatic venous thromboembolic events with this intervention was reduced. Whether this will translate into a survival benefit remains to be established, as the final analysis of this trial is still pending. Due to the paucity of presentations with further immediate practical relevance the second part of this short review will touch on two exciting abstracts dealing with the search for new therapeutic concepts, drugs and targets.

Dynamic susceptibility contrast MRI in advanced pancreatic cancer: semi-automated analysis to predict response to chemotherapy

The purpose of this study was to assess whether dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) can predict response to chemotherapy in advanced pancreatic cancer. DSC-MRI was performed using gradient-echo echo-planar imaging after bolus injection of contrast material. Fifty-four patients with advanced pancreatic cancer who were scheduled for chemotherapy were enrolled. ΔR2* was calculated using semi-automated computer analysis capable of tracking moving lesions during DSC-MRI. Pre-treatment maximum ΔR2* and clinical factors including gender, age, tumor stage (UICC III/IV), initial tumor size, and chemotherapy regimen were compared between patients with progressive disease and patients with stable disease as was determined at 3-month follow-up, and between patients with progressive disease and patients with stable disease as was determined at 6-month follow-up. Receiver operating characteristic (ROC) analysis and the Kaplan-Meier method with log-rank test were used to assess the relationship between the pre-treatment maximum ΔR2* and early progression (i.e. at 3-month follow-up). The pre-treatment maximum ΔR2* of patients with disease progression at 3-month follow-up (10.68 ± 3.88 s(-1)) was significantly different (p < 0.01) from that of patients with stable disease at 3-month follow-up (6.94 ± 3.12 s(-1)). Pre-treatment maximum ΔR2* of patients with disease progression at 6-month follow-up was not significantly different from that of patients with stable disease at 6-month follow-up, although a trend was noted (p = 0.08). Pre-treatment clinical factors were not significantly different between progressive and stable patients at 3- and 6-month follow-up. Tumor progression rate was significantly higher in patients with a higher pre-treatment maximum ΔR2* than in those with a lower pre-treatment maximum ΔR2* (median progression time, 38 vs 138 days, p < 0.01, using a cut-off value of 8.13 s(-1) as determined by ROC analysis). In conclusion, DSC-MRI may predict early progression in patients with advanced pancreatic cancer undergoing chemotherapy.

The predictive role of CA 19–9 kinetics for time-to-progression (TTP) and overall survival (OS) in patients receiving palliative first-line chemotherapy for advanced pancreatic cancer

e15637 Background: Previous studies showed contradictory results for a predictive role of CA 19–9 kinetics during chemotherapy in patients (pts) with pancreatic cancer (PC). Methods: We performed a retrospective, multicenter study in order to evaluate the role of CA 19–9 as a biomarker for TTP and OS in PC. Main inclusion criteria: histological confirmed diagnosis of PC, treatment with first-line chemotherapy for advanced disease, pre-treatment CA 19–9 level of &gt; 5.2 U/ml. As CA 19–9 measurements were conducted in different laboratories using different commercial assays, we defined a subgroup of pts where CA 19–9 was assessed exclusively by the Elecsys assay (Roche Diagnostics). For the analysis of CA 19–9 kinetics, at least one follow-up measurement between day 20 and 64 during first-line chemotherapy had to be available. Pts were divided into two subgroups of CA 19–9 responders and non-responders by cut-offs of a 25% and 50% decline, respectively. OS and TTP were estimated with the Kaplan-Meier-Method, differences between the subgroups were analyzed by using the log-rank test. Results: One hundred and eighty-six pts were included, 83 of them were tested with the Elecsys method. Median age was 63 years, 90 % of the pts were treated within prospective clinical trials. Median pre-treatment CA 19–9 was 1076 U/ml (range 5.7–100,000 U/ml), the median bilirubin was 0.6 mg/dl. Median OS and TTP were 9.8 months (mo) and 5.4 mo, respectively. In univariate analysis, pts with a CA 19–9 decline of at least 25% during chemotherapy lived significantly longer (11.9 mo vs. 8.2 mo, p=0.003) and had a significantly prolonged TTP (5.8 mo vs. 4.4 mo, p=0.018) than those with a lower decline or even CA 19–9 increase. Data for the Elecsys-measurements were comparable (OS: 13.4 mo vs. 8.6 mo, p=0.004; TTP: 7.0 mo vs. 2.6 mo, p=0.003). None of the analyses demanding a CA 19–9 drop of at least 50% reached the level of statistical significance. Conclusion: An early CA 19–9 decline of 25% during first-line chemotherapy may predict OS and TTP in pts with advanced PC. Innovative statistical methods are required to improve our understanding of the utility of CA 19–9 as a predictive biomarker in PC. [Table: see text]

Modalities for Evaluating Chemotherapeutic Efficacy and Survival Time in Patients with Advanced Pancreatic Cancer: Comparison between FDG-PET, CT, and Serum Tumor Markers

It has recently been reported that (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is useful for estimation of the chemotherapy effect. Thus, we examined the value of FDG-PET in assessing the efficacy of chemotherapy in advanced pancreatic cancer, and compared this modality with tumor markers (TMs) and CT. Nineteen patients with unresectable pancreatic adenocarcinoma were enrolled. All patients received chemotherapy with gemcitabine and S-1, an oral derivative of 5-fluorouracil, and underwent FDG-PET, CT, and serological examination for TMs before and after chemotherapy. Standardized uptake value in FDG-PET before treatment and survival time were not correlated. A good prognosis was seen after 1 course of chemotherapy in patients whose tumors were in partial or complete remission as assessed by FDG-PET [median of survival time (MST), 12.5 months] or TMs (MST, 13.5 months), but not in CT responders (MST, 10.3 months). Furthermore, patient prognosis correlated with PET and TM assessment of the best tumor response through all courses. Namely, both PET and TM were useful for the prediction of survival or chemotherapy sensitivity of the patients. FDG-PET and TMs can each play an adjunct role to CT for estimating the effect of chemotherapy and predicting survival by distinguishing between responders and non-responders among patients with advanced pancreatic cancer.

Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses.

In advanced pancreatic cancer, level one evidence has established a significant survival advantage with chemotherapy, compared to best supportive care. The treatment-associated toxicity needs to be evaluated. This study examines the secondary outcome measures for chemotherapy in advanced pancreatic cancer using meta-analyses. A systematic review was undertaken employing Cochrane methodology, with search of databases, conference proceedings and trial registers. The secondary end points were progression-free survival (PFS)/time to progression (TTP) (summarised using the hazard ratio (HR)), response rate and toxicity (summarised using relative risk). There was no significant advantage of 5FU combinations vs 5FU alone for TTP (HR=1.02; 95% CI=0.85–1.23) and toxicity. Progression-free survival (HR 0.78; CI 0.70–0.88), TTP (HR=0.85; 95% CI=0.72–0.99) and overall response rate (RR=0.56; 95% CI=0.46–0.68) were significantly better for gemcitabine combination chemotherapy, but offset by the greater grade 3/4 toxicity thrombocytopenia (RR=1.94; 95% CI=1.32–2.84), leucopenia (RR=1.46; 95% CI=1.15–1.86), neutropenia (RR=1.48; 95% CI=1.07–2.05), nausea (RR=1.77; 95% CI=1.37–2.29), vomiting (RR=1.64; 95% CI=1.24–2.16) and diarrhoea (RR=2.73; 95% CI=1.87–3.98). There is no significant advantage on secondary end point analyses for administering 5FU in combination over 5FU alone. There is improved PFS/TTP and response rate, with gemcitabine-based combinations, although this comes with greater toxicity.

Short Time to Progression under First-Line Chemotherapy Is a Negative Prognostic Factor for Time to Progression and Residual Survival under Second-Line Chemotherapy in Advanced Pancreatic Cancer

Objectives: Second-line chemotherapy is widely used in advanced pancreatic cancer. However, only few data exist concerning the question who might benefit from second-line therapy. We intended to identify prognostic factors for time to second progression (TTP2) and residual survival following second-line chemotherapy of patients with advanced pancreatic cancer. Methods: We performed a retrospective cohort study on 78 patients who started palliative chemotherapy at our department from January 2004 to June 2006 due to advanced adenocarcinoma of the pancreas. 46 patients who progressed following first-line therapy were analyzed. Results: In multivariate analyses, time to first progression (TTP1) <6 months and elevated LDH at the time of diagnosis were shown to be strong and highly significant independent prognostic factors for TTP2 and residual survival. For patients with TTP1 <6 months, prognosis was poor with a median residual survival of 4.4 versus 7.5 months for those with TTP1 ≧6 months. Conclusion: In our cohort of patients with advanced pancreatic cancer treated with second-line chemotherapy, TTP1 <6 months is a strong negative prognostic factor for TTP2 and residual survival.

Ca 19.9 as an early predictor of response to first- and second-line treatment in patients with pancreatic cancer

15547 Background: The aim of this study was to define the role of early Ca19.9 modification during first and second line chemotherapy for advanced pancreatic cancer, as a predictor of response, overall survival and time to progression. Methods: we reviewed Ca19.9 levels, before starting first and second line treatment and 30 days following the beginning of chemotherapy (first and second line) of 96 patients with advanced pancreatic cancer, who received chemotherapy at our Oncology Department from January 2002 to June 2007. Results: Median age: 63 years (37,5 - 77,9); M/F ratio 55/41 (57,3/42.7%); 57 (59.4%) received second line chemotherapy. At the time of analysis 86.5% of patients had died, with a median OS of 8.1 months. Ca 19.9 values before and during treatment are summarized in the table below. A high baseline Ca19.9 value (>10 times upper limit) was associated with a significantly shorter OS and TTP (OS: 11.3 vs 11.2 vs 6.3 months, p=0.014; TTP: 5.7 vs 3.9 vs 3.2 months, p=0.0034), and similar results were observed for second line treatment (OS:14.4 vs 11.3 vs 4.3 months, p=0.0281; TTP: 5.5 vs 4.2 vs 2.3 months, p=0.0034). We found that, both during first and second line treatment, an early increase of Ca19.9 level over 20% was associated with a higher rate of progressive disease (68.7% vs 40%; p=0.0157 in first line and 86.4% vs 59.4%; p=0.037 in second line) and a worst prognosis (OS: 5,3 vs 10,2 months; p=0,001; TTP: 2,6 vs 5,8 months; p<0,0001 for first line; OS: 7,9 vs 4,1 months, p=0,0007; TTP: 4 vs 1,4 months, p=0,0009 for second line). Conclusions: our results confirmed the prognostic role of Ca19.9 in pancreatic cancer, also in the second line setting. We also observed the role of serial determination of Ca19.9 during chemotherapy as an early predictor of response rate to treatment and patients outcome. Ca 19–9 values Number of Patients (%) Baseline Ca 19–9 96 patients Normal 13 (13.5%) ≤ 10 time upper limits 22 (22.9%) > 10 times upper limits 61 (63.5%) Ca 19–9 modification during 1st line chemotherapy 46 (47.9%) Decreased 32 (33.3%) Stable 18 (18.7%) Increased over 20% Unknown Before 2nd line chemotherapy 57 patients Normal 9 (15.8%) ≤ 10 time upper limits 5 (8.8%) > 10 times upper limits 36 (63.2%) Unknown 7 (7.7%) Ca 19–9 modification during 2nd line chemotherapy 32 (56.2%) Decreased 13 (22.8%) Stable 12 (21%) Increased over 20% Unknown No significant financial relationships to disclose.

Prognostic factors for time to progression and residual survival under second-line chemotherapy in advanced pancreatic cancer

15631 Background: Second-line chemotherapy is widely used in advanced pancreatic cancer. However, only little data exist concerning the question which patients might benefit from second-line therapy. We intended to identify prognostic factors for time to second progression and rest survival under second-line chemotherapy of advanced pancreatic cancer. Methods: We performed a retrospective cohort study of 78 patients who started palliative chemotherapy at our department from January 2004 to June 2006 due to advanced adenocarcinoma of the pancreas. This analysis focusses on 46 patients who experienced progression under first-line therapy. Results: In multivariate analyses time to first progression below 6 months and elevated LDH at the time of diagnosis were shown to be strong and highly significant independent prognostic factors for time to second progression and residual survival. For patients with time to first progression shorter than 6 months the prognosis was poor with a median residual survival of 4....

Chemotherapy for advanced pancreatic cancer

Single-agent gemcitabine, the standard chemotherapy for pancreatic cancer, has only mod-est effect. Gemcitabine has been combined with a variety of cytotoxic agents and targeted agents. Most phase Ⅲ studies, however, have failed to show improved survival compared with gemcitabine alone. One phase Ⅲ study has shown improved survival in advanced pancreatic cancer by adding erlotinib to gemcitabine. Studies evalua-ting non-gemcitabine-based regimens have showed considerable promise. Key words: Pancreatic neoplasms; Drug therapy

GEMOX as first-line chemotherapy in advanced pancreatic cancer (APC): A monoinstitutional experience

15179 Background: To date, gemcitabine (GEM) remains the cornerstone of chemotherapy (CHT) for APC. According to GERCOR and GISCAD phase III trials the combination of GEM and oxaliplatin (GEMOX) has proven superior to GEM alone in terms of response rate (RR), time to progression (TTP) and clinical benefit rate (CBR). Methods: We conducted a retrospective analysis on 19 patients (pts) affected with histologically-confirmed APC, in order to determine the impact of GEMOX as first-line chemotherapy in terms of objective responses (OR) and TTP, using the Kaplan-Meier method. Among the 19 pts considered there were 15 males and 4 females (median age at diagnosis of 60.84 yrs; ECOG 0–2). The staging, according to AJCC criteria, was: IIB in 1 case, III in 5 cases and IV in the 13 remaning cases. The only metastatic site was the liver (in 13/19 pts). Ten of the 19 pts underwent surgical treatment prior to CHT: 2 radically resected (R0) subsequently treated with GEMOX after recurrence, 4 with positive margins (R1) and 4 surgically palliated. All pts received GEM 1000 mg/m2/d1 + oxaliplatin 100 mg/m2/d2 every 2 weeks. The median number of cycles was 5.89. Results: Among the 19 pts, 3 had a partial response (PR, 15.69%), 6 had stable disease (SD, 31.57%); no complete response was observed and 10 pts had progressive disease (PD, 52.63%). The overall disease control rate (DCR: PR + SD) was 47.37% while the OR were 15.69%. The median survival observed was 9.03 months (95% C.I. 5.15–12.91) and the median TTP was 6.13 months (95% C.I. 2.81–9.46). The main toxicities were: leucopenia, piastrinopenia, diarrhoea, nausea, fever and peripheral neuropathy; 3 pts discontinued the treatment due to grade 3–4 neurotoxicity. Conclusions: In our experience GEMOX gives an improved control of APC in terms of OR and TTP, with acceptable toxicity. The OS is in accordance to literature as well as the other data. No significant financial relationships to disclose.

Second-line chemotherapy in advanced pancreatic cancer: A retrospective, single-center analysis

15187 Background: Patients with advanced pancreatic cancer profit from palliative chemotherapy. The role of second-line chemotherapy is not yet established. Methods: We performed a retrospective analysis in 98 patients who were treated at our department from 1/2004–6/2006 due to locally advanced or metastatic adenocarcinoma of the pancreas. Results: At the time of analysis 67 patients had died (median overall survival 9 months), 31 patients are still alive (median follow up 9 months). 12 patients were initially treated with radiochemotherapy. 86 patients received systemic chemotherapy; 43 of these patients were treated with second-line chemotherapy after disease progression. OS was significantly longer in patients who received second-line chemotherapy (10 months versus 5.0 months, p=0.023). Response to second-line chemotherapy was partial remission in 2 patients (4.6 %), stable disease in 18 patients (44.8 %), and progressive disease in 19 patients (44.2 %), in 3 patients the treatment was stopped due to toxicity (6.9 %). 12 patients received second-line treatment after early disease progression under first-line chemotherapy. 9 of these patients did not respond to second-line treatment, 2 achieved stable disease and 1 patient had partial remission. Elevated LDH and CA19.9 serum levels at the time of diagnosis were identified as negative prognostic factors. Conclusions: Prognosis of patients with advanced pancreatic cancer is still poor. Selected patients may benefit from salvage chemotherapy after failure of first-line chemotherapy. No significant financial relationships to disclose.

Chemoanticoagulation versus chemotherapy in advanced pancreatic cancer (APC): Results of the interim analysis of the FRAGEM trial

4583 Background: Randomised phase III studies in APC, reveal that many patients (pts) (∼20–25%) die within 3 months from randomisation [(Early Death Burden) (EDB)]. More compared to studies done in other cancers despite pts entered on similar ‘global’ clinical criteria (e.g. 7% in colorectal cancer). We hypothesised that EDB in APC is related to hyper-coagulability. Prevention of veno-thromboembolism (VTE) may result in reduction of EDB. To test this we initiated the randomised phase IIb FRAGEM study. Methods: Upon written informed consent pts with inoperable APC, are eligible for the study (MREC N° 07/02/129, UKCRN 1290). Concurrent VTE or anticoagulant therapy are exclusion criteria. Standard arm pts (arm A) receive gemcitabine 1gr/m2 weekly (Burris schedule). Arm B also receives daily dalteparin injections for 12 weeks at therapeutic dose (CLOT schedule). Primary end point is the reduction of VTE, secondary endpoint the reduction of EDB. To detect a reduction of VTE from around 25% to 5% (odds ratio of 0.158), using a two-group chi-squared test with a two-sided 5% significance level and 80% power, a minimum of 59 pts per treatment group are required. Interim analysis was planned after the first 25 pts entered into arm B to exclude toxicity from dalteparin’s therapeutic, given prophylactically, dose. These results are presented here. Results: 26 pts (50% male, 61% with metastases) in arm A and 25 pts (60% male, 44% with metastases) in arm B have been treated so far. The incidence of VTE in arm A was 31% with 3 pts developing leg deep vein thrombosis (DVT) with pulmonary embolism (PE), 2pts DVT, 1 pt splanchnic vein thrombosis and PE, 1 pt PE without DVT and 1 patient a stroke. No VTE observed in arm B. Haemorrhagic events were 7.5% and 4% in arm A and B respectively. Within the first 12 weeks period 4 pts (15%) in arm A died, 2 from PE (autopsy- confirmed in one ‘sudden death’), 1 from stroke and one from progressive cancer. The VTE related mortality was 37%. In arm B the EDB was 4% as 1 pt died from sepsis. Conclusions: Results of the interim analysis indicate that the dose of dalteparin is safe. They also support our hypothesis that reduction of VTE may result in reduction of the EDB. The trial is on course to achieve its primary endpoint. No significant financial relationships to disclose.

Combination Chemotherapy in Advanced Pancreatic Cancer: Time to Raise the White Flag?

Gemcitabine has been the standard palliative chemotherapy in advanced pancreatic cancer since 1997; this standard was established by a phase III trial that randomly assigned 126 symptomatic patients with advanced pancreatic cancer to either gemcitabine or fluorouracil (FU). 1 Treatment with gemcitabine versus FU was associated with improvements in 1-year survival (18% v 2%, respectively) and clinical benefit response (24% v 5%, respectively). Subsequently, thousands of patients have participated in large phaseIIItrialscomparinggemcitabinealonewithgemcitabineplus a second cytotoxic agent. 2-5 In the current issue, Herrmann et al 6 present another such study, comparing gemcitabine plus capecitabine with gemcitabine alone in advanced disease. The trial by Herrmann et al 6 is of high quality and was based on evidence from earlier phase studies that suggested the combination had sufficient activity to warrant further testing. 7,8 Similar to all prior studies

K‐ras oncogene silencing strategy reduces tumor growth and enhances gemcitabine chemotherapy efficacy for pancreatic cancer treatment

Pancreatic adenocarcinoma remains a fatal disease characterized by rapid tumor progression, high metastatic potential and profound chemoresistance. Gemcitabine is the current standard chemotherapy for advanced pancreatic cancer, but it is still far from optimal and novel therapeutic strategies are needed urgently. Mutations in the k-ras gene have been found in more than 90% of pancreatic cancers and are believed to play a key role in this malignancy. Thus, the goal of this study was to investigate the impact of k-ras oncogene silencing on pancreatic tumor growth. Additionally, we examined whether combining k-ras small interfering RNA (siRNA) with gemcitabine has therapeutic potential for pancreatic cancer. The treatment of tumor cell cultures with the corresponding k-ras siRNA resulted in a significant inhibition of k-ras endogenous expression and cell proliferation. In vivo, tumor xenografts were significantly reduced with k-ras siRNA(GAT) delivered by electroporation. Moreover, combined treatment with pSsik-ras(GAT) plus gemcitabine resulted in strong growth inhibition of orthotopic pancreatic tumors. Survival rate was significantly prolonged and the mean tumor volume was dramatically reduced in mice receiving the combined treatment compared with single agents. Collectively, these findings show that targeting mutant k-ras through specific siRNA might be effective for k-ras oncogene silencing and tumor growth inhibition. The improvement of gemcitabine-based chemotherapy suggests that this strategy might be used therapeutically against human pancreatic cancer to potentiate the effects of conventional therapy.

A phase II trial of gemcitabine plus capecitabine for patients with advanced pancreatic adenocarcinoma

While gemcitabine (GEM) is widely accepted for the treatment of advanced pancreatic cancer, capecitabine (CAP) has shown single agent activity and promising efficacy in combination with GEM. This phase II study was conducted to evaluate the efficacy and toxicity of GEM combined with dose escalated 14-day CAP as first-line chemotherapy for advanced pancreatic cancer. In addition, we also analyzed the correlation between CA19-9 response and clinical outcomes. Patients had advanced pancreatic adenocarcinoma, no prior systemic chemotherapy other than that given concurrently with radiation therapy, at lease one measurable disease, and adequate organ functions. The patients were treated with GEM 1,000 mg/m2 IV on days 1, 8 and CAP 1,000 mg/m2 twice a day PO on days 1-14, in 21-day cycles. The objective RR among 45 patients was 40.0% (95% CI; 25.1-54.9), including 1CR (2.2%). The median TTP and OS were 5.4 months (95% CI; 1.8-9.0) and 10.4 months (95% CI; 6.2-14.5), respectively. Patients with >or=25% decline of serum CA19-9 had significantly better outcomes in terms of TTP and OS than those who did not (P < 0.03). The most frequent, grade 3-4, non-hematologic toxicity was hand-foot syndrome (6.7%). The combination of GEM with dose escalated 14-day CAP is well tolerated and offers encouraging activity in the treatment of advanced pancreatic cancer. In addition, CA19-9 response correlates well with clinical outcomes in this population.

Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Western countries and is among the deadliest diseases in humans. At present, gemcitabine is the standard chemotherapy for advanced pancreatic cancer, although (despite its use) prognosis continues to be dismal with a median survival of < 6 months. While targeting tumor vasculature has provided improved outcomes in colon, lung, breast and renal cell cancers, trials of angiogenesis inhibitors have lagged behind in pancreatic cancer. This review provides the rationale for exploring antiangiogenic therapies in the treatment of pancreatic cancer as well as summarizes present clinical development of VEGF receptor tyrosine kinase inhibitors and their application to pancreatic cancer.

PO-56 Chemoanticoagulation versus chemotherapy in advanced pancreatic cancer (APC): results of the interim analysis of the FRAGEM trial

PO-56 Chemoanticoagulation versus chemotherapy in advanced pancreatic cancer (APC): results of the interim analysis of the FRAGEM trial

A Phase II study of gemcitabine plus zoledronic acid in subjects with Stage IV pancreatic cancer

14002 Background: Gemcitabine, the standard chemotherapy for advanced pancreatic cancer (APC), produces low response rates and short time to progression. Preclinical studies suggest that zoledronic acid inhibits pancreatic cell lines by interfering with the p21ras/raf-1/MEK1/ERKL signaling pathway. We conducted this trial to evaluate the efficacy and toxicity of gemcitabine and zoledronic acid in subjects with APC. Methods: Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma (Stage IV) not amenable to resection with curative intent. Gemcitabine 1000 mg/m2 IV was given on Days 1, 8, 15, and 22 in Cycle 1 and Days 1, 8, and 15 in subsequent cycles. Zoledronic acid 4 mg IV was given on Day 1 every 4 weeks. Toxicity was assessed at each visit. Results: Between December 2004 and July 2005, 35 subjects were enrolled. Baseline characteristics: 20 males (57%), median age 66.7 years (range, 40–83.5), and KPS of 70/80/90/100 = 8%/29%/34%/29%, respectively. Four patients had locally advanced disease (3 stage IIB and 1 stage III), 86% of subjects had Stage IV disease at diagnosis; 91% of subjects had adenocarcinoma. Prior therapy included surgery (n=15, 43%), chemotherapy (n=3, 9%), and radiotherapy (n=2, 6%). To date, there has been 1 PR and 9 SD; the clinical benefit rate (PR+SD≥6 months) was 14%. Grade 3 and 4 treatment-related toxicities included: neutropenia (22%); thrombocytopenia and fatigue, (12.5% each); and anemia, nausea/vomiting, dehydration, and diarrhea (6% each). Seven treatment-related SAEs have been reported; 28 subjects are off study. Patients discontinued treatment due to: progressive disease (PD) (n=15), toxicity (n=4, 1 each DVT, infection, back pain, and generalized weakness), withdrew consent (n=3), MD decision (n=2), patient request (n=2), and death (n=2), To date, 21 subjects have died; deaths were attributed to PD (n=16), CVA (n=1), and unknown (n=4). Conclusions: Pancreatic cancer, typically advanced at diagnosis, remains a major treatment challenge. Zoledronic acid in combination with gemcitabine was well-tolerated in this study. Future genomic testing is proposed for responders. Updated toxicity, response, and survival data will be presented. Supported by Novartis Pharmaceuticals Corp., East Hanover, NJ. No significant financial relationships to disclose.

Chemotherapy for advanced pancreatic cancer

Single-agent gemcitabine was established as standard treatment for advanced pancreatic cancer after a superior clinical benefit response was demonstrated in a randomized study comparing it to 5-fluorouracil (FU). Until recently, many subsequent randomized trials of newer, often gemcitabine-based combinations have not been able to show improved survival over gemcitabine. Combination gemcitabine and capecitabine is likely to become the preferred standard treatment, at least in the UK, on the basis of the positive interim results of the UK National Cancer Research Institute (NCRI) randomized study of chemotherapy with this combination. At present, there is no standard second-line treatment for patients who have become refractory to gemcitabine, although a recently reported study has suggested that oxaliplatin with FU and leucovorin is superior to best supportive care in these patients. This article will review and discuss the clinical trials of chemotherapy for this disease, including the more recent trials, which have included the novel targeted agents.

Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer

The primary objective of this study was to evaluate the tolerance and toxicity of radiation therapy (RT) and capecitabine in patients with advanced, unresectable pancreatic carcinoma. To control micrometastatic disease, combination chemotherapy (gemcitabine and cisplatin) before and after combined modality therapy (CMT) was planned. Patients with unresectable or metastatic pancreatic cancer were eligible. Gemcitabine 1000 mg/m2 and cisplatin 35 mg/m2 were administered on Days 1 and 8 of a 21-day cycle for two cycles. RT was then given to a dose of 50.4 Gy in 1.8 Gy fractions. Patients were treated with capecitabine 1330 mg/m2 daily during RT. After CMT, two additional cycles of gemcitabine and cisplatin completed the treatment. Twenty-three patients were treated. Eighteen patients completed CMT. One patient was removed from study during CMT for toxicity issues. Treatment delays and dose reductions were common during the final two cycles of gemcitabine and cisplatin as a result of myelosuppression. Median survival was 10.1 months (95% confidence interval [CI] = 7.6, 13.7) for all 23 patients and 12.8 months (95% CI = 8.2, 18.9) for 18 patients without metastasis. Combined modality therapy with RT and capecitabine was well tolerated. Chemotherapy after CMT was difficult to complete owing to cumulative myelosuppression. Survival, response, and toxicity were comparable to infusional 5-fluorouracil and RT.