Gemcitabine-refractory Advanced Pancreatic Cancer Research Articles

Fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy for gemcitabine-refractory advanced pancreatic cancer: A systematic review and meta-analysis of randomized controlled trials.

Fluoropyrimidine-based regimens have been investigated as the second line chemotherapy in patients with advanced pancreatic cancer refractory to gemcitabine. We conducted this systematic review and meta-analysis to evaluate the efficacy and safety profile of fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in such patients. The databases of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ASCO Abstracts and ESMO Abstracts were systematically searched. Randomized controlled trials (RCTs) that compared fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer were included. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate (ORR) and serious toxicities. Statistical analyses were performed by using Review Manager 5.3. Egger's test was performed to assess the statistical evidence of publication bias by using stata 12.0. A total of 1183 patients from six randomized controlled trials were included for this analysis. Fluoropyrimidine combination therapy increased ORR [RR 2.82 (1.83-4.33), p<0.00001] and PFS [HR 0.71 (0.62-0.82), p<0.00001], without significant heterogeneity. Fluoropyrimidine combination therapy improved OS [HR 0.82 (0.71-0.94), p = 0.006], with significant heterogeneity (I2 = 76%, p = 0.0009). The significant heterogeneity might have been caused by the different administration regimens and baseline characteristics. Peripheral neuropathy and diarrhea were more common in the regimens containing oxaliplatin and irinotecan, respectively. No publication bias was detected by Egger's tests. Compared with fluoropyrimidine monotherapy, fluoropyrimidine combination therapy had a higher response rate and longer PFS in patients with gemcitabine-refractory advanced pancreatic cancer. Fluoropyrimidine combination therapy could be recommended in the second line setting. However, due to concerns about toxicities, the dose intensities of chemotherapy drugs should be carefully considered in patients with weakness.

Efficacy and safety of 5-fluorouracil (5-FU) / levofolinate / irinotecan (FOLFIRI) for previously treated advanced pancreatic cancer (APC).

407 Background: 5-fluorouracil (5-FU) / levofolinate / irinotecan (FOLFIRI) is one of the preferred regimens for patients (pts) with advanced pancreatic cancer (APC) who received prior gemcitabine-based therapy in the National Comprehensive Cancer Network Guidelines. However, its survival benefit or safety in clinical practice is unclear. Methods: We retrospectively assessed the data of consecutive pts with APC who received FOLFIRI as a second or later-line treatment after gemcitabine-based therapy at Shizuoka Cancer Center between May 2014 and March 2020. Results: The characteristics of 102 pts included in this analysis were as follows: median age (range), 67 (39-78) y; male/female, 55/47; ECOG PS0/1/2, 21/72/9; the number of metastatic sites 0/1/2/3/4, 7/48/35/8/4; unresectable/recurrent, 84/18; UGT1A1 status wild/*6 or*28 heterozygous/homo or double-heterozygous/unknown, 40/40/5/17; treatment line of FOLFIRI 2nd/3rd/4th, 64/32/6. Previous treatment history according to the treatment line of FOLFIRI was as follows: 2nd-line, all patients received GEM-based regimen, GEM plus nanoparticle albumin bound paclitaxel in 63 pts (98.4%) and GEM in 1 (1.6%); 3rd, GEM-based and S1 in 20 (62.5%), GEM-based and 5-FU/levofolinate/oxaliplatin (FOLFOX) in 12 (37.5%); 4th, GEM-based, FOLFOX and S-1 or other agent in 5 (83.3%), 2 GEM-based regimens and S1 in 1 (16.7%). The median treatment cycle was 5 (range 1-55). The median treatment cycle according to the treatment line was as follows: 2nd-line, 7(1-55); 3rd, 4(1-14); 4th, 3.5(1-10). The initial dosage for each cytotoxic agent was as follows: bolus 5-FU injected/omited 72/30; continuous 5-FU 2400/2000/1200 mg/m2, 88/13/1; irinotecan 180/150/120/less than or equal to 100mg/m2, 27/59/13/3. The overall response rate (ORR) and disease control rate (DCR) were 5.9% and 52.9%, respectively. ORR and DCR according to the treatment line were as follows: 2nd-line, 9.3/64.1%; 3rd, 0/68.8%; 4th, 0/50.0%. At the median follow up 6.5 M, the median overall survival (OS) and progression free survival (PFS) were 6.6M and 3.1M, respectively. The median OS and PFS according to the treatment line were as follows: 2nd-line, 8.1/3.6M; 3rd, 5.1/2.1M; 4th, 6.6/2.0M. Adverse events (AEs) were observed in 70.8% pts. Grade 3 or higher AEs occurred in 27.2% pts [neutropenia in 26 (25.2%) pts, febrile neutropenia in 4 (3.9%) pts, nausea in 4 (3.9%) pts, decreased appetite in 3 (2.9%) pts]. No treatment related deaths were observed. Conclusions: FOLFIRI is well tolerated and effective especially in the second-line treatment for pts with gemcitabine-refractory APC.

Oral chemotherapy for second-line treatment in patients with gemcitabine-refractory advanced pancreatic cancer.

BACKGROUNDThere is no standard therapy for second-line treatment of gemcitabine-refractory pancreatic cancer patients with poor performance status. A combination of chemotherapy drugs 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or 5-fluorouracil/leucovorin plus nanoliposomal irinotecan can be considered as second-line treatment for such patients; however, due to toxicity, none of the regimens are recommended for patients with poor performance. Capecitabine or S-1 has relatively low toxicity and can be considered a treatment option for gemcitabine-refractory pancreatic cancer.AIMTo investigate the efficacy and toxicity of oral chemotherapy as second-line treatment in patients with pancreatic cancer.METHODSPatients who had progressive disease after first-line gemcitabine-based chemotherapy were retrospectively analyzed between January 2011 and December 2018. They were treated with capecitabine or S-1 as the second-line treatment. Capecitabine was administered as a 2500 mg/m2 divided dose on days 1-14, followed by a 1-wk rest. S-1 was taken orally based on the patient’s body surface area for 28 d, followed by 2-wk of rest. Progression-free survival and overall survival were used to compare efficacy of capecitabine and S-1.RESULTSOf the 81 patients, 41 were treated with capecitabine and 40 with S-1. The median time to treatment failure in both groups was 1.5 mo (P = 0.425). The objective response rate was similar in the two groups: 9.8% with capecitabine and 2.5% with S-1 (P = 0.359). Median progression-free survival was longer in the S-1 group than in the capecitabine group (S-1 2.7 mo, capecitabine 2.0 mo, P = 0.003). There was no significant difference in the median overall survival between the capecitabine and S-1 groups (4.3 mo vs 5.0 mo, P = 0.092). Grade 3 or 4 hand-foot syndrome was significantly more common in the capecitabine group than in the S-1 group (14.6% vs 0%, P = 0.026).CONCLUSIONCapecitabine or S-1 can be used as a second-line treatment for patients with advanced pancreatic cancer with poor performance status after progression to a gemcitabine-based regimen.

714P - Phase I study of the oncolytic viral immunotherapy agent canerpaturev (C-REV) with S-1 in patients with stage IV pancreatic cancer

714P - Phase I study of the oncolytic viral immunotherapy agent canerpaturev (C-REV) with S-1 in patients with stage IV pancreatic cancer

Oral chemotherapy as second-line treatment option for gemcitabine-refractory advanced pancreatic cancer with poor performance status.

405 Background: There is few data for effective second-line treatment in advanced pancreatic cancer, and most patients have poor performance status after progressive disease. We evaluated the efficacy, toxicity, and median dose intensity of oral chemotherapy, capecitabine, or TS-1 in gemcitabine-refractory advanced pancreatic cancer for second-line treatment. Methods: Patients who have progressive disease after first-line gemcitabine-based chemotherapy were retrospectively analyzed between Jan. 2011 and Nov. 2017. These patients were treated with capecitabine or TS-1 as second-line treatment. Capecitabine were administered as 2,500 mg/m2 divided dose on day 1-14, followed by one week rest. In TS-1 group, TS-1 was taken orally based on patient’s BSA (60mg twice daily in BSA &gt; 1.5, 50mg twice daily in BSA 1.25-1.5, and 40mg twice daily in BSA &lt; 1.25) through 28 days, by two week rest. Median dose intensity was compared by calculating a percent of target dose achieved in the average cycle for each patient. Results: Of the total 62 patients, 41 patients were treated with capecitabine and 21 patients were treated with TS-1. The median age was 61 years for the capecitabine group compared with 62 years for the TS-1 group. In capecitabine group, males were 56%, and in TS-1 group, males were 66%. 29% of capecitabine group received prior fluorouracil base therapy, and 47% of TS-1 group were receiving such therapy. The objective response rate was similar in the two groups: 12.2% with capecitabine and 4.8% with TS-1 (p = 0.358). There was no difference in median progression free survival between capecitabine and TS-1 (2.1 months vs. 2.7 months, p = 0.102), however, TS-1 group showed better median overall survival time than capecitabine group (6.9 months vs. 4.6 months, p = 0.048). Most of the adverse events were similar in both group, except that grade 3 or 4 mucositis was more common in TS-1 group. There was no significant difference in median dose intensity between two groups. (Capecitabine 91.5% vs. TS-1 90.1%, p = 0.216). Conclusions: Oral agents such as TS-1 or capecitabine can be second-line treatment for advanced pancreatic cancer patients with poor performance status after progression to gemcitabine-based regimen.

TAS-118 (S-1 plus leucovorin) versus S-1 in patients with gemcitabine-refractory advanced pancreatic cancer: a randomised, open-label, phase 3 study (GRAPE trial)

BackgroundIn our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS). Patients and methodsThis randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40–60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40–60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS. ResultsA total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82–1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67–0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups. ConclusionTAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.

Attenuated FOLFIRINOX in the salvage treatment of gemcitabine-refractory advanced pancreatic cancer: a phase II study

BackgroundCombination therapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) chemotherapy drastically improves survival of advanced pancreatic cancer patients. However, the efficacy of FOLFIRINOX as a second-line treatment after gemcitabine failure has not been tested prospectively. We investigated the feasibility and safety of attenuated FOLFIRINOX in patients with gemcitabine-refractory advanced pancreatic cancer.MethodsA multicenter phase II prospective open-label, single-arm study was conducted at 14 hospitals. Patients with histologically proven invasive ductal pancreatic adenocarcinoma, a measurable or evaluable lesion, Eastern Cooperative Oncology Group performance status 0 or 1, adequate organ function, and aged 19 years or older were eligible. Attenuated FOLFIRINOX consisted of oxaliplatin 65 mg/m2, irinotecan 135 mg/m2, and leucovorin 400 mg/m2 injected intravenously on day 1 and 5-fluorouracil 2000 mg/m2 continuously infused intravenously over 46 h on days 1–2, repeated every 2 weeks. The primary endpoint was progression-free survival from the initiation of FOLFIRINOX. Secondary endpoints were the objective response rate, disease control rate, overall survival, safety, and tolerability. We estimated overall survival and progression-free survival using the Kaplan–Meier methods.ResultsWe enrolled 39 patients from 14 institutions. The objective response rate was 10.3%, while the disease control rate was 64.1%. The 6-month and 1-year overall survival rates were 59.0% and 15.4%, respectively. Median progression-free survival and overall survival were 3.8 months (95% confidence interval [CI] 1.5–6.0 months) and 8.5 months (95% CI 5.6–11.4 months), respectively. Grade 3 or 4 adverse events were neutropenia (41.0%), nausea (10.3%), anorexia (10.3%), anemia (7.7%), mucositis (7.7%), pneumonia/pleural effusion (5.1%), and fatigue (5.1%). One treatment-related death attributable to septic shock occurred.ConclusionAttenuated FOLFIRINOX may be promising as a second-line therapy for gemcitabine-refractory pancreatic cancer.

Randomized phase II study of S-1 monotherapy versus gemcitabine plus S-1 in gemcitabine-refractory advanced pancreatic cancer.

429 Background: Gemcitabine is one of the standard chemotherapeutic agents for pancreatic cancer in a first-line setting. In a second-line setting, there are various unmet needs. After gemcitabine chemotherapy, S-1 is mainly used and sometimes gemcitabine plus S-1 (GS) is used. Cytotoxic effect of gemcitabine had been reported to have the potential to be enhanced when used with fluorouracil. This randomized study aimed to evaluate the efficacy and safety of gemcitabine plus S-1 in gemcitabine-refractory advanced pancreatic cancer. Methods: This phase II study consisted of patients (pts) who were randomly allocated into the GS group (gemcitabine 1,000 mg/m2 on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle) or the S-1 group (S-1 80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle) at a 1:1 ratio. The primary endpoint was the evaluation of progression-free survival (PFS). The sample size of 90 pts was chosen based on the randomized phase II selection design reported by Simon et al.(1985). The design suggests a correct selection probability of 75% with two-sided significance level of 0.10 if median PFS is 3.3 mo and 2.0 mo in GS and S-1 groups. Results: From Jan 2012 to March 2015, randomized 51 pts were examined (GS: 26, S-1: 25). This study was discontinued due to slow accrual. The median PFS of GS group was 2.0 mo while the S-1 group was 2.1 mo. The hazard ratio was 1.06 [95%CI 0.60-1.86]; (p=0.844). The median survival times were 3.8 mo in GS group and 5.5 mo in S-1 group, respectively. The hazard ratio was 1.02 [95%CI 0.57-1.81]; (p=0.96). The response rates were 4.2% and 4.3%. The disease control rates were 33.4% and 30.4%. Although bone marrow suppression is higher in GS group, the toxicities were manageable in both groups. Grade 3/4 toxicities (GS/S-1 %) included: neutropenia, 53.8/8; hemoglobin, 30.8/28.0; thrombocytopenia, 7.7/4.0; nausea, 0/8.0; anorexia 11.5/16.0, fatigue 7.7/0 and diarrhea, 3.8/4.0. Conclusions: Gemcitabine plus S-1 is not more effective than S-1 in gemcitabine-refractory advanced pancreatic cancer. Clinical trial information: 000007173.

Antitumor Effects of Eribulin Mesylate in Gemcitabine-resistant Pancreatic Cancer Cell Lines.

One reason of poor survival rate of patients with pancreatic cancer is the development of chemoresistance. The aim of the present study was to investigate the effects of eribulin mesylate in gemcitabine-refractory advanced pancreatic cancer cell lines. Three human pancreatic cancer cell lines (AsPC-1, Panc-1, and SUIT-2) and human pancreatic endoderm (hPE) cells were used to evaluate the antitumor effects of gemcitabine and eribulin mesylate. Cell viability after treatment of cells with different concentrations of gemcitabine and eribulin mesylate was evaluated using water-soluble tetrazolium salts (WST) assays; cytotoxic effects were evaluated on the basis of morphological changes to cells. Gemcitabine had no effect on cell viability of AsPC-1 nor Panc-1 cells, whereas gemcitabine reduced cell viability of SUIT-2 cells in a dose-dependent manner. Eribulin mesylate significantly reduced cell viability of both AsPC-1 and Panc-1 cells (p<0.001 and p=0.002, respectively), but had no effect on hPE cells. Microscopic examination of AsPC-1 and Panc-1 cells after treatment with eribulin mesylate revealed morphological changes that included cell shrinkage, membrane blebbing, and fragmentation of the cells after drug exposure, and these were concentration-dependent effects. The findings of the present study suggest that eribulin mesylate may be a promising potential anticancer drug for gemcitabine-refractory advanced pancreatic cancer.

A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer

We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC). Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS). Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37-0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54-1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47-1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group. The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting. Japan Pharmaceutical Information Center: JapicCTI-111554.

Retrospective analysis of fixed dose rate infusion of gemcitabine and S-1 combination therapy (FGS) as salvage chemotherapy in patients with gemcitabine-refractory advanced pancreatic cancer: inflammation-based prognostic score predicts survival.

The purpose of this study was to assess the efficacy and safety of fixed dose rate infusion of gemcitabine and S-1 combination therapy (FGS) in patients with gemcitabine (GEM)-refractory pancreatic cancer (PC) and to explore independent variables associated with survival. We retrospectively reviewed consecutive patients with GEM-refractory PC who received FGS at our institution from March 2009 to December 2013. GEM was administered by fixed dose rate intravenous infusion of 1,200mg/m(2) as a 120-min infusion on day 1, and S-1 was administered orally twice a day at a dose of 40mg/m(2) on days 1-7. Cycles were repeated every 14days. Sixty-one patients with GEM-refractory PC received FGS. Sixteen patients received FGS as third-line treatment. Twenty-nine patients (48%) had a history of S-1 administration. The objective response rate was 13%, and the disease control rate was 49%. The median progression-free survival time was 2.7months, and the median overall survival time was 6.0months. Major Grade 3 or 4 adverse events included neutropenia (15%), diarrhea (3%), anorexia (2%), and fatigue (2%). A high inflammation-based prognostic score (modified Glasgow prognostic score (mGPS), which incorporates C-reactive protein and albumin), a performance status >0, and serum carbohydrate antigen 19-9 level >2,000IU/ml were independently associated with a poor outcome. FGS might be effective and well tolerated as salvage chemotherapy in a practical setting. The inflammation-based prognostic score is a simple and reliable indicator of survival in the setting of salvage chemotherapy.

714P - Fixed Dose Rate Gemcitabine and S-1 Combination Therapy (Fgs) As Salvage Chemotherapy for Gemcitabine-Refractory Advanced Pancreatic Cancer

ABSTRACT Aim: No standard salvage chemotherapy regimens has been established for patients with advanced pancreatic cancer after failure of gemcitabine-based treatment. Although a phase I/II clinical trial of FGS was conducted, the number of patients enrolled was small and the efficacy and safety of FGS is still not well known. Methods: We retrospectively reviewed 67 patients who received FGS as salvage chemotherapy at our institution from March 2009 to Mach 2014. The selection criteria in this study was progressive disease under gemcitabine-based chemotherapy, ECOG performance status Results: Sixty-six patients were selected for the analysis. Twenty-two patients of them had received FGS as third line treatment. The overall responce rate was 12% and the disease control rate was 45%. The median progression-free survival time was 2.7 months and the median overall survival time was 6.0 months. The common grade 3/4 toxicities were leukopenia (11%), neutropenia (15%), diarrhea (3%), anorexia (2%) and fatigue (2%). Univariate analysis showed that performance status of >0, presence of ascites, serum carcinoembryonic antigen level of > 10 ng/ml, serum albumin level of 500 IU/L and serum C-reactive protein level of > 1.0 mg/dl were significantly associated with a poor prognosis. Multivariate analysis identified serum C-reactive protein level of > 1.0 mg/dl and serum albumin level of Conclusions: FGS as salvage chemotherapy for patients with gemcitabine-refractory advanced pancreatic cancer is marginally effective and well tolerated in a practical setting. These results suggest FGS is of value to be further investigated in a clinical trial in patients with gemcitabine-refractory pancreatic cancer. Disclosure: All authors have declared no conflicts of interest.

A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer

BackgroundErlotinib induced skin toxicity has been associated with clinical benefit in several tumour types. This phase II study evaluated the efficacy of erlotinib, dose escalated to rash, in patients with advanced pancreatic cancer previously treated with gemcitabine. MethodsErlotinib was given at an initial dose of 150mg/day, and the dose was escalated by 50mg every 2weeks (to a maximum of 300mg/day) until >grade 1 rash or other dose limiting toxicities occurred. Erlotinib pharmacokinetics were performed, and baseline tumour tissue was collected for mutational analysis and epidermal growth factor receptor (EGFR) expression. The primary end-point was the disease control rate (objective response and stable disease >8weeks). ResultsFifty-one patients were accrued, and 49 received treatment. Dose-escalation to 200–300mg of erlotinib was possible in 9/49 (18%) patients. The most common ⩾grade 3 adverse events included fatigue (6%), rash (4%) and diarrhoea (4%). Thirty-seven patients were evaluable for response, and the best response was stable disease in 12 patients (32% (95% confidence interval (CI) 17–47%)). Disease control was observed in nine patients (24% (95% CI: 10–38%)). Median survival was 3.8months, and 6month overall survival rate was 32% (95% CI 19–47%). Mutational analysis and EGFR expression were performed on 29 patients, with 93% having KRAS mutations, none having EGFR mutations, and 86% expressing EGFR. Neither KRAS mutational status nor EGFR expression was associated with survival. ConclusionsErlotinib dose escalated to rash was well tolerated but not associated with significant efficacy in non-selected patients with advanced pancreatic cancer.

S-1 monotherapy or in combination with leucovorin as second-line treatment in gemcitabine-refractory advanced pancreatic cancer: A phase II study.

e15222 Background: Previous studies have revealed that the fluorouracil derivative S-1as first-line treatment can bring survival benefit and good tolerability for patients with unresectable pancrea...

5-Fluorouracil/Leucovorin Combined with Irinotecan and Oxaliplatin (FOLFIRINOX) as Second-Line Chemotherapy in Patients with Advanced Pancreatic Cancer Who Have Progressed on Gemcitabine-Based Therapy

Background/Aims: There is no standard consensus on a strategy in the second-line setting for gemcitabine-refractory advanced pancreatic cancer. This study evaluated the activity and tolerability of oxaliplatin, irinotecan, 5-fluorouracil and leucovorin (FOLFIRINOX) as a second-line therapy in advanced pancreatic adenocarcinoma pretreated with a gemcitabine-based regimen. Methods: A retrospective survey was carried out on 18 patients with advanced pancreatic cancer who had been on gemcitabine-based chemotherapy and were then treated with FOLFIRINOX as a second-line therapy. Results: One patient (5.6%) had a confirmed complete response, 4 (22.2%) had confirmed partial responses and 5 (27.8%) had stable disease, resulting in a rate of disease control of 55.6% (95% CI, 33.3-77.8%). The median progression-free survival and median survival were 2.8 months and 8.4 months, respectively. Seven patients (38.9%) experienced grade 3-4 neutropenia. Grade 3 or 4 nonhematologic adverse events included nausea (38.9%) and vomiting (16.7%). Conclusions: These results suggest the modest clinical activity regarding efficacy and the acceptable toxicity profile with the FOLFIRINOX regimen as a second-line treatment.

FOLFIRINOX as second-line chemotherapy in patients with advanced pancreatic cancer who have progressed on gemcitabine-based therapy

Objective: There is no standard consensus on a strategy in the second-line setting for gemcitabine refractory advanced pancreatic cancer. This study aimed to evaluate the activity and tolerability of oxaliplatin, irinotecan, 5-fluorouracil (5-FU) and leucovorin (FOLFIRINOX) as second-line therapy in locally advanced unresectable or metastatic pancreatic adenocarcinoma pretreated with gemcitabine based regimen. Methods: A retrospective survey was carried out with 18 patients (Eastern Cooperative Oncology Group performance status score of 0–1) with advanced pancreatic cancer who received a gemcitabine based chemotherapy and who were treated with FOLFIRINOX as second-line therapy between June 2011 and December 2012.

Phase II clinical trial to evaluate the efficacy and safety of activated T-lymphocyte cell therapy in gemcitabine refractory advanced pancreatic cancer

high volume multidisciplinary pancreas center. Independent two-sample t-tests were used to compare continuous variables, and chi-squared tests were used to compare categorical variables. Kaplan-Meier methods were employed to initially test survival between groups and then Cox-Proportional Hazard Models were used to control for additional variables. Results: We identified 6031 patients in the SEER database and 345 patients (5.7% of the national total) at a high-volume single center, who had resection for pancreatic adenocarcinoma between 1993-2007. There was no difference in the average age (65.4 vs. 65.2) or sex (49.5% vs. 49.6% male) of the patients in the two groups (p>0.05). Using SEER historic staging criteria (localized, regional, distant), cancers resected in the SEER group were broken down as 12.6% localized, 71.0% regional, and 16.4% distant. Cancers resected at the high volume center were broken down as 36.8% localized, 62.3% regional, and 0.9% distant. There was therefore, a higher proportion of resectable cancers (localized + regional) undergoing surgery at the high volume center compared to the SEER group (99% vs 84%, p= 0.031). Only 1% of patients taken for surgery at the single center were not resectable because of distant disease. 22.6% of patients at the single center had vascular reconstruction representing a technically difficult operation with high morbidity and mortality. 5-year survival was significantly increased in the high volume versus the SEER group (12.46% vs. 5.37%) by Kaplan-Meier methods (p<0.001), but as expected, not by Cox-Proportional Hazard Models controlling for stage, age, sex, and year of surgery (HR 1.012, 95%CI 0.892-1.149, p=0.848). Conclusions: Increased survival of patients with resected pancreatic adenocarcinoma seen in a high-volume multidisciplinary pancreas center may be explained by more prudent identification of resectable cases. This is likely secondary to better preoperative detection, staging, and multidisciplinary expertise. Dedicated high-volume centers are an important means of improving survival from pancreas cancer.

Effect of second-line treatment with capecitabine and thalidomide in patients with advanced pancreatic cancer

This study investigates the efficacy and tolerability of capecitabine plus thalidomide in patients with advanced pancreatic cancer who previously underwent gemcitabine-based therapy. Sixty-one patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem-containing regimen were enrolled. The patients were randomly divided into two groups. One group (31 patients) was treated with capecitabine alone, and another group was treated with capecitabine plus thalidomide. Capecitabine was administered orally twice a day at a dose of 1, 250 mg/m(2) for 14-day followed by 7-day rest and oral thalidomide 100 mg was given daily without interruption until disease progression or occurrence of unacceptable toxicity. The PFS was 2.8 months (95%CI 2.4 - 3.2) vs. 3.1 months (95%CI 2.6-3.6, P < 0.05) and the OS was 6.1 months (95%CI 5.3 - 6.9) vs. 6.3 months (95%CI 5.2 - 7.4, P = 0.426). In the capecitabine alone group, one patient experienced a partial response (PR), 10 patients showed stable disease (SD) and 20 patients had progressive disease (PD). The another group, two patients experienced a partial response (PR), 11 patients SD, and 17 patients PD. The disease control rates were 35.5% and 43.3%, respectively. The major adverse reaction in the two groups was grade 3 diarrhea. Capecitabine plus thalidomide regimen is marginally effective and well tolerated in the second-line setting in patients with gemcitabine-refractory advanced pancreatic cancer.

Gemcitabine and cisplatin combined with regional hyperthermia as second-line treatment in patients with gemcitabine-refractory advanced pancreatic cancer

Purpose: There is no standard second-line therapy for patients with advanced pancreatic cancer (APC) after gemcitabine (G) failure. Cisplatin (Cis)-based chemotherapy has shown activity in APC. It is proven that cytotoxicity of G and Cis is enhanced by heat exposure at 40° to 42°C. Therefore G plus Cis with regional hyperthermia (RHT) might be beneficial for patients with G-refractory APC.Patients and methods: We retrospectively analysed 23 patients with advanced (n = 2) or metastatic (n = 21) pancreatic cancer with relapse after G mono first-line chemotherapy (n = 23). Patients had received G (day 1, 1000 mg/m2) and Cis (day 2 and 4, 25 mg/m2) in combination with RHT (day 2 and 4, 1 h) biweekly for 4 months. We analysed feasibility, toxicity, time to second progression (TTP2), overall survival (OS) and clinical response.Results: Between October 1999 and August 2008 23 patients were treated. Haematological toxicity was low with no grade 4 event. Hyperthermia-associated toxicity consisted of discomfort because of bolus pressure (3%), power-related pain (7%) or position-related pain (17%). Median TTP1 was 5.9 months (95% confidence interval (CI): 2.6–9.2), median TTP2 was 4.3 months (95%CI: 1.2–7.4) and OS 12.9 months (95%CI: 9.9–15.9). The disease control rate in 16 patients with available CT scans was 50%.Conclusion: We show first clinical data of G plus Cis with RHT being clinically active in G-pretreated APC with low toxicity. A prospective controlled phase II second-line clinical trial (EudraCT: 2005-003855-11) and a randomised phase III adjuvant clinical trial offering this treatment (HEAT; EudraCT: 2008-004802-14) are currently open for recruitment.

P-0107 Gemcitabine and Cisplatin Combined with Regional Hyperthermia as Second-Line Treatment in Patients with Gemcitabine-Refractory Advanced Pancreatic Cancer

IntroductionGemcitabine (G) is the standard first-line treatment in patients with advanced pancreatic cancer (APC). Currently there is no standard second-line therapy for patients after G-failure. Cisplatin (Cis)-based chemotherapy has shown activity in APC. From preclinical research it is proven that cytotoxicity of G and Cis is enhanced by heat exposure at 40° to 42°C. Here we show first clinical data on the combination of G plus Cis with regional hyperthermia (RHT; 40° to 42°C) as second-line treatment in APC patients with G-refractory disease. MethodsWe retrospectively analyzed 23 patients with advanced (n=2) or metastatic (n=21) pancreatic cancer with relapse after G mono (n=23) first-line chemotherapy (time to first progression; TTP1). Patients had received G (day1, 1000mg/m2) and Cis (day 2 and 4, 25mg/m2) in combination with RHT (day 2 and 4, 1 hour) using the BSD 2000 system. A total of 8 cycles including 16 RHT applications was prescribed in a biweekly schedule. The treatment protocol was approved by the local ethics committee (project number 79/98) and signed informed consent was received from each patient before start of therapy. We analyzed feasibility and toxicity, addressing both hematological and non-hematological side effects according to NCI criteria. Time to second progression (TTP2) and overall survival (OS) was analyzed for all patients. Clinical response according to RECIST criteria was assessed for patients with available CT scans. ResultsBetween 10/99 and 08/08 23 pts were treated and received a median of 5 [range 1-12] chemotherapy cycles and 6.5 [range 1-16] hyperthermia treatments. Hematological toxicity was low with no grade 4 event, but grade 3 anemia and leukopenia in six and three patients. Hyperthermia-associated toxicity consisted of discomfort because of bolus pressure (3%), power-related pain (7%) or position-related pain (17%), with a total of 6 break ups (3%) of hyperthermia sessions in 5 patients. Median TTP1 was 5.9 months (95% CI: 2.6-9.2), median TTP2 was 4.3 months (95% CI: 1.2-7.4) and OS 12.9 months (95% CI: 9.9-15.9). The disease control rate in 16 patients with available CT scans was 50% (1 PR, 7 SD, 8 PD). ConclusionWe show first clinical data that G plus Cis combined with RHT is clinically active in G-pre-treated advanced pancreatic cancer with low toxicity. A prospective controlled phase II clinical trial of G+CIS+RHT (EudraCT: 2005-003855-11) using this setting is currently open for recruitment.