Treatment Of Metastatic Pancreatic Cancer Research Articles

Impact of gemcitabine on the treatment of metastatic pancreatic cancer

A previous randomized trial showed gemcitabine was superior to 5-fluorouracil in overall patient survival. However, the incremental improvement in survival was minimal. It is 2.5 years since gemcitabine has become available for the treatment of pancreatic cancer in clinical practice in Japan. The current study was conducted to examine whether treatment outcomes have changed since the introduction of gemcitabine therapy. Ninety-one consecutive patients with metastatic pancreatic cancer treated with systemic chemotherapy at the National Cancer Center Hospital East were surveyed. Patients admitted before April 2001 received 5-fluorouracil, and those admitted subsequently received gemcitabine. The patients were divided into the gemcitabine group (n = 50) and the non-gemcitabine group (n = 41), and these groups were compared for five outcomes, objective response rate, non-progressive disease rate, carbohydrate antigen (CA)19-9 response rate, actual survival time, and difference between estimated and observed survivals. The estimated survival time was determined using the prognostic index reported in the previous study. Except for the objective response rate, the four other outcomes in the gemcitabine group were significantly superior to those in the non-gemcitabine group. The frequency of non-progressive disease, CA19-9 response, and favorable prognosis compared with the estimated survival, were 58%, 22%, and 60%, respectively, in the gemcitabine group, and 22%, 6%, 30%, respectively, in the non-gemcitabine group. The median survival time in the gemcitabine and non-gemcitabine group was 5.73 and 2.87 months, respectively. It is suggested that there was a definite improvement in pancreatic cancer treatment after gemcitabine was introduced.

A prospective randomized trial of gemcitabine alone or gemcitabine + cisplatin in the treatment of metastatic pancreatic cancer

4144 Background: To determine the efficacy and toxicity of gemcitabine alone (GEM) versus GEM + cisplatin (G + C) in the treatment of metastatic pancreatic cancer. Methods: From Jan-98 to Jun-02, 46 patients with metastatic pancreatic cancer were studied. Twenty-five patients were randomized to receive GEM (1000 mg/m2/week × 3 every 4 weeks), and 21 patients to G + C (GEM 1000 mg/m2/week and cisplatin 25 mg/m2/week × 3 every 4 weeks). The primary endpoint was patients' survival. Results: The planned accrual was 24 patients per arm. The reported accrual was 25 patients in GEM group and 21 in G + C group. The median duration of follow-up was 5.3 months. Sex, age, pre-treatment serum biochemistries, tumor size and location, and performance status were similar between both groups. Gemcitabine dose intensity was similar between GEM and G + C (684 ± 32 vs 617 ± 31 mg/m2/wk). Cisplatin dose intensity was 15.1 ± 0.9 mg/m2/wk × 9.9 ± 1.8 weeks. Median survival and median time to progression (TTP) were 4.6 months and 2.8 months for GEM and 5.6 months and 2.8 months for G + C patients (p= 0.75 and p= 0.9). Clinical benefit (including pain control, performance status, and body weight gain) was 36% for GEM and 29 % for G + C (p> 0.05). Quality-adjusted-life-months survival were 5.6 ± 0.3 months for GEM and 3.8 ± 0.2 months for G + C patients (p< 0.001). Response rates were 12% (3 PR) for GEM and 10% (2 PR) for G + C patients (p> 0.05). Grade 3–4 neutropenia (8% vs 19%), anemia (8% vs 10%) or hospitalization days per month of survival (6.8 ± 2.2 vs 6.2 ± 1.6 days) was not significantly different between GEM and G + C patients, but G + C had higher rate of thrombocytopenia than GEM patients (24% vs 4%, p = 0.012). Conclusions: GEM and G + C had comparable and modest response rates for metastatic pancreatic cancer, but GEM produced lesser toxicities than G + C. No significant financial relationships to disclose.

Advanced pancreatic cancer: a multi-institutional trial with gemcitabine and thalidomide

4082 Background: Advances in treatment of metastatic pancreatic cancer remain challenging with median survivals reported in the 4–6 month range following standard gemcitabine chemotherapy. Thalidom...

GTX chemotherapy for metastatic pancreatic cancer: Response, survival, and toxicity data

4271 Background: In vitro studies in our lab demonstrated synergistic cytotoxicity with 5FUR, gemcitabine, and docetaxel (GTX) against human PC lines with mutant p53, activated ras and deleted p16. This increased Bax and decreased Bcl-XL levels by a p53 independent mechanism involving the MAPK pathway with decreased ERK phosphorylation. Methods: We performed a retrospective chart review of all identifiable patients treated with GTX by the authors. (The regimen consists of capecitabine 1000mg/m2/day total as BID doses days 1–14; on days 4 and 11 gemcitabine (750 mg/m2/IV over 75 min) and docetaxel (30 mg/m2 ) are given IV. Response rates were measured per WHO criteria; survival was dated from the first GTX treatment. Results: We treated 35 metastatic pancreatic cancer patients with GTX chemotherapy dating from 2001 onwards. 94% of patients had metastases in the liver. We did not exclude patients for poor performance status. Of these, 28 completed at least three cycles of chemotherapy and were considered evaluable for response. At the metastatic sites, there were 3 CR and 11 PR for a 50% response rate. (40% on intent-to-treat basis). At the primary tumor (n=25, 3 pts had Whipple), there were 4 CR and 6 PR for a 40% response rate (31% on intent-to-treat basis). 34% of patients were previously treated with gemcitabine based regimens. Median survival for all 35 is at least 8.6 months and 10.5 months for those who complete 3 cycles. The longest survivor is alive at 1056 days. Toxicities were mild; of 32 patients evaluated for toxicity, there were 6 grade 3–4 leukopenias; 3 grade 3–4 anemias; 5 grade 3–4 thrombocytopenias. Ten patients experienced hand-foot syndrome, 11 patients abdominal cramps, 17 patients had diarrhea. There were 2 grade 4 infections (no deaths). 14 of 18 (78%) patients with an elevated CA 19–9 had greater than a 90% drop. In general, the regimen was well tolerated by patients. Conclusions: The GTX regimen represents a potential advance in the treatment of metastatic pancreatic cancer. It demonstrates an excellent response rate and superior survival of an extremely poor prognosis group of patients. A prospective phase II trial is in progress and a phase III trial is being planned. No significant financial relationships to disclose.

GTX chemotherapy for metastatic pancreatic cancer: Response, survival, and toxicity data

4271 Background: In vitro studies in our lab demonstrated synergistic cytotoxicity with 5FUR, gemcitabine, and docetaxel (GTX) against human PC lines with mutant p53, activated ras and deleted p16. This increased Bax and decreased Bcl-XL levels by a p53 independent mechanism involving the MAPK pathway with decreased ERK phosphorylation. Methods: We performed a retrospective chart review of all identifiable patients treated with GTX by the authors. (The regimen consists of capecitabine 1000mg/m2/day total as BID doses days 1–14; on days 4 and 11 gemcitabine (750 mg/m2/IV over 75 min) and docetaxel (30 mg/m2 ) are given IV. Response rates were measured per WHO criteria; survival was dated from the first GTX treatment. Results: We treated 35 metastatic pancreatic cancer patients with GTX chemotherapy dating from 2001 onwards. 94% of patients had metastases in the liver. We did not exclude patients for poor performance status. Of these, 28 completed at least three cycles of chemotherapy and were considered evaluable for response. At the metastatic sites, there were 3 CR and 11 PR for a 50% response rate. (40% on intent-to-treat basis). At the primary tumor (n=25, 3 pts had Whipple), there were 4 CR and 6 PR for a 40% response rate (31% on intent-to-treat basis). 34% of patients were previously treated with gemcitabine based regimens. Median survival for all 35 is at least 8.6 months and 10.5 months for those who complete 3 cycles. The longest survivor is alive at 1056 days. Toxicities were mild; of 32 patients evaluated for toxicity, there were 6 grade 3–4 leukopenias; 3 grade 3–4 anemias; 5 grade 3–4 thrombocytopenias. Ten patients experienced hand-foot syndrome, 11 patients abdominal cramps, 17 patients had diarrhea. There were 2 grade 4 infections (no deaths). 14 of 18 (78%) patients with an elevated CA 19–9 had greater than a 90% drop. In general, the regimen was well tolerated by patients. Conclusions: The GTX regimen represents a potential advance in the treatment of metastatic pancreatic cancer. It demonstrates an excellent response rate and superior survival of an extremely poor prognosis group of patients. A prospective phase II trial is in progress and a phase III trial is being planned. No significant financial relationships to disclose.

Advanced pancreatic cancer: a multi-institutional trial with gemcitabine and thalidomide

4082 Background: Advances in treatment of metastatic pancreatic cancer remain challenging with median survivals reported in the 4–6 month range following standard gemcitabine chemotherapy. Thalidomide, which has immunomodulatory and anti-angiogenesis properties has shown promising results in malignant and non-malignant conditions. K-ras mutations, which are present in 90% of patients with pancreatic adenocarcinoma can result in overexpression of VEGF, making Thalidomide an agent to explore. Methods: Phase II trial of gemcitabine 1000mg/m2day 1,8,15 every 28 days, with thalidomide dose escalation from 200mg daily to maximum tolerated dose by 12 weeks. Objectives: RR, TTP, overall survival, clinical benefit response (CBR), tolerability. Results: 27 patients (24 metastatic/3 locally advanced) were treated between 12/01 and 11/03, median age 60 (range 41–76), 17 males/10 females, all with a KPS of ≥ 70%; 6 received prior radiation therapy. Average Thalidomide dose 320 mg (range 50–700 mg). Grade 3–5 toxicities noted in 23 patients: sepsis 2, pneumonia 1, syncope 2, GI bleed 1, DVT 2, neutropenia 11, thrombocytopenia 1, peripheral neuropathy 1, stroke 1, and depressed level of consciousness 4. Constipation ≤ grade 2 was common. There were 4 deaths during treatment. Median number of cycles given 3, with average 4.6 (range 1–17). Response: Of 21 evaluable patients, PR: 3, stable: 13, progressive disease: 5. CBR: 35% scored positive based on pain scale, KPS, and weight gain. Median survival: 183 days with average 232 days (range 37–635+ days); 9 of 27 evaluable patients survived > 6+ months, and 4 > one+ year. Median TTP: 112 days with average 146 days (range 13–518 days). A >50% reduction in CA 19–9 occurred in 55% of patients. Conclusions: Gemcitabine with thalidomide appears to be a promising combination in the treatment of advanced pancreatic adenocarcinoma with suggestion of improvement in TTP and CBR compared to historical data from single agent Gemcitabine. Further studies with gemcitabine and newer immunomodulatory agents are warranted. No significant financial relationships to disclose.

A prospective randomized trial of gemcitabine alone or gemcitabine + cisplatin in the treatment of metastatic pancreatic cancer

A prospective randomized trial of gemcitabine alone or gemcitabine + cisplatin in the treatment of metastatic pancreatic cancer

Metastatic pancreatic cancer: emerging strategies in chemotherapy and palliative care.

This update is devoted to discussion of optimal supportive and palliative care of patients with pancreatic cancer. Approximately 33,000 new cases of pancreatic cancer are predicted for the U.S. in 2002. Because diagnosis and intervention occur late in the course of this disease, the vast majority of patients already have metastatic disease at the time of diagnosis. These tumors are relatively resistant to systemic chemotherapy, making pancreatic cancer the fourth leading cause of cancer-related death in the U.S. and the Western world. For these reasons, efforts at identifying and treating disease-related symptomatology are priorities. This update overviews symptom management, supportive care strategies, and both standard and emerging palliative chemotherapy options. The incorporation of molecularly targeted therapies into treatment of metastatic pancreatic cancer is reviewed as well. These strategies are of relevance to internists, gastroenterologists, oncologists, and other specialists who care for patients with pancreatic cancer.

Phase II Study of Gemcitabine, UFT and Leucovorin in Patients with Advanced Pancreatic Cancer

The combination of gemcitabine with protracted 5-fluorouracil(5-FU) in the treatment of metastatic pancreatic cancer has shown activity with tolerable toxicity. The administration of UFT may simulate the effects of a protracted infusion of 5-FU. Patients with previously untreated metastatic or unresectable measurable pancreatic adenocarcinoma received gemcitabine (800 mg/m2 i.v., administered as an 80-min infusion on days 1, 8 and 15), UFT (200 mg/m2/day, on days 1 to 21), and oral leucovorin (90 mg/day, on days 1 to 21). Thirty patients were enrolled in this study. Five patients had partial responses, with an overall response rate of 17% (5/30), using the intent-to-treat principle (95% confidence interval (CI), 3-30%). Nine out of 25 (36%) patients experienced clinical benefit responses (95% CI; 17-55%). The median time to progression was 3.0 months, and the median overall survival was 7.2 months. The principal adverse event was neutropenia. The combination of gemcitabine, UFT, plus oral leucovorin shows significant antitumor activity and a beneficial clinical effect with an acceptable level of toxicity.

Irinotecan combined with gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (G-FLIP) is an effective and noncrossresistant treatment for chemotherapy refractory metastatic pancreatic cancer.

Single agents have only modest activity as treatment for metastatic pancreatic cancer with response rates of less than 10% and median survivals of less than 6 months. Evaluations of single-agent gemcitabine and rubitecan as second-line treatment for relapsed pancreatic cancer have reported good patient tolerability and median survivals of 3.85 months and 4.7 months, respectively. Regimens incorporating two drugs have demonstrated encouraging activity and clinical impact compared with single-agent therapy. G-FLIP is a regimen designed to incorporate four active single agents into a tolerable and active combination. This analysis is a retrospective evaluation of the efficacy and safety of the G-FLIP regimen as second-line chemotherapy in a series of consecutively treated patients with metastatic pancreatic cancer. G-FLIP was administered over 48 hours and repeated every 2 weeks. Day 1 treatment consisted of sequentially administered gemcitabine 500 mg/m(2), irinotecan 80 mg/m(2), leucovorin 300 mg, 5-fluorouracil (5-FU) 400 mg/m(2) bolus followed by infusional 5-FU 600 mg/m(2) over 8 hours. Day 2 treatment consisted of leucovorin 300 mg and 5-FU 400 mg/m(2) bolus, followed by cisplatin 50 to 75 mg/m(2), and then infusional 5-FU 600 mg/m(2) over 8 hours. Thirty-four patients with histologically confirmed metastatic pancreatic cancer were consecutively treated. The median patient age was 64.5 years (range 41-82 years) and all patients had objective disease progression on prior therapy: 32 patients had disease progression with gemcitabine and 31 had disease progression with a gemcitabine/5-fluorouracil/cisplatin combination. Grade 3-4 hematological toxicities included anemia (23%), thrombocytopenia (53%), and neutropenia (38%). There were no grade 3-4 neutropenic fevers, treatment-related mortalities, or withdrawals. Nonhematological grade 3-4 toxicities were rare: nausea/vomiting (3%), neurotoxicity (3%), nephrotoxicity (6%), and diarrhea (3%). Based on RECIST criteria a partial response (PR) was attained in eight patients (24%) and seven patients had stable disease (SD). Seven and six patients who attained a PR or SD, respectively, had disease progression with prior gemcitabine-based therapy. The median time to disease progression for all 34 patients was 3.9 months and 5.9 months for the eight patients who attained a PR. Median overall survival for all 34 patients was 10.3 months. Adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative to switching to different drug classes for treatment of relapsed/resistant cancer. The promising clinical outcomes and moderate toxicity associated with G-FLIP in this heavily pretreated group warrant development of this novel regimen including tests as first-line therapy in patients with diseases likely to be responsive to the drugs contained in this combination.

Radiation therapy and 5-fluorouracil in pancreatic cancer

Combination chemotherapy has not been shown to be superior to single-agent 5-fluorouracil (5-FU) in the treatment of metastatic pancreatic cancer. Initial studies from Duke University suggest a role for radiation in the management of locally unresectable presentations of this disease. In vivo studies showed that 5-FU could act as a radiation sensitizer. This concept was subsequently tested in a randomized trial by the Gastrointestinal Tumor Study Group (GITSG). In their studies, combined modality therapy using radiation and 5-FU-based chemotherapy prolonged survival in both adjuvant and locally unresectable settings and remains as a standard therapeutic option for appropriately selected patients. Variations on this approach designed to potentiate 5-FU efficacy are under active clinical investigation. This review discusses past and current studies involving 5-FU and radiation and examines some newer strategies involving 5-FU as well as other agents currently of interest.