GS Therapy Research Articles

Risk factors for irreversible organ damages in peri- and postmenopausal women with systemic lupus erythematosus

Objective: to identify irreversible organ damages and factors influencing their development and to compare existing musculoskeletal injuries with the activity of systemic lupus erythematosus (SLE).Patients and methods. The investigation enrolled 197 peri- and postmenopausal female outpatients (mean age, 50.94±9.1 years) with SLE, who were followed up at Clinical Rheumatology Hospital Twenty-Five, Saint Petersburg. The mean disease duration was 9.7±7.5 years. Cytostatic and glucocorticoid (GC) treatment regimens and dosages in the examinees were analyzed on the basis of their primary medical records. The investigators assessed the current disease activity by the SLE Disease Activity Index (SLEDAI-2K) and the Lupus Low Disease Activity State (LLDAS) and irreversible organ damages by the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (DI).Results and discussion. 93.4% of the patients continued to receive GS therapy at the time of inclusion in the study. The median GS maintenance dose was 12.5 mg/day. Almost half of the patients (n=86/43.7%) were in menopause (its mean duration was 12.8±7.1 years). Half of the examinees were noted to have remission (n=36/18.3%) or low SLE activity (n=92/46.7%) according to the SLEDAI-2K. Fifty-seven (28.9%) patients met all 5 LLDAS criteria; at the same time other 96 (48.7%) patients met 4 out of the 5 criteria, the 5th criterion being a high GC maintenance dose. High DI scores of ≥4 were found in two thirds (n=131/66.5%) of the examinees. Musculoskeletal system injuries ranked first among other disorders: osteoporosis (OP) and muscle weakness were detected in 76 (38.6%) and 69 (35.0%) patients, respectively. Regression analysis involving all statistically significant factors showed that the degree of damage was influenced by age (p=0.013215), total GS dose (p=0.000047), and previous therapy with cyclophosphamide (p=0.041505).Conclusion. The contribution of GS therapy to irreversible damage accrual is obvious in peri- and postmenopausal women with SLE. Timely dose adjustment or complete withdrawal of GS during remission in SLE is one of the key factors that substantially reduce the risk of progression of irreversible organ damages due to the prevention of OP and osteoporotic fractures in these patients.

A long-term survival case treated with conversion surgery following chemotherapy after diagnostic metastasectomy for pancreatic cancer with synchronous liver metastasis

BackgroundPancreatic cancer with distant metastases is classified as “unresectable,” for which the standard treatment is systemic chemotherapy. The effectiveness of radical resection for pancreatic cancer with distant metastases is unknown. Here, we report a case of long term survival treated with conversion surgery following chemotherapy after diagnostic metastasectomy for pancreatic cancer with synchronous liver metastasis.Case presentationA 73-year-old man was referred to our hospital to examine and treat for cancer of the pancreatic body. Computed tomography (CT) scan revealed a 26-mm hypovascular tumor in contact with the common hepatic artery (CHA) (> 180°), the celiac artery (< 180°), and portal vein at the pancreatic body. Resectability was determined as “borderline resectable.” Two courses of gemcitabine plus S-1 combination therapy (GS) were administered as neoadjuvant chemotherapy (NAC). CT scan showed tumor shrinkage (21 mm), determined as stable disease (SD) according to Response Evaluation Criteria in Solid Tumors (RECIST). Although the abdomen was opened for radical resection, a small nodule on the liver was detected and removed. Since the nodule was diagnosed as adenocarcinoma by intraoperative frozen section, resection of the primary tumor was not performed. After three subsequent courses of GS therapy, no distant metastases were detected under radiological findings. Distal pancreatectomy with celiac artery resection (DP-CAR) was performed as radical surgery 6 months after the initial diagnosis. Histological diagnosis was well-differentiated tubular adenocarcinoma, showing ypT1 ypN1 M1 stage IV, negative surgical margin (R0), and grade III in the Evans classification. S-1 was administered every other day from 6 months after resection up to the present. The patient has been alive with no recurrence for 5 years after the initial diagnosis and 4.5 years after the resection.ConclusionThere is a case that received survival benefits from conversion surgery following chemotherapy after diagnostic metastasectomy in pancreatic cancer with synchronous liver metastasis.

FDG-PET reveals improved cardiac regeneration and attenuated adverse remodelling following Sitagliptin + G-CSF therapy after acute myocardial infarction.

Dual therapy comprising G-CSF for mobilization of bone marrow-derived progenitor cells (BMPCs), with simultaneous pharmacological inhibition of dipeptidylpeptidase-IV for enhanced myocardial recruitment of circulating BMPC via the SDF-1α/CXCR4-axis, has been shown to improve survival after acute myocardial infarction (AMI). Using an innovative method to provide non-invasive serial in vivo measurements and information on metabolic processes, we aimed to substantiate the possible effects of this therapeutic concept on cardiac remodelling after AMI using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET). AMI was induced in C57BL/6 mice by performing surgical ligation of the left anterior descending artery in these mice. Animals were then treated with granulocyte-colony stimulating factor + Sitagliptin (GS) or placebo for a duration of 5 days following AMI. From serial PET scans, we verified that the infarct size in GS-treated mice (n = 13) was significantly reduced at Day 30 after AMI when compared with the mice receiving placebo (n = 10). Analyses showed a normalized FDG uptake on Day 6 in GS-treated mice, indicating an attenuation of the cardiac inflammatory response to AMI in treated animals. Furthermore, flow cytometry showed a significant increase in the anti-inflammatory M2-macrophages subpopulation in GS-treated animals. In comparing GS treated with placebo animals, those receiving GS-therapy showed a reduction in myocardial hypertrophy and left ventricular dilatation, which indicates the beneficial effect of GS treatment on cardiac remodelling. Remarkably, flow cytometry and immunohistochemistry showed an increase of myocardial c-kit positive cells in treated mice (n = 12 in both groups). Using the innovative method of micro-PET for non-invasive serial in vivo measurements of metabolic myocardial processes in mice, we were able to provide mechanistic evidence that GS therapy improves cardiac regeneration and reduces adverse remodelling after AMI.

SY11-2 - Adjuvant Chemotherapy for Resected Pancreatic Cancer: Focusing on the Jsap Study

Although approximately 20% of patients with pancreatic cancer (PC) undergo surgery, their prognosis is relatively poor, as most develop recurrences after resection. Adjuvant therapies have been used in attempts to improve the prognosis of these patients, but a consensus has not been established for many years. However, recently performed large-scale phase III studies, such as ESPAC-1 and CONKO-001, have revealed that adjuvant chemotherapy using 5-FU plus leucovorin or gemcitabine (GEM) improves the prognosis of PC patients after surgery. Furthermore, JASPAC-01, a phase III study conducted in Japan last year, has demonstrated that S-1 is superior to GEM for resected PC with respect to overall survival. Consequently, S-1 has become the standard adjuvant therapy for resected PC in Japan. In this presentation, we will review the latest information on clinical trials for adjuvant therapy and will report the results of studies conducted by our group (Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer: JSAP). We recently performed a phase I/II study (JSAP03) of GEM and S-1 combination (GS) therapy for resected PC and are presently conducting a phase III study (JSAP04) comparing GEM vs. GS therapy. Although GS therapy did not demonstrate a significant survival benefit in a phase III study for unresectable advanced PC (GEST), its application in an adjuvant setting may be more appropriate, as previous studies have demonstrated high response rates against PC.

A phase II trial of gemcitabine and S-1 therapy in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer (JSAP-03).

263 Background: Although anti-tumor effect of gemcitabine (G) and S-1 (S) therapy is high for advanced pancreatic cancer (PC) patients, safety and effectiveness of postoperative GS adjuvant therapy has not been fully examined. Methods: Eligibility criteria included macroscopically curative resection of invasive ductal PC and no prior chemotherapy. Patients were recruited in 19 institutes. The primary endpoint was overall survival (OS). The patients received G (800 mg/m2/week) intravenously over 30 min on day 1 and S (60 mg/m2/day) orally twice daily from days 1 to 7 every 14 days for 12 cycles. Results: Fifty-five patients were enrolled in this study. One patient was excluded from the analysis due to no malignant pathology. Remaining 54 patients were analyzed. Deaths were observed in 17 patients (31.5%). Median overall survival was not reached. Estimated 1-year and 2-year OS were 88.9% (95% CI, 76.9-94.8) and 72.1% (95%CI, 58.1-82.2), respectively. Recurrences were observed in 31 patients (57.4%). Estimated 1-year and 2-year disease-free survival were 57.4% (95% CI, 43.2-69.3) and 44.4% (95%CI, 30.9-57.0), respectively. G3 febrile neutropenia was observed in 1.9 % of the patients, whereas the most common adverse reactions were neutropenia (G3/4: 59.2%, G4: 25.9%). There were no G4 adverse events except neutropenia and hyperkalemia (1.9%). G3 adverse events included anemia (3.7%), alanine aminotransferase elevation (3.6%), fatigue (1.9%), nausea (1.9%), vomiting (1.9%) and infection without neutropenia (1.9%). The protocol treatments could not finish in 6 patients due to adverse reactions. Conclusions: Our phase II results suggest that the postoperative GS therapy is a promising regimen that merits further investigation. Phase III trial of postoperative G versus GS therapy is now going on (JSAP-04).

Multicenter Phase II Study of Gemcitabine and S-1 Combination Therapy (GS Therapy) in Patients With Metastatic Pancreatic Cancer

The aim of this multicenter Phase II study was to assess the efficacy and toxicity of gemcitabine and S-1 combination therapy for metastatic pancreatic cancer. Chemotherapy-naïve patients with histologically or cytologically proven metastatic pancreatic adenocarcinoma were eligible for this study. Gemcitabine was administered at a dose of 1000 mg/m(2) over 30 min on days 1 and 8, and oral S-1 at a dose of 40 mg/m(2) twice daily from days 1 to 14, repeated every 3 weeks. A total of 55 patients were included and the efficacy and toxicity were analyzed in 54 patients who received at least one dose of gemcitabine and S-1 combination therapy. Although no complete response was seen, a partial response was achieved in 24 patients, resulting in an overall response rate of 44.4% (95% confidence interval: 30.9-58.6%). The median progression-free survival was 5.9 months (95% confidence interval: 4.1-6.9 months) and the median overall survival was 10.1 months (95% confidence interval: 8.5-10.8 months) with a 1-year survival rate of 33.0%. The major Grade 3-4 toxicities were neutropenia (80%), leucopenia (59%), thrombocytopenia (22%), anorexia (17%) and rash (7%). Hematological toxicity was mostly transient and there was only one episode of febrile neutropenia ≥Grade 3. Gemcitabine and S-1 combination therapy produced a high response rate with good survival in patients with metastatic pancreatic cancer. A randomized Phase III study to confirm the efficacy of gemcitabine and S-1 combination therapy is ongoing.

A phase I/II trial of gemcitabine and S-1 therapy in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer (JSAP-03).

e14625 Background: Although anti-tumor effect of gemcitabine (G) and S-1 (S) therapy is extremely high for advanced pancreatic cancer (PC) patients (pts), safety and effectiveness of postoperative GS has not been fully examined. Methods: Eligibility criteria included macroscopically curative resection of invasive ductal PC and no earlier radiation or chemotherapy. Pts were recruited in 2 institutes at phase I part, and in 2+17 institutes at phase 2 part. The primary endpoint of phase 2 part was overall survival. The pts received G intravenously over 30 min on day 1 and S orally twice daily from days 1 to 7 every 14 days for 12 cycles. Pts were scheduled to receive G (mg/m2/week) and S (mg/m2/day) at 3 dose levels: 800/60 (level 0), 1,000/60 (level 1, starting dose) and 1,000/80 (level 2). Toxicities were evaluated at days 1 and 8 for the first 2 cycles, and at day 1 thereafter. Results: Between Apr. 08 and Dec. 08, 13 pts were enrolled in the phase 1 part. At the starting dose of level 1, 3 of the 6 pts experienced dose limiting toxicities (febrile neutropenia or G4 neutropenia). Of additional 7 pts enrolled at level 0, only one experienced febrile neutropenia. We therefore decided the dose of the phase 2 part was level 0, and enrolled additional 48 pts for level 0 from 15 institutes between Feb. 09 and Sep. 09. At the time of writing, Dec. 09, 47 of the 55 pts enrolled in the phase 2 part were assessable for adverse events. G3 febrile neutropenia was observed in 2.1% of the pts, whereas the most common adverse reactions were neutropenia (G3/4: 59.6%, G4: 27.7%). There were no G4 adverse events except neutropenia, leukopenia (2.1%) and hyperkalemia (2.1%). G3 adverse events included anemia (4.3%), alanine aminotransferase elevation (4.3%), fatigue (2.1%), nausea (2.1%), vomiting (2.1%) and infection without neutropenia (2.1%). The protocol treatments could not finish in 6 pts due to adverse drug reactions. Survival data has not been mature, yet. Conclusions: The most common toxicity of this biweekly schedule of GS therapy was neutropenia. The GS therapy using a G dose of 800 mg/m2 and an S dose of 60 mg/m2/day was well tolerated in patients with resected pancreatic cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly, Taiho Pharmaceutical

GEMCITABINE AND S-1 COMBINATION THERAPY IN PATIENTS WITH ADVANCED STAGE OF PANCREATIC CANCER

Aim: This study was conducted to assess the efficacy and toxicity of gemcitabine and S-1 combination therapy (GS therapy) for advanced stage of pancreatic cancer. We also evaluated the second line therapy after GS therapy failure in clinical practice. Methods: Patients (Pts) with histologically and/or clinically proven pancreatic adenocarcinoma were eligible for the study. Other eligibility criteria included: no previous treatment for pancreatic cancer except surgery, age ≥20 and ≤80 years, PS of 0 1 or 2, and adequate organ function. G was given intravenously at a dose of 1,000 mg/m2 over 30 min on days 1 and 8, and S was given orally at a dose of 40 mg/m2 twice daily from day 1 to day 14, in 21-day cycles. Results: There were 19 males and 17 females. The median age of pts was 64 years. 36 pts were given a total of 235 cycles of treatment, with a median of 5 cycles each (range 1-27). Although no CR was seen, a PR was achieved 14%. 36% had SD, whereas 50% had PD. The median progression free survival was 4.5 months and the median overall survival was 10.0 months with a 1-year survival rate of 37.7%. No difference of median overall survival was observed between PS 0-1 and 2. The major grade 3-4 toxicities were leucopenia (56%), thrombocytopenia (8%), anorexia (17%), rash (36%), nausea (14%) and fatigue (17%). Most hematological toxicity was transient. After failure of GS therapy second line therapy was selected mostly cisplatin (n = 8) and CPT-11 (n = 5). Median survival of the group who used any second line therapy was 5.2 months (n = 21), whereas best supportive group was 3.6 months (n = 7). Conclusions: GS therapy produced a good survival associated with an acceptable toxicity profile. Any second line therapy may improve a survival after GS therapy compared with best supportive care. A randomized phase III trial to confirm the efficacy of GS therapy is under way.

A multicenter phase II study of gemcitabine and S-1 combination therapy (GS therapy) in patients with metastatic pancreatic cancer

4550 Background: As shown in our previous phase I study (Oncology 2005, 69:421–427), gemcitabine and S-1 combination therapy (GS therapy) appears to be feasible and effective against advanced pancreatic cancer. The present multicenter phase II study was conducted to confirm the efficacy and toxicity of GS therapy for metastatic pancreatic cancer. Methods: Patients with histologically or cytologically proven pancreatic adenocarcinoma with at least one measurable metastatic lesion were eligible for the study. Other eligibility criteria included: no previous treatment for pancreatic cancer except surgery, age =20 and =74 years, ECOG performance status of 0 or 1, and adequate organ function. Gemcitabine was given intravenously at a dose of 1,000 mg/m2 over 30 min on days 1 and 8, and S-1 was given orally at a dose of 40 mg/m2 twice daily from day 1 to day 14, repeated every 3 weeks. The objective response rate was assessed according to RECIST. Results: A total of 55 patients from 10 institutions were enrolled between October 2004 and July 2005. The efficacy and toxicity were analyzed in 54 patients who received at least one course of GS therapy. The median number of treatment courses was 7 (range, 1–24+). Although no complete response was seen, a partial response was achieved in 24 patients, resulting in an overall response rate of 44% (95% CI, 30.9–58.6%). Twenty-six patients (48%) had stable disease. The median progression-free survival was 5.9 months (95% CI, 4.1–6.9 months) and the median overall survival was 10.1 months (95% CI, 8.5–10.8 months) with a 1-year survival rate of 33%. The major grade 3–4 toxicities were neutropenia (80%), leucopenia (59%), thrombocytopenia (22%), anorexia (17%), rash (7%), nausea (6%) and fatigue (6%). Hematological toxicity was mostly transient and there was only one episode of infection with grade 3–4 neutropenia. No treatment-related deaths occurred during the study. Conclusions: GS therapy produced a high response rate and good survival associated with an acceptable toxicity profile in patients with metastatic pancreatic cancer. A randomized phase III trial to confirm the efficacy of GS therapy is planned. No significant financial relationships to disclose.