Phase I/II study of gemcitabine as a fixed dose rate infusion and S-1 combination therapy (FGS) in gemcitabine-refractory pancreatic cancer patients

Purpose

There is no standard regimen for gemcitabine (Gem)-refractory pancreatic cancer (PC) patients. In a previous phase II trial, S-1 was found to exhibit marginal efficacy. Gem administration by fixed dose rate infusion of 10?mg/m²/min (FDR-Gem) should maximize the rate of intracellular accumulation of gemcitabine triphosphate and might improve clinical efficacy. We conducted the phase I/II of FDR-Gem and S-1 (FGS) in patients with Gem-refractory PC.

Methods

The patients received FDR-Gem on day 1 and S-1 orally twice daily on days 1–7. Cycles were repeated every 14?days. Patients were scheduled to receive Gem (mg/m²/week) and S-1 (mg/m²/day) at four dose levels in the phase I: 800/80 (level 1), 1,000/80 (level 2), 1,200/80 (level 3) and 1,200/100 (level 4). Forty patients were enrolled in the phase II study at recommended dose.

Results

The recommended dose was the level 3. In the phase II, a partial response has been confirmed in seven patients (18%). The median overall survival time and median progression-free survival time are 7.0 and 2.8?months, respectively. The common adverse reactions were anorexia, leukocytopenia and neutropenia.

Conclusion

This combination regimen of FGS is active and well tolerated in patients with Gem-refractory PC.     

A phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for unresectable biliary tract cancer

Background

Many clinical trials have been conducted with gemcitabine- or 5-fluorouracil-based regimens as treatment for unresectable biliary tract cancer; however, the results remain unsatisfactory. Because further therapeutic improvements are required, we conducted a phase I study of arterial infusion chemotherapy using a combination of gemcitabine and 5-fluorouracil.

Methods

In the first 3 cohorts, patients were to receive an arterial infusion of gemcitabine 600, 800 or 1000?mg/m², respectively, over 30?min on days 1 and 15, plus a continuous arterial infusion of 5-fluorouracil 300?mg/m²/day on days 1–5 and 15–19. In the final cohort, patients were to receive an arterial infusion of gemcitabine 1000?mg/m² over 30?min on days 1 and 15, plus 5-fluorouracil 400?mg/m²/day on days 1–5 and 15–19.

Results

Eighteen patients were enrolled. In the final cohort, three of six patients experienced grade 3 non-hematological toxicities (cholecystitis, cellulitis and pneumonia). Thus, we determined the maximum tolerated doses of gemcitabine and 5-fluorouracil in arterial infusion chemotherapy to be 1000 and 400?mg/m², respectively.

Conclusion

This regimen of gemcitabine and 5-fluorouracil is tolerable and warrants further investigation in biliary tract cancer.     

A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients

Background

This phase I study was conducted to evaluate the feasibility and to determine the recommended doses of the combination therapy of S-1 and irinotecan (CPT-11) in patients with advanced non-small cell lung cancer (NSCLC) as second-line treatment.

Methods

Patients with NSCLC who were previously treated with one chemotherapy regimen and had a performance status of 0 or 1 were eligible. CPT-11 was administered at 60 mg/m² (level 1), 80 mg/m² (level 2) on days 1 and 8, and oral S-1 was administered at 80 mg/day for body surface area (BSA) less than 1.25 m², 100 mg/day for BSA 1.25–1.5 m², and 120 mg/day for BSA more than 1.5 m² on days 1–14 every 3 weeks. The dose-limiting toxicity (DLT) was defined as grade 4 leukocytopenia or neutropenia, grade ≥3 neutropenia with fever over 38°C, grade ≥3 thrombocytopenia, or grade ≥3 major nonhematological toxicities.

Results

Nine patients were enrolled in the study. None of 3 patients enrolled in level 1 had any DLT. Of 6 patients in level 2, 2 patients had grade 3 diarrhea and one had grade 3 interstitial pneumonia. Level 1 was declared as the recommended dose.

Conclusion

The feasibility of the combination therapy of S-1 and CPT-11 was shown in the second-line setting for the treatment of advanced NSCLC. The recommended dose of CPT-11 was 60 mg/m² combined with standard dose of S-1 for phase II trials of pretreated advanced NSCLC patients.     

Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study

Background

Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy.

Methods

Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800–1,000 mg/m² gemcitabine on days 1, 8, and 15 and then every 3–4 weeks or 40–80 mg/m²/day S-1 on days 1–28 and every 3–6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm.

Results

Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10 % of DLT, the recommended dose was 1,000 mg/m² gemcitabine biweekly and 80 mg/m²/day S-1 on days 1–28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted.

Conclusion

We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10 %.     

Phase I/II study of S-1 combined with biweekly irinotecan chemotherapy in previously treated advanced non-small cell lung cancer

Purpose

This phase I/II study was designed to evaluate a combination of irinotecan and S-1 a new regimen for salvage chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC).

Methods

The study group comprised patients with advanced or metastatic NSCLC who had previously received at least one platinum-containing chemotherapy. Patients received irinotecan on days 1, 15 and oral S-1 (40?mg/m² twice daily as a fixed dose) on day 1 to 14 of a 28-day cycle.

Results

In the phase I part, irinotecan was given in escalating doses of 70 (Level 1), 80 (Level 2), and 90?mg/m² (Level 3). Three of the 5 patients given Level 3 had dose-limiting toxicity, and Level 2 (80?mg/m² of irinotecan) was designated as the recommended dose. In phase II, 38 patients received a median of 7.4 cycles of irinotecan at the recommended dose. The overall response rate was 15.8?% (90?% confidence interval (CI): 6.1–25.5?%), and the median progression-free and overall survival times were 4.5?months (95?% CI: 3.5–5.0) and 15.0?months (95?% CI: 9.5–20.6) months, respectively. Toxicity was generally mild. Grade 3 or higher toxicity included neutropenia in 17.9?% of the patients, thrombocytopenia in 5.1?% and nausea in 7.7?%.

Conclusion

Combination chemotherapy with S-1 and irinotecan was considered an effective salvage regimen in patients with advanced or metastatic NSCLC.     

Phase I study of bevacizumab combined with irinotecan and S-1 as second-line chemotherapy in patients with advanced colorectal cancer

Purpose

The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan has been reported to be a promising regimen for advanced colorectal cancer. However, the safety and efficacy of bevacizumab (BV) to combine with irinotecan and S-1 has not been determined. The aim of the study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BV combined with irinotecan plus S-1, and to observe the safety and efficacy of this regimen as second-line chemotherapy in patients with advanced colorectal cancer.

Methods

This study initially had been planned as a phase I/II study. Eighty mg/m² of irinotecan on days 1 and 8, 80 mg/m² of S-1 for 14 consecutive days, and two doses of BV (Level 1; 10 mg/kg, Level ?1; 7.5 mg/kg) were administered on day 1 every 3 weeks.

Results

Fourteen patients were enrolled in phase I of the study between January 2008 and September 2010. Dose-limiting toxicities were diarrhea, abdominal pain, and infection. The MTD and RD of BV were determined to be 10 mg/kg and 7.5 mg/kg, respectively. The main adverse events were leukopenia, anorexia, and diarrhea. There were no treatment-related deaths. An independent review committee was scheduled to evaluate safety in phase I, but this trial closed early due to toxicity.

Conclusions

This study identified the risk of gastrointestinal toxicity with the combination of irinotecan, S-1 and BV as second-line chemotherapy in patients with advanced colorectal cancer.     

Phase II trial of S-1 in combination with gemcitabine for chemo-naïve patients with locally advanced or metastatic pancreatic cancer

Background

We performed a phase II study of combination chemotherapy with S-1 plus gemcitabine for treating chemo-naïve patients with unresectable pancreatic cancer to evaluate the efficacy and toxicity.

Patients and methods

Patients with histologically confirmed unresectable pancreatic cancer were eligible. The treatment consisted of S-1 (40 mg/m² p.o. b.i.d. from D1 to 14) and gemcitabine (1,250 mg/m² on D1 and 8), repeated every 3 weeks.

Results

Thirty-two patients were enrolled between March 2005 and December 2007. No complete response was observed and a partial response was observed in 14 patients (44.0%), stable disease in eight patients (25.0%), and progressive disease in eight patients (25.0%). The median time to progression was 4.92 months (95% CI: 4.16–5.67 months), and the median overall survival was 7.89 months (95% CI: 5.96–9.82 months). The survival duration was significantly longer for the patients with a good performance status compared with that of the patients with a poor performance status. The major toxicities were grade 3–4 neutropenia (9, 28.1%), grade 3/4 thrombocytopenia (5, 15.6%), and grade 3 diarrhea (5, 15.6%).

Conclusion

The combination chemotherapy of S-1 and gemcitabine showed promising antitumor activity and manageable toxicities, and especially for the good performance status patients with unresectable pancreatic cancer.     

Combination therapy consisting of gemcitabine, carboplatin, and docetaxel as an active treatment for advanced urothelial carcinoma

Background

To evaluate the efficacy and toxicity of a combination chemotherapy consisting of gemcitabine, carboplatin, and docetaxel (GCD) in patients with advanced urothelial carcinoma (UC) as a phase II trial.

Materials and methods

Patients with metastatic or locally advanced unresectable UC were eligible for this trial. All enrolled patients were considered to be “unfit??for cisplatin-based chemotherapy, or to have methotrexate, vinblastine, doxorubicin, cisplatin (MVAC)-refractory UC. The chemotherapy regimen consisted of gemcitabine 1000?mg/m² on days 1 and 8, and carboplatin (with a target area under the curve of 5) and docetaxel 70?mg/m² on day 1; this was repeated every 21?days.

Results

Thirty-five patients were enrolled, with a median age of 68?years. A total of 89 cycles were administered (median, 2 cycles). Major toxicities were Grade 3/4 neutropenia in 28 (80.0%) patients and Grade 3/4 thrombocytopenia in 18 (51.5%). An objective response rate (ORR) was 11 of 21 patients (52.4%), including a complete response in 1 (4.8%). The median overall survival (OS) was 13.1?months (1-year survival rate, 60%) and the median progression-free survival (PFS) was 5.0?months. Among 16 patients who had previously received MVAC, the ORR, the median PFS, the median OS and 1-year survival rate was 56.3%, 5.0?months, 12.6?months and 54%, respectively.

Conclusions

GCD chemotherapy is active and well tolerated as a first- or second-line therapy for patients with advanced UC. Response rate, duration and survival did not differ between those with and without a history of MVAC treatment.     

A phase I trial of combination therapy using gemcitabine and S-1 concurrent with full-dose radiation for resectable pancreatic cancer

Purpose

Use of the fourth-generation oral fluoropyrimidine S-1 together with gemcitabine has shown striking anticancer effects. In this single-arm phase I trial of preoperative combination therapy using gemcitabine and S-1 concurrently with radiotherapy, we verified the safety and feasibility and determined the maximum-tolerated dose of each drug in patients with resectable pancreatic cancer.

Methods

A standard 3+3 dose escalation scheme was used. Patients with cytologically or histologically proven resectable pancreatic ductal adenocarcinoma were administered 30-min intravenous gemcitabine infusions on days 1, 8, 22, and 29 and S-1 orally on days 1–5, 8–12, 22–26, and 29–33. A total radiation dose of 50.4 Gy (1.8 Gy/day, 5 times per week, 28 fractions) was concurrently delivered. Surgical exploration was scheduled 4–7 weeks after the final radiation fraction.

Results

Twenty-one patients were enrolled. No treatment-related deaths occurred during this study. Recommended doses were determined to be 80 mg/m² of S-1 daily and 1,000 mg/m² of gemcitabine. CA19-9 was reduced to <50 % of baseline values in 12 (75 %) of 16 measurable patients. Nineteen of 21 enrolled patients successfully underwent surgical resection.

Conclusions

Preoperative chemoradiotherapy consisting of gemcitabine and S-1 concurrent with full-dose radiation is feasible and well tolerated.     

A phase I trial of gemcitabine,S-1 and LV combination (GSL) therapy in advanced pancreatic cancer

Purpose

In our previous randomized controlled trial, the addition of S-1 to gemcitabine for advanced pancreatic cancer did not prolong overall survival (OS) significantly, despite its higher response rate and longer progression-free survival (PFS). Leucovorin is known to enhance efficacy of S-1, and we conducted this phase I trial of combination therapy of gemcitabine, S-1 and leucovorin (GSL).

Methods

Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Gemcitabine was administered at an escalating dose of 600, 800 and 1,000 mg/m² over 30 min on day 1, and oral S-1 at a dose of 40 mg/m² twice daily and oral leucovorin at a dose of 25 mg twice daily on days 1–7, every 2 weeks. A standard “3 + 3” phase I dose escalation design was utilized.

Results

Fifteen patients were enrolled across three dose levels. Three patients developed DLTs: two patients in level 1 (grade 3 anorexia in 1 and grade 3 anorexia, stomatitis and diarrhea in 1) and one patient in level 2 (grade 3 deep vein thrombosis). No DLT was observed in level 3. Response rate and the disease control rate were 33 and 93 %, respectively. The median PFS and OS were 5.4 and 16.6 months. Ten of 12 patients (83 %) with elevated CA19-9 at baseline had a ≥50 % decline.

Conclusions

RD of gemcitabine in GSL was determined as 1,000 mg/m². GSL was well tolerable and showed promising results in advanced pancreatic cancer.     

A phase I trial of S-1 with concurrent radiotherapy in patients with locally recurrent rectal cancer

Background

The purpose of this phase I trial of S-1 chemotherapy in combination with pelvic radiotherapy for locally recurrent rectal cancer was to determine the maximum tolerated dose (MTD), recommended dose (RD), and dose-limiting toxicity (DLT) of S-1.

Methods

We enrolled 9 patients between April 2005 and March 2009. Radiotherapy (total dose, 60 Gy in 30 fractions) was given to the gross local recurrent tumor and pelvic nodal metastases using three-dimensional radiotherapy planning. We administered oral S-1 twice a day on days 1–14 and 22–35 during radiotherapy. The dose of S-1 was initially 60 mg/m²/day and was increased to determine the MTD and RD for this regimen.

Results

DLT appeared at dose level 2 (70 mg/m²/day) in 2 patients, who experienced grade 3 enterocolitis and consequently required suspension of S-1 administration for longer than 2 weeks. Hematological toxicity was mild and reversible. At the initial evaluation, complete regression and partial regression were seen in 1 patient (11%) and 2 patients (22%), respectively.

Conclusion

This phase I trial of S-1 chemotherapy with pelvic radiotherapy for locally recurrent rectal cancer revealed that the MTD for S-1 was 70 mg/m²/day and the RD was 60 mg/m²/day.     

A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer

Background

To investigate the combination of S-1 and irinotecan (CPT-11) as an alternative to infusional 5-fluorouracil/leucovorin plus CPT-11, we performed a phase I trial to determine the maximum tolerated dose, recommended dose (RD), and dose-limiting toxicities (DLTs) in patients with metastatic or recurrent colorectal cancer.

Patients and methods

S-1 and CPT-11 doses were escalated using a standard 3?+?3 design. S-1 was administered orally at 70?mg/m² (levels 1?C3) or 80?mg/m² (levels 4 and 5) for 14 consecutive days followed by 1-week rest. CPT-11 was administered intravenously on day 1, at 175?mg/m² (level 1), 200?mg/m² (level 2), 225?mg/m² (levels 3 and 4), or 250?mg/m² (level 5). Treatment was repeated every 3?weeks, unless disease progression or severe toxicities were observed.

Results

Twenty-three patients were treated. One patient at each of levels 2 and 4 developed a DLT, grade 3 ileus, and grade 3 diarrhea, respectively. At both levels, an additional three patients did not experience DLTs. At level 5, two of five patients experienced DLTs, including grade 3 enteritis and grade 4 neutropenia for more than 5?days. The RD was determined at level 4 (80?mg/m² S-1 and 225?mg/m² CPT-11). An objective response was observed in 7 of 17 patients with measurable disease: 2 of 5 at level 2; 3 of 4 at level 4; and 2 of 4 at level 5.

Conclusions

The RDs of CPT-11 and S-1 were determined as 225 and 80?mg/m², respectively, and further phase II trials are warranted.     

A phase II study of induction chemotherapy with gemcitabine plus S-1 followed by chemoradiotherapy for locally advanced pancreatic cancer

Purpose

The aim of this study was to investigate the feasibility and efficacy of induction chemotherapy with gemcitabine and S-1 followed by chemoradiotherapy for locally advanced pancreatic cancer.

Methods

Patients with locally advanced unresectable pancreatic cancer received four cycles of induction chemotherapy consisting of 30-min intravenous infusions of gemcitabine 1,000 mg/m² on days 1 and 8 and oral S-1 40 mg/m² twice daily on days 1–14 of a 21-day cycle. Those without disease progression received chemoradiotherapy of 30 Gy in ten fractions with 250 mg/m² of gemcitabine on days 1 and 8.

Results

A total of 20 patients were treated. Median follow-up time was 431 days (range 133–1,014 days). Four cycles of induction chemotherapy were completed in 18 patients, and 16 patients received chemoradiotherapy, which was completed without delay in all. Grade 3–4 toxicities associated with induction chemotherapy were neutropenia (50%); anemia (20%); thrombocytopenia (10%); febrile neutropenia (5%); nausea (10%); anorexia (10%); and vomiting, fatigue, dehydration, stomatitis, and rash (5%). Grade 3–4 toxicities among those receiving chemoradiotherapy were neutropenia (13%) and anemia (6%). Median progression-free survival was 8.1 months. Median overall survival was 14.4 months, with a 1-year survival rate of 54.2%.

Conclusions

The regimen of induction chemotherapy with gemcitabine and S-1 followed by chemoradiotherapy used in the present study demonstrated promising activity in locally advanced pancreatic cancer. Further consideration of radiation schedule and duration of induction chemotherapy is required to enhance the efficacy of this strategy.     

Feasibility study of S-1 adjuvant chemotherapy in patients with colorectal cancer

Background

We evaluated the safety, efficacy, and compliance of 1-year treatment with S-1 in patients with stage II/III resectable colorectal cancer.

Methods

S-1 was administered orally in two divided doses daily. The dose was assigned according to body surface area (BSA) as follows: BSA <1.25 m², 80 mg/day; BSA ≥1.25 to <1.5 m², 100 mg/day; and BSA ≥1.5 m², 120 mg/day. S-1 was given for 28 consecutive days, followed by a 14-day rest. The study objects were the rate of completion of treatment as planned at 1 year, the ratio of the actually administered dose to the planned dose at 1 year, and the total number of days of treatment.

Results

At 1 year, the rate of completion of treatment as planned was 77.7 % (42/54 patients), and the ratio of the actually administered dose to the planned dose was 82.9 %. The mean and median total numbers of days of treatment were 209 and 252, respectively. Grade 3 or higher toxicity (watery eyes) occurred in only 1 patient.

Conclusion

S-1 adjuvant chemotherapy had acceptable compliance, safety, and efficacy in patients with colorectal cancer. S-1 adjuvant chemotherapy is considered a possible standard treatment regimen for colorectal cancer.     

Second-line chemotherapy with irinotecan plus cisplatin after the failure of S-1 monotherapy for advanced gastric cancer

Background

For advanced gastric cancer (AGC), second-line chemotherapy after the failure of S-1 has not yet been established. The present study aimed to retrospectively evaluate the efficacy and safety of irinotecan plus cisplatin (IP) therapy after the failure of S-1 in patients with AGC.

Methods

The subjects included 87 patients with AGC who received IP therapy as second-line chemotherapy. Irinotecan (70 mg/m²) was administered by intravenous infusion followed by an intravenous infusion of cisplatin (80 mg/m²) on day 1. On day 15, irinotecan (70 mg/m²) alone was administered. The treatment was repeated every 4 weeks until disease progression, patient refusal, or severe adverse events.

Results

The median patient age was 62 years (range, 39–75 years), and the median number of treatment cycles was 3 (range, 1–9). Out of the 87 patients, 70 were assessable for clinical response. There were 2 complete responses and 18 partial responses. The overall response rate was 28.6% (95% confidence interval [CI], 18.4%–40.6%) and the disease control ratio was 70.0%. The median time to progression and median survival time from the first day of IP therapy were 4.3 months and 9.4 months, respectively. The 1-year survival rate was 34.6%. Severe (grade 3/4) leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 34%, 40%, 28%, and 8% of patients, respectively. Grade 3/4 nonhematologic toxicities included anorexia (17%), febrile neutropenia (10%), diarrhea (6%), fatigue (5%), nausea (2%), and elevated creatinine (1%).

Conclusions

The combination of irinotecan plus cisplatin as second-line chemotherapy for AGC appears to be an effective and feasible treatment option after S-1 failure.     

A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601)

Purpose

We conducted a phase II study to evaluate the efficacy and safety of a triplet regimen of docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer.

Methods

Docetaxel (40?mg/m²) and cisplatin (70 or 60?mg/m²) were given on day 1 of a 28-day cycle. S-1 (40?mg/m²) was given twice daily on days 1?C14. Treatment with this regimen was continued for a maximum of 6 cycles. Subsequently, patients with no disease progression received a combination of docetaxel and S-1.

Results

Fifty-nine patients were enrolled. The median number of administered cycles was 8 (range, 1?C25). Because some patients had serious myelosuppression and renal dysfunction with 70?mg/m² of cisplatin, dose of cisplatin was reduced to 60?mg/m² after 19 patients had been treated. Common severe toxic effects of grade 3 or 4 were leukocytopenia (44%), neutropenia (72%), anemia (15%), and febrile neutropenia (14%). The overall response rate of this group was 81% (95% confidence interval (CI), 71?C91%). The median overall survival and progression-free survival were 18.5 (95% CI, 15.6?C21.5) and 8.7 (95% CI, 6.7?C10.7) months, respectively.

Conclusions

Triplet of docetaxel, cisplatin, and S-1 is a well-tolerated and highly active regimen for advanced or recurrent gastric cancer. A 60?mg/m² of cisplatin is as effective as 70?mg/m² of cisplatin.     

Intravenous and Intraperitoneal Paclitaxel with S-1 for Refractory Pancreatic Cancer with Malignant Ascites: an Interim Analysis

Objectives

Here, we reported an interim analysis of feasibility and safety in the first 10 cases of 30 cases in a phase II trial of intravenous and intraperitoneal paclitaxel combined with S-1 for gemcitabine-refractory pancreatic cancer with malignant ascites.

Methods

Paclitaxel was administered intravenously at 50 mg/m² and intraperitoneally at 20 mg/m² on days 1 and 8 every 3 weeks, and S-1 was administered at 80 mg/m²/day for 14 consecutive days, followed by 7-day rest.

Results

Between April 2011 and February 2012, ten patients were enrolled. A partial response was achieved in two patients (20 %) and a disease control rate of 50 %. The median time to progression and overall survival were 2.1 and 3.4 months, respectively. Malignant ascites was completely resolved in two patients (20 %). Major grade 3/4 adverse events were myelosuppression including neutropenia (50 %) and catheter-related infection (10 %).

Conclusions

This novel combination chemotherapy was feasible and showed promising results in pancreatic cancer patients with malignant ascites (clinical trial registration number: UMIN000005306).     

A phase I study evaluating the role of the anti-epidermal growth factor receptor (EGFR) antibody cetuximab as a radiosensitizer with chemoradiation for locally advanced pancreatic cancer

Purpose

(1) To determine the safety of the epidermal growth factor receptor (EGFR) antibody cetuximab with concurrent gemcitabine and abdominal radiation in the treatment of patients with locally advanced adenocarcinoma of the pancreas. (2) To evaluate the feasibility of pancreatic cancer cell epithelial?Cmesenchymal transition (EMT) molecular profiling as a potential predictor of response to anti-EGFR treatment.

Methods

Patients with non-metastatic, locally advanced pancreatic cancer were treated in this dose escalation study with gemcitabine (0?C300?mg/m²/week) given concurrently with cetuximab (400?mg/m² loading dose, 250?mg/m² weekly maintenance dose) and abdominal irradiation (50.4?Gy). Expression of E-cadherin and vimentin was assessed by immunohistochemistry in diagnostic endoscopic ultrasound fine-needle aspiration (EUS-FNA) specimens.

Results

Sixteen patients were enrolled in 4 treatment cohorts with escalating doses of gemcitabine. Incidence of grade 1?C2 adverse events was 96%, and incidence of 3?C4 adverse events was 9%. There were no treatment-related mortalities. Two patients who exhibited favorable treatment response underwent surgical exploration and were intraoperatively confirmed to have unresectable tumors. Median overall survival was 10.5?months. Pancreatic cancer cell expression of E-cadherin and vimentin was successfully determined in EUS-FNA specimens from 4 patients.

Conclusions

Cetuximab can be safely administered with abdominal radiation and concurrent gemcitabine (up to 300?mg/m²/week) in patients with locally advanced adenocarcinoma of the pancreas. This combined therapy modality exhibited limited activity. Diagnostic EUS-FNA specimens could be analyzed for molecular markers of EMT in a minority of patients with pancreatic cancer.     

奥沙利铂联合替吉奥胶囊治疗晚期胃癌患者62例的临床观察(英文)

Objective:The aim of this study was to evaluate the efficacy and safety profile of DeFazio(S-1)combined with oxaliplatin against unresectable advanced or metastatic gastric cancer.Methods:Oxaliplatin was given intravenously at 130mg/m2for 2 h on d1 and S-1 was administered bid.at 80 mg/m2/day on d1–14 followed by a 7-day rest during the 3-week schedule.Results:All 62 patients were assessed for efficacy and adverse events.The response and disease control rates were 47.3%and 80.8%,respectively.The median time to progression was 7.8 months,and the median overall survival was11.6 months.The grade 3/4 adverse events were hematological toxicities,including neutropenia(11.3%),thrombocytopenia(9.7%)and gastrointestinal reactions(6.5%).Conclusion:The SOX regimen(oxaliplatin,130 mg/m2d1;S-1,80 mg/m2/day,bid.d1-14,q3w)provide a favorable efficacy and safety profile in patients with advanced gastric cancer.     

Paclitaxel as second-line chemotherapy in patients with gemcitabine-refractory pancreatic cancer: a retrospective study

Background

We evaluated the efficacy and feasibility of paclitaxel in patients with gemcitabine-refractory pancreatic cancer. We also evaluated the correlation between tumor marker decline and response rate.

Methods

Thirty patients histologically diagnosed with pancreatic cancer who had undergone paclitaxel treatment as salvage chemotherapy were retrospectively analyzed. Paclitaxel treatment was performed with 80?mg/(m²?week) for 3?weeks followed by 1?week rest, and this was continued until failure. Tumor marker response was evaluated by measuring levels of carbohydrate antigen 19-9, carcinoembryonic antigen, and DUPAN-2 monthly.

Results

In total, 272?weekly paclitaxel treatments were performed. The median number of treatments per patient was 8 (range 1??2). The median overall survival from the start of paclitaxel treatment was 6.7?months (range 1.2??8.8). The response rate was 10% (3/30 patients) and the disease control rate was 46.7% (14/30 patients). Although grade 3 and 4 hematological and non-hematological toxicities were seen in 7 and 6 patients, respectively, adverse events were managed by conservative treatment. We found a significant correlation between the disease control rate and tumor marker decline within 2?months of paclitaxel treatment (P?=?0.01). Patients with tumor marker decline tended to survive longer.

Conclusion

Weekly administration of paclitaxel in patients with gemcitabine-refractory pancreatic cancer seems to be well tolerated and can be effective. Paclitaxel treatment should be considered as salvage chemotherapy after gemcitabine failure in patients with good performance status.