A retrospective study of S-1 and oxaliplatin combination chemotherapy in patients with refractory pancreatic cancer

Purpose

The aim of this study was to evaluate S-1 and oxaliplatin combination chemotherapy (SOX) in patients with refractory pancreatic cancer (PC).

Methods

Consecutive patients with advanced PC refractory to gemcitabine who were treated with oral S-1 (80 mg/m²) on days 1–14 and intravenous oxaliplatin (100 mg/m²) on day 1 every 3 weeks were studied retrospectively. The primary end point was the objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), the disease control rate (DCR), and safety.

Results

Between March 2009 and October 2011, 30 patients were treated with SOX, with a median of two courses (range 1–8). The ORR and DCR were 10.0 and 50.0 %, respectively. Median PFS and OS were 3.4 months (95 % confidence interval [CI] 1.3–5.3) and 5.0 months (95 % CI 3.4–7.4), respectively. The median PFS and OS were 5.6 and 9.1 months in patients receiving S-1 and oxaliplatin as a second-line treatment. Major grade 3 or 4 adverse events included neutropenia (10.0 %), anemia (3.3 %), and diarrhea (6.7 %).

Conclusions

SOX was well tolerated and moderately effective in patients with refractory PC.     

Gemcitabine in patients previously treated with platinum-containing chemotherapy for refractory thymic carcinoma: radiographic assessment using the RECIST criteria and the ITMIG recommendations

Background

The key drugs for chemotherapy of thymic carcinoma are gradually being revealed in phase II and conventional retrospective studies. Gemcitabine is regarded as one of these key drugs according to the findings of clinical trials in which it was combined with capecitabine. However, the activity of single-agent gemcitabine concerning refractory thymic carcinoma remains unclear.

Patients and methods

We conducted a retrospective review of the medical records of refractory thymic carcinoma patients previously treated with platinum-containing chemotherapy between 1980 and 2014.

Results

Of all 11 patients in this study, the objective response rate regarding gemcitabine was 36.4 % [95 % confidence interval (CI) 15.2–64.6] using the RECIST criteria and the response criteria proposed by the ITMIG. The median progression-free survival time was 4.3 months (95 % CI 0.7–11.0). The survival time from the start of gemcitabine treatment was 28.5 months (95 % CI 5.5–47.8), and from the start of first-line chemotherapy was 46.5 months (95 % CI 7.3–47.8).

Conclusions

Gemcitabine achieved a moderate response and has the potential to be used as a key drug for thymic carcinoma. Some patients treated with gemcitabine demonstrated prolonged cancer control even in later lines of chemotherapy.

     

Sequential gemcitabine and platinum versus first-line combination of gemcitabine and platinum for advanced pancreatic cancer treatment: a retrospective study

Objective

The purpose of this study was to investigate the impact of combinational versus sequential gemcitabine and platinum on prognosis of advanced pancreatic cancer.

Methods

Two hundred and three patients with advanced pancreatic cancer were selected. They were divided into GemP (first-line gemcitabine and platinum), Gem-then-P (sequential gemcitabine and platinum), Gem/other (first-line gemcitabine-based therapy without subsequent platinum), and Gem (first-line gemcitabine-based therapy without subsequent systemic therapy) groups. The Kaplan–Meier method and log-rank test were used for survival analyses. Cox regression model and propensity score matching were used for prognostic analyses.

Results

The median survival was 12.5 months [95 % confidence interval (CI), 11.2–13.7] in the GemP group (N = 65), 8.3 months (95 % CI 5.0–11.7) in the Gem-then-P group (N = 35), 11.6 months (95 % CI 4.6–18.5) in the Gem/other group (N = 26), and 4.7 months (95 % CI 3.3–6.0) in the Gem group (N = 77) (P < 0.001). Considering the GemP and Gem-then-P groups, performance status, serum creatinine, and response to first-line treatment were independent prognostic factors for overall survival in the multivariate analysis. No specific factors were identified for predicting the choice between GemP and Gem-then-P.

Conclusions

First-line gemcitabine and platinum-based combinations were not superior to sequential gemcitabine and platinum for overall survival. The best sequence of chemotherapy for advanced pancreatic cancer should be explored in future clinical trials.     

Phase II study of oral vinorelbine in combination with capecitabine as second line chemotherapy in metastatic breast cancer patients previously treated with anthracyclines and taxanes

Purpose

Effective treatment options for patients with metastatic breast cancer (MBC) resistant/refractory to anthracyclines and/or taxanes are limited. Intravenous and oral combination of vinorelbine (VRL) and capecitabine were shown to be feasible and effective in first-line MBC. In order to evaluate the activity of the combination of an all oral regimen in a more advanced setting, we investigated a regimen combining oral VRL and capecitabine in a phase II study as second-line chemotherapy of MBC patients previously treated with anthracyclines and taxanes.

Patients and methods

Forty patients (median age 52 years) with MBC received the combination of oral VRL 60 mg/m² on days 1, 8 and 15 plus capecitabine 1,000 mg/m² bid given from day 1 to day 14 in an open-label, international, multicentre, phase II study. Cycles were repeated every 3 weeks. The primary endpoint was response rate (RR) evaluated by an independent panel review. Secondary objectives included safety, duration of response, progression-free survival, overall survival and quality of life.

Results

All the patients had received prior chemotherapy with anthracyclines and taxanes, 75% were refractory/resistant to anthracycline and/or taxane, 72.5% presented with visceral involvement and the last prior chemotherapy for 87.5% of the patients was for advanced disease setting. The median number of administered cycles per patient was 4 (range 1–31). Eight responses were documented and validated by an independent panel review, yielding RRs of 20% [95% CI: 9–35.6] in the intent-to-treat (treated) population and 23.5% [95% CI: 10.7–41.2] in the 34 evaluable patients. Median progression-free survival and median overall survival were 3.4 months [95% CI: 2.3–5.5] and 11.3 months [95% CI: 8.1–16.4], respectively. The principal toxicities were anaemia, neutropenia (rarely complicated; only one patient experienced febrile neutropenia), fatigue and gastrointestinal toxicities with very few grade 3–4 non-haematological toxicities.

Conclusions

In second-line treatment of MBC patients previously treated with anthracyclines and taxanes, oral VRL plus capecitabine is a safe regimen with an efficacy comparable to the other available combination regimens used in this heavily and resistant/refractory (75% of patients) pre-treated patients’ population. Moreover, this well-tolerated combination offers the advantages of an all oral regimen.     

Treatment outcomes of gemcitabine alone versus gemcitabine plus platinum for advanced biliary tract cancer: a Korean Cancer Study Group retrospective analysis

Purpose

ABC-02 trial of gemcitabine plus cisplatin combination showed prolongation of overall survival in biliary tract cancer (BTC) patients. In this multicenter retrospective study, we evaluated the treatment outcome of gemcitabine combined with platinum (GP) compared to that of gemcitabine (G) alone in Korean BTC patients.

Methods

One hundred and fifty-one patients with histologically confirmed biliary tract adenocarcinoma were enrolled at nine institutions between July 2003 and May 2011, including 100 treated with GP and 51 treated with G.

Results

With a median follow-up of 7.7 months (range 0.4–38.3 months), the median overall survival (OS) was 12.4 months [95 % confidence interval (CI) 9.4–15.6 months] of the G group, which was not significantly different for the median OS of 11.0 months (95 % CI 9.7–12.3 months) of the GP group (p = 0.599). The median progression-free survival (PFS) was 3.9 months (95 % CI 0.8–7.0 months) in the G group and 3.3 months (95 % CI 2.6–4.0 months) in the GP group (p = 0.504). Overall response rates (ORR) were 18.8 % in G group and 23.9 % in GP group (p = 0.485).

Conclusions

There was no significant difference in ORR, PFS, or OS for patients between the G group and the GP group, which was different from the ABC-02 trial. Therefore, gemcitabine monotherapy and GP combination are both effective regimens for Korean BTC patients.     

Phase II study of biweekly gemcitabine followed by oxaliplatin and simplified 48-h infusion of 5-fluorouracil/leucovorin (GOFL) in advanced pancreatic cancer

Purpose

To evaluate the efficacy and safety profile of a triplet regimen consisting of gemcitabine, oxaliplatin, and infusional fluorouracil and leucovorin (LV) in advanced pancreatic carcinoma (APC).

Patients and methods

Chemotherapy-naïve patients with histo-/cytologically proven unresectable APC, and bi-dimensionally measurable diseases were eligible. Treatment consisted of fixed-dose rate (10 mg/m²/min) infusion of 800 mg/m² gemcitabine followed by 2-h infusion of 85 mg/m² oxaliplatin and then 48-h infusion of fluorouracil and LV (3,000 and 300 mg/m², respectively) every 2 weeks (the GOFL regimen). The primary end-point was objective response rate.

Results

Forty-five patients were enrolled and received a median of seven [95% confidence interval (CI) 6.4–8.8] cycles of treatment. On intent-to-treat analysis, the overall response and disease-control rates were 33.3% (95% CI 21.4–48.0%) and 68.9% (95% CI 54.8–83.0%), respectively. Clinical benefit response was observed in 46.2% of initially symptomatic patients. The median time-to-tumor progression and overall survival were 5.1 (95% CI 4.0–6.3) months and 8.7 (95% CI, 6.1–11.3) months, respectively. Major grade 3–4 toxicities were neutropenia (28.9%, with 4.4% complicated with fever), peripheral sensory neuropathy (15.6%), nausea/vomiting (13.3%), and diarrhea (6.7%).

Conclusions

The triplet regimen is feasible and exhibits promising activity against APC, deserving further exploration.     

A single-center analysis of the survival benefits of adjuvant gemcitabine chemotherapy for biliary tract cancer

Background

Surgical resection is the only curative treatment of biliary tract cancer (BTC). However, the prognosis of BTC remains unsatisfactory. The aim of this study is to evaluate the benefits of adjuvant gemcitabine chemotherapy for BTC.

Methods

We performed a historical cohort study that involved 198 patients who underwent R0 surgical resection. Patients who underwent major hepatectomy were administered biweekly intravenous gemcitabine at a dose of 800 mg/m². Otherwise, patients were administered intravenous gemcitabine at a dose of 1,000 mg/m² in 3 weekly infusions, which were followed by a 1-week pause. The primary outcome was overall survival. The hazard ratio (HR) of adjuvant chemotherapy was estimated by propensity score-stratified Cox regression that was adjusted for confounders.

Results

Forty patients received adjuvant chemotherapy. The HR of adjuvant chemotherapy was 0.47 [95 % confidence interval (CI) 0.28–0.95; P = 0.03]. Subgroup analysis showed that the survival benefits were possibly modified by lymph node positivity (HR 0.19; 95 % CI 0.07–0.58; interaction, P = 0.22), stage III (HR 0.11; 95 % CI 0.02–0.50; interaction, P < 0.01), intrahepatic cholangiocarcinoma (ICC) (HR 0.09; 95 % CI 0.01–0.67; interaction, P = 0.05), and poorly differentiated tumor (HR 0.16; 95 % CI 0.03–0.85; interaction, P = 0.13).

Conclusions

Adjuvant gemcitabine chemotherapy for BTC may be effective, particularly for patients with stage III and ICC.     

Gemcitabine and oxaliplatin in patients with unresectable biliary cancer including gall bladder cancer: a Korean Cancer Study Group phase II trial

Purpose

Chemotherapy represents a palliative treatment, with poor response rates and a median survival of less than 6 months in patients with biliary tract cancers (BTCs). The aim of this study was to evaluate the efficacy and safety of the combination chemotherapy with gemcitabine and oxaliplatin (GEMOX) in patients with BTCs including gall bladder cancer.

Methods

We carried out a nationwide multicenter phase II study evaluated the efficacy and safety of GEMOX as first-line therapy in patients with advanced BTCs. Eligible patients with previously untreated locally advanced or metastatic BTCs received gemcitabine 1,000 mg/m² (day 1 and 8) and oxaliplatin 100 mg/m² (day 1), every 3 weeks.

Results

Fifty-three patients were evaluated, 60% had cholangiocarcinoma and the remaining 40% gall bladder cancer; the objective response rate was 18.9% (10/53 patients including 1 Complete response) [14.9%; 95% confidence interval (CI), 7.4–25.7%] in the treated population. Stable disease were observed in 27/53 (50.9%) patients, disease control rate was achieved in 69.8% of all patients. Median progression-free survival was 4.8 months (3.1–6.5, 95% CI) and median overall survival was 8.3 months (5.8–10.8, 95% CI). Grade 3/4 toxicities included neutropenia (33.9% of patients) and thrombocytopenia (7.6%).

Conclusions

The GEMOX regimen demonstrated a modest antitumor activity and is well tolerated in patients with advanced BTCs.     

Frontline treatment with gemcitabine,oxaliplatin and erlotinib for the treatment of advanced or metastatic pancreatic cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG)

Purpose

Intravenous gemcitabine is the standard of care for patients with metastatic cancer of the pancreas. Gemcitabine-based chemotherapy combinations, either doublets or triplets, have been tested in the past but have offered a small advantage (Brodoefel et al. in Eur J Radiol 73:594–600, 2010). In the present study, we present the results of the triplet gemcitabine–oxaliplatin–erlotinib combination as firstline treatment in this setting.

Patients and methods

Seventy-one eligible patients were included in this study. All patients received chemotherapy with gemcitabine (1,100 mg/m² on days 1 and 8) plus oxaliplatin (130 mg/m² on day 8) and erlotinib (100 mg p.o./day for 21 days). The treatment cycle was 21 days.

Results

Partial response was achieved in 15 patients (21 %; 95 % CI 11.63–30.62) and stable disease in 15 patients (21 %). Forty-one patients (57.8 %) experienced disease progression. Median progression-free survival was 5.2 months (range 0.6–34.7; 95 % CI 3.71–6.76). The median overall survival was 10.5 months (95 % CI 7.39–13.61) and the 1-year survival estimate 47.3 %. The main adverse events were grade 3/4 anemia occurring in three (4.2 %) patients and grade 3 and 4 thrombocytopenia occurring in eight (11.3 %) and three (4.2 %) patients, respectively. Grade 4 neutropenia was rare (1.4 %), and one patient presented febrile neutropenia.

Conclusion

This study demonstrated that the combination of gemcitabine, oxaliplatin and erlotinib is active, well tolerated and safe for patients with metastatic adenocarcinoma of the pancreas. However, the results do not seem to be better than those reported with chemotherapy alone.     

A multicenter phase II study of biweekly capecitabine in combination with oxaliplatin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer

Purpose

We evaluated the safety and efficacy of biweekly capecitabine in combination with oxaliplatin in previously untreated patients with locally advanced or metastatic gastric cancer.

Methods

Patients received oral capecitabine 1,000 mg/m² twice daily on days 1–10 plus oxaliplatin 85 mg/m² as a 2-h intravenous infusion on day 1, every 2 weeks (XELOX). The primary endpoint was overall response rate. Secondary endpoints included progression-free survival, overall survival, and toxicity.

Results

From March 2007 to October 2010, 46 patients were enrolled in this phase II study. The median age was 64 years (range 32–85). A total of 391 (median 7.5, range 1–29) cycles were delivered. Among the 41 patients evaluable for tumor response, 9 showed partial response and 25 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 22 % (95 % CI 10–42 %) and 20 % (95 % CI 9–34 %), respectively. In the ITT analysis, the progression-free survival and overall survival were 5.6 months (95 % CI 4.1–6.3 months) and 8.0 months (95 % CI 6.3–10.1 months), respectively. The most common hematological toxicities were thrombocytopenia (35 %) and leucopenia (34 %), whereas the most common non-hematological toxicities were neuropathy (35 %), fatigue (33 %), diarrhea (27 %), vomiting (26 %), and hand-foot syndrome (25 %). Major grade 3–4 toxicities were anemia (11 %), diarrhea (9 %), and hand-foot syndrome (7 %). No patient died of treatment-related toxicities.

Conclusions

Although the biweekly XELOX regimen failed its primary response rate endpoint, it showed modest efficacy and an acceptable safety profile in the treatment of advanced gastric cancer.     

Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction

Purpose

We assessed the impact of hepatic dysfunction on the safety and pharmacology of gemcitabine/capecitabine in patients with advanced pancreatico-biliary cancer.

Methods

We included 12 patients receiving 3 weekly gemcitabine 1,000 mg/m² day 1, 8 and oral capecitabine 650 mg/m² b.i.d. over 2 weeks until disease progression or intolerable toxicity. Patients were included into one normal hepatic function cohort [total bilirubin (TB) ≤15 μmol/L] and 3 cohorts with increasing TB (16–39, 40–80, >80 μmol/L). Three patients with a creatinine clearance <60 ml/min were also included. Patients were sampled for gemcitabine, difluoro-deoxy uridine, intracellular gemcitabine triphosphates, capecitabine, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine and 5-fluorouracil up to 4 h after initiation of chemotherapy on day 1, and up to 90 min on day 8. All compounds were analyzed using validated liquid chromatography–tandem mass spectrometry. Nonlinear mixed-effect modeling was used for population analysis.

Results

Hepatic dysfunction was caused by intrahepatic cholestasis in 4 out of 8 patients (50 %) and extrahepatic cholestasis in another 4 patients (50 %). Dose-limiting toxicity was increasing hyperbilirubinemia and severe neutropenia in 2 patients each. Hepatic dysfunction was not associated with dose-limiting toxicity or severe hematological or non-hematological toxicity. However, hepatic dysfunction was associated with low clearance of both gemcitabine (p = 10^?3) and capecitabine (p = 10^?5), and low intracellular gemcitabine triphosphate concentrations (p = 10^?3).

Conclusions

Gemcitabine/capecitabine can be given at the standard dose in patients with severe hyperbilirubinemia, though the present data suggest that gemcitabine’s activity may be limited due to poor intracellular activation. In patients with severe hyperbilirubinemia, initial monotherapy with capecitabine should be considered, followed by the addition of gemcitabine with improving hyperbilirubinemia.     

Phase II trial of gemcitabine plus UFT as salvage treatment in oxaliplatin,irinotecan and fluoropyrimidine-refractory metastatic colorectal cancer

Purpose

To investigate the efficacy of gemcitabine plus uracil–tegafur (UFT) combination chemotherapy as a salvage treatment in patients with metastatic colorectal cancer (MCRC).

Methods

This single-arm phase II study was conducted at three institutions in Korea. Patients with MCRC refractory to fluoropyrimidine, oxaliplatin and irinotecan were enrolled. Gemcitabine 800 mg/m² was administered intravenously on days 1, 8 and 15. UFT 200 mg/m²/day was taken orally in three divided doses on days 1–21. Cycles were repeated every 4 weeks, and tumor evaluation was carried out every 8 weeks. The primary endpoint of this study was 8-week progression-free survival (PFS) rate.

Results

Forty-one patients were enrolled. Fourteen patients received gemcitabine/UFT as a third-line treatment and 37 patients as a fourth-line or later-line therapy. Toxicities were easily manageable, and non-hematologic toxicities of ≥grade 3 were rare. The most common toxicity of ≥grade 3 was neutropenia (20.0 %). One patient showed partial response (response rate, 2.4 %) and 14 (34.1 %) showed stable disease. The 8-week PFS rate was 42.3 %. The median PFS was 1.7 months [95 % confidence interval (CI) 1.6–1.8 months], and the median overall survival was 9.2 months (95 % CI 5.8–12.6 months).

Conclusions

Overall efficacy of gemcitabine/UFT in refractory MCRC was unsatisfactory. However, we could find a minor proportion of patients who showed prolonged tumor stabilization to gemcitabine/UFT. Further studies are warranted to identify a patient subgroup that might have benefits from gemcitabine/UFT therapy.     

Phase II trial of gemcitabine and S-1 for patients with advanced pancreatic cancer

Purpose

To evaluate the efficacy and safety of combined gemcitabine and S-1 as first-line chemotherapy for patients with locally advanced or metastatic pancreatic cancer.

Methods

This study included patients who had been diagnosed with unresectable, locally advanced or metastatic adenocarcinoma arising from the pancreas, which was histologically or cytologically confirmed and involved at least 1 unidimensionally measurable lesion. The regimen consisted of intravenous 1,000 mg/m² gemcitabine on day 1 and 8 combined with oral S-1 on days 1–14 every 21 days. The dosage of S-1 was based on the body surface area (BSA) as follows: 40 mg bid (total 80 mg/day) for a BSA of <1.25, 50 mg bid (total 100 mg/day) for a BSA of ≥1.25 but <1.5, and 60 mg bid (total 120 mg/day) for a BSA of ≥1.5. Treatment consisted of at least 2 courses unless rapid disease progression was noted. The primary end points were the response and disease control rates, and the secondary end points were toxicity and survival.

Results

Thirty-seven patients were enrolled between August 2005 and December 2010. The median number of chemotherapy cycles was 4 (range 1–28 cycles). Response to treatment could be evaluated in 31 patients. None of the patients showed complete response, but 5 achieved partial response. The response rate was thus 13.5 % [95 % confidence interval (CI) 2.7–24.3 %] in the intent-to-treat population. Sixteen patients (43.2 %; 95 % CI 27–59.5 %) showed stable disease, and the overall disease control rate was 56.8 % (95 % CI 40.6–72.9 %). For all 37 patients, the median progression-free survival was 4.6 months (95 % CI 1.8–7.6 month), and the median overall survival was 9.4 month (95 % CI 5.8–12.6 month). Chemotherapy-related grade 3/4 hematological toxicities were neutropenia (36.1 %), leucopenia (22.2 %), and anemia (13.9 %). The non-hematological toxicities were generally mild.

Conclusions

Combination chemotherapy with gemcitabine and S-1 was effective, convenient, and safe in patients with advanced pancreatic 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.     

Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer

Purpose

The aim of this study was to evaluate efficacy and safety of gemcitabine plus S-1 (GS) combination chemotherapy in patients with unresectable pancreatic cancer.

Methods

Patients were randomly assigned to receive GS (oral S-1 60 mg/m² daily on days 1–15 every 3 weeks and gemcitabine 1,000 mg/m² on days 8 and 15) or gemcitabine (1,000 mg/m² on days 1, 8, and 15 every 4 weeks). The primary endpoint was progression-free survival (PFS).

Results

One hundred and one patients were randomly assigned. PFS was significantly longer in the GS arm with an estimated hazard ratio (HR) of 0.65 (95 % CI 0.43–0.98; P = 0.039; median 5.3 vs 3.8 months). Objective response rate (ORR) was also better in the GS arm (21.6 vs 6 %, P = 0.048). Median survival was 8.6 months for GS and 8.6 months for GEM (HR 0.93; 95 % CI 0.61–1.41; P = 0.714). Grade 3–4 neutropenia (44 vs 19.6 %, P = 0.011) and thrombocytopenia (26 vs 8.7 %, P = 0.051) were more frequent in the GS arm.

Conclusions

GS therapy improved PFS and ORR with acceptable toxicity profile in patients with unresectable pancreatic cancer.     

Multicenter phase II study of capecitabine combined with nedaplatin for recurrent and metastatic nasopharyngeal carcinoma patients after failure of cisplatin-based chemotherapy

Purpose

There is no standard second-line regimen for recurrent and metastatic nasopharyngeal carcinoma patients after failure of cisplatin-based chemotherapy. A multicenter phase II study was conducted to evaluate the efficacy and toxicity of capecitabine combined with nedaplatin for these patients.

Patients and methods

In the multicenter, open-label, single-arm phase II study, patients with recurrent and metastatic nasopharyngeal carcinoma who failed to previous cisplatin-based chemotherapy were enrolled. Patients received oral capecitabine (1,000 mg/m² twice daily from day 1 to 14) and intravenous nedaplatin (80 mg/m², day 1) every 3 weeks for two cycles at least.

Results

A total of forty-eight patients were enrolled and included in the intention-to-treat analysis of efficacy and adverse events. Treatment was well tolerated. Grade 3/4 toxicities included neutropenia (8.4 %), anemia (2.1 %), diarrhea (4.2 %), stomatitis (6.3 %), and hand-foot syndrome (HFS) (4.2 %). There were two complete response (4.2 %), eighteen partial responses (37.5 %), giving an overall response rate of 41.7 % [95 % confidence interval (CI) 27.7–55.8]. With a median follow-up period of 12.1 months, the median time to progression was 5.8 months (95 % CI 3.9–7.8 months) and median overall survival was 12.4 months (95 % CI 9.6–16.8 months).

Conclusion

Capecitabine combined with nedaplatin offers a satisfactory clinical activity and an acceptable safety profile for recurrent and metastatic nasopharyngeal carcinoma patients after failure of cisplatin-based chemotherapy.     

A phase II trial of prolonged,continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma

Purpose

Low-dose, prolonged infusion of gemcitabine has effects similar to standard doses in several cancers. We evaluated the toxicity and efficacy of low-dose gemcitabine in prolonged infusion plus cisplatin in patients with advanced pleural mesothelioma.

Methods

Patients with mesothelioma received gemcitabine (250 mg/m²) in a 6-h infusion plus cisplatin (35 mg/m²) on days 1 and 8 every three weeks. We used the modified response evaluation criteria in solid tumours. This study is registered in clinical trials (NCT01869023).

Results

We included 39 patients; 82.1 % were low risk according to the European Organisation for Research and Treatment of Cancer prognostic group. Partial response was observed in 53.8 % (21/39), stable disease in 33.3 % (13/39) and progression in 12.8 % (5/39). The median progression-free survival was 6.9 months (95 % CI 3.2–10.6 months), and the associated factors were the EORTC risk and histology. The median overall survival was 20.7 months (95 % CI 10.7–30.8 months). The functional, physical and emotional roles and dyspnoea, insomnia and pain symptom scales improved. The most commonly graded 3/4 side effects were neutropenia (24.4 %), lymphopenia (14.6 %), thrombocytopenia (14.7 %) and anaemia (12.2 %).

Conclusions

Low-dose, prolonged gemcitabine infusion plus cisplatin has acceptable toxicity and high efficacy with improved quality of life, representing an affordable regimen for the low-income population.     

Phase 1, open-label,dose-escalation,and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors

Background

Statins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer.

Methods

Patients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000 mg/m² on days 1, 8, and 15 plus simvastatin 40 mg once daily) or GP (gemcitabine 1,000 mg/m² on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP).

Results

Between December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4 months (95 % CI 0.7–4.1 months) and 3.6 months (95 % CI 3.1–4.1 months) in the GS and GP arms, respectively (P = 0.903). The overall disease control rate was 39.7 % (95 % CI 12.2–33.8 %) and 57.1 % (95 % CI 19.8–44.2 %) in the GS and GP arms, respectively (P = 0.09). The 1-year expected survival rates were similar (27.7 and 31.7 % in the GS and GP arms, respectively; P = 0.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis.

Conclusions

Adding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer.     

A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere

Purpose

Docetaxel and capecitabine combination is synergistic in preclinical models. We investigated the efficacy and toxicity of this combination as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma (mPC), pretreated with gemcitabine-based chemotherapy.

Methods

Eligible patients were treated with capecitabine 800 mg/m² orally PO bid on days 1–14 in combination with intravenous docetaxel 30 mg/m² on days 1 and 8 of each 21-day cycle. The primary end point was overall response rate. Using a three-stage sequential design, two interim analyses for early stopping due to lack of efficacy were planned and conducted after 13 and 26 patients were accrued. Secondary end points included time to treatment failure, progression-free survival (PFS), overall survival (OS) and 50 % drop in CA19-9 levels.

Results

Forty-three patients were evaluable for toxicity and 42 evaluable for response, at a median age of 64 years. The majority of patients (74 %) had ECOG PS 0-1. Six patients (14 %) achieved a partial tumor response, and stable disease for ≥2 cycles was observed in 59 % of patients (n = 25). Thirty-five percent (n = 11/31) of patients had a ≥50 % decrease in CA19-9 levels. The median PFS was 3.7 months (95 % CI 2.1–4.3 months), and the median OS was 5.3 months (95 % CI 4.3–8.6 months). Treatment was generally well tolerated. Grade 3 toxicity and grade 4 toxicity were seen in 45 and 5 % of patients, respectively. One patient had a potential treatment-related mortality.

Conclusions

The combination of capecitabine and docetaxel is active and well tolerated in mPC patients pretreated with gemcitabine-based therapy.