Effect of cystathionine beta-synthase variant 844ins68bp and methylenetetrahydrofolate reductase A1298C polymorphisms in xenografts on 5-FU efficacy and doubling time

The association of MTHFR and CBS variants with the doubling time and responsiveness to several chemodrugs was analyzed in 26 human cancer xenografts. The tumors homozygous for the absence of insertion (NN) for the CBS 844ins68bp were more chemosensitive than those with insertion (NI) to TS-1 (P=0.0048), suggesting a potential effect of this variant on fluoropyrimidine efficacy. Furthermore, the doubling time of tumors with a variant C allele (AC or CC) in MTHFR-A1298C was significantly longer than that of tumors with a normal allele (AA) (P=0.0008). Twenty-nine cellular proliferation-related genes were associated with MTHFR-A1298C genotyping and with the doubling time.     

伊立替康联合5-FU/CF治疗转移性结直肠癌46例

目的：评价伊立替康（CPT—11）联合5-FU／CF方案治疗FOLFOX4或LV5FU2方案失败的结直肠癌的客观疗效，临床受益和不良反应。方法：用CPT—11联合5-FU／CF方案治疗晚期结直肠癌患者46例，采用2周方案，即CPT—11 180mg／m^2 iv d1，CF200mg／m^2 iv d1-2，5-FU400mg iv bolusd1，5-FU600mg／m^2 iv，22hd1—2，每2周重复。观察期3—6个月。结果：完全缓解0例，部分缓解18例（有效率39．13％），稳定20例（43．47％），进展8例（17．39％）。临床受益率82．6％（19／23）。临床反应评价有效者36例（78．86％），生活质量显著提高。结论：CPT-11联合5-Fu／CF方案可作为转移性结直肠癌的二线治疗。     

First-in-Human Phase 1b Trial of Quinacrine Plus Capecitabine in Patients With Refractory Metastatic Colorectal Cancer

BackgroundQuinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of quinacrine plus capecitabine in patients with treatment-refractory mCRC.Patients and MethodsUsing a modified Simon accelerated titration design, adults with treatment-refractory mCRC were treated with capecitabine 1000 mg/m² twice daily for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP).ResultsTen patients (median age of 60 years) were treated in phase 1b. The first 2 quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with quinacrine 200 mg twice daily. Five additional patients tolerated quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients.ConclusionCapecitabine and quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m² by mouth twice daily on days 1-14 and quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.     

Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial

AimThe optimal second-line regimen for treating advanced gastric cancer (AGC) remains unclear. While irinotecan (CPT-11) plus cisplatin (CDDP) combination therapy and CPT-11 monotherapy have been explored in the second-line setting, the superiority of second-line platinum-based therapies for AGC patients initially treated with S-1 monotherapy has not yet been evaluated; therefore, we aimed to examine the survival benefit of CPT-11/CDDP combination over CPT-11 monotherapy.MethodsAGC patients showing progression after S-1 monotherapy for advanced cancer or recurrence within 6 months after completion of S-1 adjuvant therapy were randomly allocated to CPT-11/CDDP (CPT-11, 60 mg/m²; CDDP, 30 mg/m², q2w) or CPT-11 (150 mg/m², q2w).ResultsSixty-eight advanced and 95 recurrent cases were evaluated. The median overall survivals were 13.9 (95% confidence interval [CI]: 10.8–17.6) and 12.7 (95% CI: 10.3–17.2) months for CPT-11/CDDP and CPT-11, respectively (hazard ratio: 0.834; 95% CI: 0.596–1.167, P = 0.288). No significant differences were observed in the secondary end-points, including progression-free survival (4.6 [95% CI: 3.4–5.9] versus 4.1 [95% CI: 3.3–4.9] months) and response rate (16.9% [95% CI: 8.8–28.3] versus 15.4% [95% CI: 7.6–26.5]). The incidences of grade 3–4 anaemia (16% versus 4%) and elevated serum lactate dehydrogenase levels (5% versus 0%) were higher for CPT-11/CDDP than for CPT-11. Exploratory subgroup analysis revealed that CPT-11/CDDP was significantly more effective for intestinal-type AGC, compared with CPT-11 (overall survival: 15.8 versus 14.0 months; P = 0.019).ConclusionNo survival benefit was observed upon adding CDDP to CPT-11 after S-1 monotherapy failure.     

氟尿嘧啶类药物在结、直肠癌术后化疗中副反应的比较

目的 比较5-FU、氟铁龙、希罗达3种氟尿嘧啶类药物在结、直肠癌术后化疗中的副反应。方法 64例结肠、直肠癌术后病例分成3组:分别采用静脉滴注5-FU/CF、口服氟铁龙/CF和口服希罗达方案。观察3组病例在化疗过程中出现的副反应及其程度。结果 5-FU/CF组副反应主要为骨髓抑制(34.6％)、恶心(23％)、呕吐(11.5％)。氟铁龙/CF组副反应主要为腹泻(55％)、口炎(25％)和手足综合征(10％)。希罗达组副反应主要为腹泻(28％)、手足综合征(38.9％)和口炎(16.6％)。结论 3种化疗方案均可导致不同程度的副反应,尤其是氟铁龙/CF方案的胃肠道反应发生率高,且程度较重。     

Fluorine-19 or phosphorus-31 NMR spectroscopy: a suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs

Fluorine-19 or phosphorus-31 NMR (¹⁹F NMR or ³¹P NMR) spectroscopy provides a highly specific tool for identification of fluorine- or phosphorus-containing drugs and their metabolites in biological media as well as a suitable analytical technique for their absolute quantification. This article focuses on the application of in vitro ¹⁹F or ³¹P NMR to the quantitative metabolic studies of some fluoropyrimidine or oxazaphosphorine drugs in clinical use. The first part presents an overview of the advantages (non-destructive and non-selective direct quantitative study of the biological matrices) and limitations (expensive cost of the spectrometers, limited mass or concentration sensitivity) of NMR spectroscopy. The second part deals with the criteria to be considered for successful quantification by NMR (uniform excitation over the entire spectral width of the spectrum, resonance signals properly characterised by taking into account T₁ values and avoiding NOE enhancements, optimisation of the data processing, choice of a suitable standard reference). The third and fourth parts report some examples of quantification of 5-fluorouracil, its prodrug capecitabine, 5-fluorocytosine and their metabolites in bulk solutions (biofluids, tissue extracts, perfusates and culture media) and heterogeneous media (excised tissues and packed intact cells) as well as cyclophosphamide and ifosfamide in biofluids. These two parts emphasise the high potential of in vitro ¹⁹F or ³¹P NMR for absolute quantification, in a single run, of all the fluorine- or phosphorus-containing species in the matrices analysed. The limit of quantification in bulk solutions is 1–3 μM for ¹⁹F NMR and approximately 10 μM for ³¹P NMR. In heterogeneous media analysed with ¹⁹F NMR, it is 2–5 nmol in excised tissues and cell pellets.     

Single-Agent Versus Double-Agent Chemotherapy in Concurrent Chemoradiotherapy for Esophageal Squamous Cell Carcinoma: Prospective,Randomized, Multicenter Phase II Clinical Trial

Lessons Learned

• The efficacy of single‐agent chemotherapy was not significantly different from that of double‐agent chemotherapy in concurrent chemoradiotherapy for inoperable esophageal squamous cell carcinoma.
• Single‐agent concurrent chemoradiotherapy had lower gastrointestinal and hematologic toxicity.
• Overall survival and progression‐free survival were not significantly different between single‐ and double‐agent concurrent chemoradiotherapy.

BackgroundThis multicenter, randomized, phase II trial aimed to compare the efficacy and safety of single‐agent concurrent chemoradiotherapy using the oral fluoropyrimidine S‐1 with those of double‐agent concurrent chemoradiotherapy using S‐1 and cisplatin in patients with inoperable esophageal squamous cell carcinoma.MethodsPatients with inoperable esophageal squamous cell carcinoma (clinical stages I to III) were randomly allocated to the single‐agent group (S‐1) or the double‐agent group (S‐1/cisplatin). The concurrent intensity‐modulated radiation therapy plan was similar for both groups: planning target volume 1.8 Gy/f*30–33f and planning gross target volume of 2 Gy/f*30–33f. The primary outcome measure was the endoscopic complete response rate.ResultsOf the 105 patients randomized, 89 were assessable. The endoscopic complete response rate was 46.9% (23/49) in the single‐agent group and 52.5% (21/40) in double‐agent group. The median progression‐free survival within a median follow‐up of 23 months was 20 and 21 months, respectively. The median overall survival was 26 months and not reached, respectively. Grade 3 hematological toxicities occurred in 4.1% and 27.5% of the patients in the single‐ and the double‐agent group, respectively.ConclusionSingle‐agent chemotherapy in concurrent chemoradiotherapy for inoperable esophageal squamous cell carcinoma has good efficacy and safety, thus warranting a phase III trial.     

Retrospective analysis of adjuvant chemotherapy for curatively resected gastric cancer

AIM:To determine the efficacy of adjuvant chemotherapy for gastric cancer in clinical practice,a retrospective analysis was conducted in a high-volume Chinese cancer center.METHODS:Between November 1995 and June 2007,a total of 423 gastric or esophagogastric adenocarcinoma patients who did(Arm A,n=300)or did not(Arm S,n=123)receive radical gastrectomy followed by postoperative chemotherapy were enrolled in this retrospective analysis.In Arm A,monotherapy(fluoropy rimidines,n=25),doublet(platinum/fluoropyrimidines,n=164),or triplet regimens[docetaxel/cisplatin/5FU(DCF),or modified DCF,epirubicin/cisplatin/5FU(ECF)or modified ECF,etoposide/cisplatin/FU,n=111]were administered.Disease-free survival(DFS)and overall survival(OS)were compared between the two arms.A subgroup analysis was carried out in Arm A.A multivariate analysis of prognostic factors was conducted.RESULTS:Stage?Ⅰ,ⅡandⅢcancers accounted for9.7%,35.7%and 54.6%of the cases,respectively,according to the American Joint Committee on Cancer(AJCC)staging system,7th edition.Only 178(42.1%)patients had more than 15 lymph nodes harvested.Hazard ratio estimates for Arm A compared with Arm S were 0.47(P<0.001)for OS and 0.59(P<0.001)for DFS.The 5-year OS rate was 52%in Arm A vs36%in Arm S(P=0.01);the adverse events in Arm A were mild and easily controlled.Ultimately,73 patients(26.5%)who received doublet or triplet regimens switched to monotherapy with fluoropyrimidines.The OS and DFS did not differ between monotherapy and the combination regimens,however,both were statistically improved in the subgroup of patients who were switched to monotherapy with fluoropyrimidines after doublet or triplet regimens as well as patients who received≥8 cycles of chemotherapy.CONCLUSION:In clinical practice,platinum/fluoropyrimidines with adequate treatment duration is recommended for stageⅡ/Ⅲgastric cancer patients accordingto the 7th edition of the AJCC staging system after curative gastrectomyeven with limited lymphadenectomy.     

Improvement of prognosis for unresectable biliary tract cancer

AIM:To evaluate the chemotherapeutic outcomes and confirm the recent improvement of prognosis for unresectable biliary tract cancer.METHODS:A total of 186 consecutive patients with unresectable biliary tract cancer,who had been treated with chemotherapy between 2000 and 2009 at five institutions in Japan,were retrospectively analyzed.These patients were divided into three groups based on the year beginning chemotherapy:Group A(2000-2003),Group B(2004-2006),and Group C(2007-2009).The data were fixed at the end of December 2011.Overall survival and time-to-progression were analyzed and compared chronologically.RESULTS:No patient characteristics were significantly different among the three groups.The gallbladder was involved in about half of the patients in each group,and metastatic biliary tract cancer was present in three quarters of the enrollees.In Group A,5-fluorouracilbased chemotherapies were primarily selected as firstline chemotherapy,and only 24% were treated with second-line chemotherapy.In Group B,gemcitabine or S-1 monotherapy was mainly introduced as firstline chemotherapy,and 51% of the patients who were refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with monotherapy.In Group C,the combination therapy with gemcitabine and S-1 was mainly chosen as first-line chemotherapy,and 53% of the patients refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with combination therapy.The median timeto-progressions were 4.4 mo,3.5 mo and 5.9 mo in Groups A,B and C,respectively(4.4 mo vs 3.5 mo vs 5.9 mo,P < 0.01).The median overall survivals were 7.1,7.3,and 11.7 mo in Groups A,B and C(7.1 mo vs 7.3 mo vs 11.7 mo,P = 0.03).Induction rates of all three drugs(gemcitabine,platinum analogs,and fluoropyrimidine) in Groups A,B and C were 4%,2% and 27%(4% vs 2% vs 27%,P < 0.01).CONCLUSION:The prognosis of unresectable biliary tract cancer has improved recently.Using three effective drugs(gemcitabine,platinum analogs,and fluoropyrimidine) may     

Chemotherapy for metastatic disease: review from JCOG trials

The Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (GIOSG/JCOG) has conducted several clinical trials to establish standard chemotherapy for unresectable or recurrent gastric cancer. From the late 1980s to early 1990s, two phase II studies by JCOG evaluated oral fluoropyrimidines, and others introduced Western chemotherapy regimens. Thereafter, the first phase III study (JCOG9205), comparing 5-fluorouracil (5-FU), 5-FU plus ciplatin (CDDP) (FP), and uracil and tegafur (UFT) plus mitomycin (UFTM), could not show a survival benefit of either FP or UFTM over 5-FU alone. In the late 1990s, new active agents such as irinotecan (CPT-11) and S-1 (new oral fluoropyrimidine) showed promising results in their phase II trials. The latest phase III study (JCOG9912), comparing 5-FU, CPT-11 plus CDDP, and S-1, showed significant noninferiority of S-1 to 5-FU in overall survival, associated with a better response rate and progression-free survival and acceptable toxicities, and concluded that S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer. Simultaneously, another Japanese phase III trial comparing S-1 with S-1 plus CDDP showed a survival benefit of S-1 plus CDDP. At present, S-1 plus CDDP is recognized as standard chemotherapy for unresectable or recurrent gastric cancer, and new treatment with molecular target agents is under development.