Quality of life during and after adjuvant anthracycline-taxane-based chemotherapy with or without Gemcitabine in high-risk early breast cancer: results of the SUCCESS A trial.

PURPOSE: In high-risk early breast cancer, adjuvant taxane-Gemcitabine combinations result in a recurrence-free survival similar to single-agent taxanes. However, haematologic toxicities and need for dose reductions are more frequent in combinations. Which option ultimately provides a better quality of life (QoL) is unknown. We compared the QoL curves before, during, and up to one year after three cycles of Fluorouracil-epirubicin-cyclophosphamide followed by three cycles of Docetaxel-Gemcitabine or Docetaxel. METHODS: Overall, 3691 women with recent R0-resection of a primary epithelial breast cancer participated in the nationwide SUCCESS A clinical trial. The centres sent QoL questionnaires of the European Organisation for Research and Treatment of Cancer before and up to 15 months after randomisation to Docetaxel-Gemcitabine versus Docetaxel. Multilevel analysis by chemotherapy arm estimated the QoL time curves, questionnaire return, and dropout. RESULTS: The combination caused one-point higher global QoL (95% confidence ±1; p = 0.05) and 1.1 lower odds of adherence to the outcome (95% confidence 1.0-1.1; p = 0.23) than the monotherapy. In both groups, a 10-point decrease during therapy preceded a 16-point increase after chemotherapy (p < 0.001). The secondary QoL outcomes showed transient superiority of the combination at the end of chemotherapy. Discontinuation from chemotherapy and its reasons were equal in both groups. CONCLUSIONS: While patients perceive a one-point QoL difference as meaningless, a six-point increase is clinically relevant for them. That is, both regimens cause the same relevant long-term QoL improvement. With the similar recurrence-free survival, the lower toxicity, and the shorter chemotherapy duration in mind, taxanes without Gemcitabine are the preference. This challenges previous recommendations supporting combinations.

[New FP Therapy Was Effective for a Case of Massive Hepatocellular Carcinoma].

A 62 year-old woman was hospitalized with the diagnosis of pneumonia, and a huge mass was recognized in the right lobe of the liver during a CT scan. AFP and PIVKA-Ⅱ were elevated to 101.05 ng/mL and 2,177 mAU/mL. The liver function test indicated Child-Pugh classification A, liver damage degree B, and ICG R15 34%. We judged a radical cure resection impossible. We treated the patient with arterial injections of modified new FP therapy. No side effect occurred during the first course. Liver dysfunction with fever and hematuria occurred during the second course, leading to discontinuation of therapy. Because a prominent reduction in the size of the tumor was achieved, liver resection is scheduled. New FP therapy can be expected to attain a favorable result that may allow for curative resection of the tumor.

[Multi-center trial based on SCMC-ALL-2005 for children's acute lymphoblastic leukemia].

OBJECTIVE: Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. To further utilize the rich resources to develop suitable protocol for Chinese pediatric ALL, Shanghai Children's Medical Center and 4 other pioneer children's ALL treatment centers collaborated to start a multi-center clinical trial to assess the feasibility and efficacy of SCMC-ALL-2005 protocol and try to revise the protocol based on the evidences found in this study. METHOD: Totally 655 cases of ALL patients recruited in the trial between May 1st 2005 and April 30th 2009 were diagnosed, stratified and treated with the same criteria and protocol based on SCMC-ALL-2005. χ(2) test was used for assessing the distribution similarity among centers, and the survival function was studied by Kaplan-Meier curve and Log-Rank χ(2) test. Among them 599 cases (91.4%) completed the MIC diagnosis. Comparing the distribution of age, gender, immunotype, white blood cell count at diagnosis and risk stratification among centers, most of the P values were > 0.1 except P value of immunotype distribution which was 0.013. Till Sep. 30th 2011, 613 patients (93.6%) were followed up. The medium follow up period for survivals was 49.13 months. RESULT: The predicted 5-Year events free survival (EFS) was (69.9% ± 2.1%), 5-year overall survival(OS) was (77.6% ± 2.0%); 5-year relapse was (23.9% ± 2.0%). Among different risk groups, the predicted 5-year EFS, OS and relapse rate for low-risk (LR) were (82.0% ± 2.6%), (83.6% ± 3.0%) and (16.1% ± 2.5%) respectively; for medium-risk (MR) were (66.4% ± 3.1%), (76.8% ± 2.7%) and (26.3% ± 3.0%) respectively; for high-risk (HR) were (27.4% ± 9.3%), (48.9% ± 7.3%) and (60.0% ± 12.8%) respectively. Relapse was still the most important event which caused treatment failure (up to 59.5% of the failure). Herein relapsed, the most common relapse site was bone marrow (76.6% in those relapsed); the percentage of central nervous system relapse was 12.9% and the percentage of testis relapse in boys was 14.3%. Prognostic factor study indicated that higher peripheral white blood cell count at diagnosis, age younger than 1 year and molecular markers of BCR-ABL1 and MLL-AF4 predict the poorest outcomes. Survival curve analysis: survival platform started at 30 months in high risk group and at 50 months in medium risk group since the first chemotherapy. While in low risk group, there were two platforms at 20 months and 50 months. Between them was an obvious relapse peak. CONCLUSION: SCMC-ALL-2005 protocol was an effective and feasible protocol for childhood ALL to be adopted in most centers. But it could be better if some modification is made.

Significance of biological markers for predicting prognosis and selecting chemotherapy regimens of advanced gastric cancer patients between continuous infusion of 5-FU and a combination of 5-FU and cisplatin.

BACKGROUND: Our previous phase II study of 5-fluorouracil (5-FU) and cisplatin (FP) for treatment of advanced gastric cancer showed that strong immunoreactivity for vascular endothelial growth factor (VEGF) is associated with chemoresponse. Patients with four or five of the favorable phenotypes, p53 (-), bcl-2 (-), gluthathione S-transferase pi (-), thymidylate synthase (-), and VEGF (+), survived longer than those with three or less of these phenotypes. The purpose of this study is to confirm our previous results and to compare the significance of those markers between continuous infusion of 5-FU (5-FUci) and FP. METHODS: Pretreatment biopsies from 131 of 210 advanced gastric cancer patients enrolled to JCOG9205 were analyzed immunohistochemically for the presence of the five markers. RESULTS: Median survival times of patients treated with 5-FUci (n = 65) or FP (n = 66) were 216 and 253 days, respectively (P = 0.6953). After FP treatment, patients with four or five favorable phenotypes (n = 20) survived longer than those with three or less favorable phenotypes (n = 46) (334 days and 243 days, respectively; P = 0.0463), and the survival times of 34 and 32 patients with VEGF (-) and (+) were similar (269 days and 253 days, respectively; P = 0.6317). After 5-FUci, 30 patients with VEGF (+) survived for a shorter time than 35 patients with VEGF (-) (142 days and 302 days, respectively; P = 0.0043). CONCLUSION: The number of favorable phenotypes is prognostic for gastric cancer patients treated with FP, and VEGF has a different impact on survival between treatment with 5-FUci and FP.

Oxaliplatin pharmacokinetics during a four-hour infusion.

A new platin compound, oxaliplatin, has significant activity in advanced colorectal carcinomas. However, its pharmacokinetics have not been characterized adequately yet. This study extensively analyzes the pharmacokinetics of both ultrafiltrable (free) and protein-bound platin in 13 patients receiving 130 mg/m2 oxaliplatin as a 4-h infusion in combination with 375 mg/m2 5-fluorouracil as a 24-h infusion for advanced colorectal carcinomas. The interpatient variability was very low for all parameters analyzed. The levels of free platin decreased triphasically, with a mean terminal half-life of 27.3+/-10.6 h. The area under the time-concentration curve was 20.17+/-6.97 microg.h/ml and the total and renal clearances amounted to 222+/-65 and 121+/-56 ml/min, respectively. The values for the volume of distribution and for the maximum concentration at the end of infusion were 349+/-132 liters and 1612+/-553 ng/ml, respectively. On the basis of the simulation of the plasma levels and the urinary excretion of platin following the long-term administration of oxaliplatin as a constant-rate and a chronomodulated infusion, additional analyses are warranted to fully characterize the pharmacokinetics of the drug in these settings.

Cisplatin-induced nephrotoxicity and the protective effect of fosfomycin on it as demonstrated by using a crossover study of urinary metabolite levels.

BACKGROUND: Cisplatin induces nephrotoxicity and this study evaluated the protective effect of fosfomycin on it in 11 gynecological cancer patients. METHODS: The N-acetyl-beta-D-glucosaminidase (NAG), beta 2-microglobulin (beta 2MG), creatinine (uCr) and total protein (TP) levels in a 24-hour urine specimen as well as the blood urea nitrogen (BUN) and serum creatinine (sCr) were measured before and after CAPF chemotherapy alone (control) or with fosfomycin. RESULTS: The results were statistically analyzed by using the t-test. NAG, beta 2MG, uCr and TP levels increased significantly after chemotherapy in the control patients, but BUN and sCr levels did not change significantly. The NAG level in the control group was twice as high as in the fosfomycin group 8 days after chemotherapy (p < 0.01). The uCr and TP in control patients increased significantly after chemotherapy when compared to those in patients coad-ministered fosfomycin. There were no significant changes in beta 2MG, BUN and sCr levels. CONCLUSIONS: Cisplatin affected the levels of NAG, beta 2MG, uCr and TP without influencing BUN and sCr levels. Fosfomycin, therefore, may be useful as a supplemental treatment for reducing cisplatin nephrotoxicity, especially proximal tubular damage.

Determination of S-1 (combined drug of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate) and 5-fluorouracil in human plasma and urine using high-performance liquid chromatography and gas chromatography-negative ion chemical ionization mass spectrometry.

A high-performance liquid chromatography (HPLC) and gas chromatography-negative ion chemical ionization mass spectrometry (GC-NICI-MS) method was developed for the analysis of the combined antitumor drug S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate) and active metabolite 5-fluorouracil in human plasma and urine. Tegafur was fractionated from biological fluids by extraction with dichloromethane and analyzed by HPLC. 5-Fluorouracil and 5-chloro-2,4-dihydroxypyridine were extracted with ethyl acetate from the residual layer after extraction of tegafur, and converted to pentafluorobenzyl (PFB) derivatives. Potassium oxonate was cleaned up with an anion-exchange column (Bond Elut NH2). The extracted potassium oxonate was degraded to 5-azauracil and converted to PFB derivatives. The PFB derivatives were analyzed by GC-NICI-MS. A stable isotope was employed as the internal standard in the GC-NICI-MS analysis. The limits of quantitation of tegafur, 5-fluorouracil, 5-chloro-2,4-dihydroxypyridine and potassium oxonate in plasma were 10, 1, 2 and 1 ng/ml, respectively. The reproducibility of the analytical method according to the statistical coefficients is approximately 10%. The accuracy of the method is good; that is, the relative error is < 10%. The methods were applied to pharmacokinetic studies of S-1 in patients.

Detection of genotoxic substances in cancer patients receiving antineoplastic drugs.

A short-term bacterial mutation test, the SOS Chromotest, has been used to detect the excretion in urine of genotoxic metabolites of antineoplastic drugs administered to cancer patients. In this test, the damage to the DNA of the test bacteria is expressed by the production of beta-galactosidase, which can be quantitatively assessed and is proportional to the concentration of the drug. Kinetic curves of excretion for adriamycin, bleomycin, dacarbazine, cis-platinum and vincristine and their mixtures have been constructed from standard curves relating the intensity of the beta-galactosidase response to the concentration of drugs dissolved in normal urine. Comparative data on extraction and concentration of the drugs from urine or serum by means of selective resin or silica columns are presented.