Chromosome Aberrations and pharmacokinetics in patients receiving tauromustine as either a single or a repeated dose

Tauromustine (TCNU) is an exploratory drug that has demonstrated activity in various solid tumors. We examined chromosome aberrations and plasma levels of the drug in two groups of patients receiving either a single dose of 130?mg/m² or 40?mg/m² on 3 consecutive days. Peak plasma concentrations (mean ±SD) were obtained at a similar time after both treatments, i.e., at 38±25, 32±24, 28±14, and 40±26 min after administration of 130?mg/m² on day 1 and after that of 40?mg/m² on days 1, 2, and 3, respectively. In addition, the cumulative area under the curve (AUC value) determined after administration of 40?mg/m²×3 was similar to that noted after treatment with a single dose of 130?mg/m², i.e., 180 and 179?μg min ml^-1, respectively. Both treatments induced chromosome aberrations (CAs) in peripheral blood lymphocytes. A dose-dependent increase in the number of CAs was found, with 40?mg/m² producing 5.5% CAs and 130?mg/m² yielding 20.9% CAs at 24?h after treatment. In addition, although the drug concentration declined to a level under the detection limit between the daily treatments, drug-induced chromosome damage was cumulative, with the 90-min values increasing from 4.8% on day 1 to 14.3% CAs on day 3. In individual patients, no correlation was found between CAs and kinetic parameters; however, the total mean CA yield was in agreement with the total drug exposure (CAs, 14.3% and 14.6%, AUC 180±62.8 and 179±115?μg min ml^-1, respectively).     

Analysis of complications in patients treated with abdomino-pelvic radiation therapy for ovarian carcinoma.

Between 1971 and 1985, 598 patients with ovarian carcinoma were treated with abdomino-pelvic radiation therapy. Acute complications included nausea and vomiting in 364 patients (61%) which were severe in 36, and diarrhea in 407 patients (68%), severe in 35. Leukopenia (less than 2.0 x 10(9) cells/liter) and thrombocytopenia (less than 100 x 10(9) cells/liter) occurred in 64 patients (11%) each. Treatment interruptions occurred in 136 patients (23%), and 62 patients (10%) did not complete treatment. In both situations the most common cause was myelosuppression. Late complications included chronic diarrhea in 85 patients (14%), transient hepatic enzyme elevation in 224 (44%), and symptomatic basal pneumonitis in 23 (4%). Serious late bowel complications were infrequent: 25 patients (4.2%) developed bowel obstruction and 16 required operation. Multivariate analysis was unable to determine any significant prognostic factors for bowel obstruction; however, the moving-strip technique of radiation therapy was associated with a significantly greater risk of developing chronic diarrhea, pneumonitis, and hepatic enzyme elevation than was the open beam technique. We conclude that abdomino-pelvic radiation therapy as used in these patients is associated with modest acute complications and a low risk of serious late toxicity.     

鼻咽癌螺旋断层放射治疗过程中实际受照射剂量的研究

  目的  通过螺旋断层放射治疗（tomotherapy）系统的自适应模块,分析鼻咽癌患者靶区和危及器官的剂量在治疗过程中与初始计划的差异,为临床提供帮助。  方法  回顾性分析2014年2月至2015年2月昆明医科大学第一附属医院运用tomotherapy系统治疗的10例鼻咽癌患者,通过tomotherapy系统中的自适应模块和Mimvista 6.50软件的计算,将初始计划定义为Plan 1;进行图像引导患者总的实际受照射剂量定义为Plan 2。比较两项计划中肿瘤靶区及危及器官的剂量学差异。  结果  Plan 2中计划靶区体积（planning gross target volume,PGTV）的D98、D95的剂量较Plan 1分别下降11.91%、6.88%（P=0.001,P=0.006）。Plan 2中左侧腮腺的Dmean、D50较Plan 1分别增加42.23%、63.82%（P＜0.001、P=0.001）;Plan 2中右侧腮腺的Dmean、D50较Plan 1分别增加38.64%、66.76%（P=0.002,P=0.004）。Plan 2中脊髓的D2剂量较Plan 1也明显增加,增加了16.49%（P=0.026）。  结论  鼻咽癌患者在行tomotherapy过程中,非常有必要进一步纠正因解剖结构和摆位所带来的误差,保证放疗计划的精准性。      

Therapeutic efficacy and pharmacokinetics of vindesine and vindesine-cisplatin in previously treated patients with non-small cell lung carcinoma

Twenty-nine patients with non-small cell lung cancer refractory to prior therapy were treated with either vindesine (VDS) alone (3 mg/m2 every week) or the combination of VDS plus cisplatin (DDP) (100 mg/m2 every 28 days). Serial blood and urine samples were collected to assess the pharmacokinetics of VDS and DDP. All patients were evaluable for toxicity and 27 were evaluable for response. No objective antitumor responses were observed. Peripheral neuropathy manifested by paresthesias, muscle weakness, and constipation were observed in 20 treated patients, and hematologic toxicity consisting of thrombocytopenia and/or leukopenia occurred in 18 patients. The plasma and urinary pharmacokinetics of VDS and DDP measured in this study indicate that VDS and DDP do not interfere with each other and that the pharmacokinetics in previously treated and untreated patients are similar. The antitumor responses and degree of toxicity observed in this trial compare unfavorably with previously reported VDS and VDS-DDP trials in previously untreated patients with this disease and suggest that prior exposure to chemotherapy might both decrease antitumor activity and enhance toxicity of these chemotherapeutic agents.     

Conservative therapy for endometrial carcinoma in young women treated with repeated curettage and progestogen

Three women less than 35 years old, who wanted to preserve their fertility, were conservatively treated with repeated endometrial curettage and medroxyprogesterone acetate (600mg/d) for endometrial carcinoma. Treatments were given once a month for 6 to 8 months. No patient had evidence of recurrence for at least 16 months after the treatment, and 1 patient subsequently delivered 2 full-term babies. This conservative treatment by endometrial curettage with progestogens may be considered for young patients with early endometrial lesions who wish to preserve their fertility.     

国产紫杉醇治疗上皮性卵巢癌周疗方案与月疗方案的比较

目的比较紫杉醇每周一次给药和每月一次给药两种方法治疗上皮性卵巢癌的疗效和副反应,探讨不同给药方式的优缺点,力图寻找卵巢癌治疗的最佳方案.方法将57例上皮性卵巢癌患者分为2组,周疗组(WG)紫杉醇60～80 mg/m2,iv(2h),d1,8,15;月疗组(MG)紫杉醇135 mg/m2,iv(3 h),d1;两组均与卡铂联用,3～4周为一疗程,所有病例至少使用3疗程.结果周疗组中位生存期为64个月,月疗组为67个月.周疗组晚期患者3,4年生存率分别为80.0%和58.3%;月疗组3,4,5年生存率分别为68.7%、39.3%和26.1%.周疗组胃肠道反应、白细胞减少、面色潮红等毒副反应发生率较月疗组少.结论使用每疗程分次给紫杉醇治疗上皮性卵巢癌的周疗法较传统月疗法在提高疗效和减少毒副反应方面有一定优势.     

Long-term survival of patients with advanced ovarian carcinoma treated with cisplatin-based chemotherapy regimens

Long-term results of different studies employing cisplatin-based chemotherapy in advanced ovara in cancer are just beginning to be published. Available data suggest that the rate of relapse decreases but does not cease, and the question of whether cisplatin-based chemotherapy results in an improved cure in advanced ovarian cancer is still unanswered. The long-term survival results published so far are reviewed. Furthermore the impact of other drugs, especially doxorubicin, in addition to cisplatin is discussed.     

Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma

Background: Platinum compounds are the most active drugs in ovarian cancer treatment; cisplatin and carboplatin demonstrated similar efficacies but different toxicity profiles. Paclitaxel combined with cisplatin as first-line treatment improved overall survival when compared to a cisplatin-cyclophosphamide combination, but generated higher rates of neutropenia, febrile neutropenia and neurotoxicity. The paclitaxel-carboplatin combination may be better tolerated than cisplatin–paclitaxel.Design: The objective of the present study was to assess the efficacy and safety of the combination of paclitaxel and carboplatin in previously treated advanced ovarian cancer patients.Patients and methods: During or after platinum-based chemotherapy, 73 patients with progressive advanced epithelial ovarian carcinoma were enrolled to receive every four weeks a three-hour infusion of paclitaxel 175 mg/m² followed by a 30-minute carboplatin infusion. The carboplatin dose was calculated to obtain the recommended area concentration-versus-time under the curve of 5 mg·ml^-1·min.Results: Toxicity and response could be evaluated for 72 and 62 patients, respectively. Eleven complete and 15 partial responses gave an overall response rate of 42% (95% CI: 30%–54%). Response rates for platinum-refractory patients and those with early (3 and <12 months) and late (>12 months) relapses were 24%, 33% and 70%, respectively. The respective median response duration, the median progression-free survival and median overall survival were 8, 6 and 14 months. Myelosuppression was the most frequent and severe toxicity. Grade 3 and 4 neutropenia occurred, respectively in 30% and 23% of the cycles; 6% of the cycles benefited from medullary growth factors. Only one episode of febrile neutropenia was observed. Grade 3 and 4 thrombocytopenia occurred, respectively during 3% and 1% of the cycles. Alopecia was frequent. Transient peripheral neuropathy developed in 47% of patients but was severe in only one patient. One early death was attributed to progressive disease and possibly to therapy.Conclusion: This combined paclitaxel–carboplatin therapy is effective and can be safely administered to ovarian cancer patients who relapse after one or two regimens of platinum-based chemotherapy.     

Comparison of conventional dose and double dose carboplatin in patients receiving cyclophosphamide plus carboplatin for advanced ovarian carcinoma: a North Central Cancer Treatment Group Study

Between March 1992 and November 1994, 91 patients with stage III and IV ovarian carcinoma were enrolled in a randomized comparative study of cyclophosphamide 600 mg/m² plus carboplatin 300 mg/m² vs. cyclophosphamide 600 mg/m² plus carboplatin 600 mg/m², each regimen given monthly for six cycles. Patients on the intensive regimen also received 10 μg/kg of granulocyte macrophage colony stimulating factor (GM-CSF) (molgramostim) daily for 14 days following each chemo-therapy treatment. The study was closed prematurely because of very poor case accrual following the preliminary announcement (in May 1993) that paclitaxel appeared superior to cyclophosphamide in the platinum-based treatment of ovarian cancer. More than 4 years after our last case entry, we analyzed the survival results for the 44 eligible patients who received the conventional dose of carboplatin and the 43 eligible patients receiving our intensified dose of carboplatin. More than 90% of the treated patients receiving the conventional dose regimen received at least 75% of the planned doses at each of the six treatment intervals, whereas the percentage of treated patients able to receive at least 75% of the assigned intensive dose regimen had declined from 95% in cycle 2 to 53% by cycle 6. Furthermore, although 32 patients received all six planned cycles of treatment in the conventional regimen group, only 15 received all six cycles of the intensified regimen. Patients receiving the intensive regimen had more fever, dermatitis, lethargy, musculoskeletal pain, and pulmonary complications than did the conventional dose patients. Median survival times for the two treatment groups were very similar (38.5 and 38.1 months, respectively, for the conventional and intensive regimens), and we saw no evidence that the distribution of survival times differed between the treatment regimens (p = 0.95).     

Population pharmacokinetics and pharmacogenetics of vincristine in paediatric patients treated for solid tumour diseases

Purpose  

The interindividual variability of vincristine pharmacokinetics is quite large, but the origins of this variability are not properly understood. The aim of this study was to develop a population pharmacokinetic model of vincristine in a paediatric population treated for solid tumour disease and evaluate the impact of different ABCB1, CYP3A4 and CYP3A5 polymorphisms on the different pharmacokinetic parameters.     

Radiation dose and leukemia risk in patients treated for cancer of the cervix

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.     

High dose chemotherapy with autologous stem cell support in the treatment of patients with ovarian carcinoma: long term results for 105 patients

BACKGROUND: In this study, the authors reviewed long term results and prognostic factors of high dose chemotherapy (HDC) with autologous stem cell support administered to 105 patients with epithelial ovarian carcinoma. METHODS: Prior to HDC, platinum-based chemotherapy was given to optimize (n = 94) and/or to mobilize peripheral blood stem cells (n = 33). After maximum debulking surgery, HDC with stem cell support was given; it consisted of cyclophosphamide, doxoribicin, and cisplatin (Regimen A, administered to 58 patients) or cyclophosphamide and carboplatin (Regimen B, administered to 47 patients). RESULTS: Five-year overall and disease free survival (OS, DFS) rates (%) according to stage were IC: 92.3, 92.3; II: 73.3, 73.3; III: 58.1, 35.7; IV: 33.7, 22.6; relapsed: 37.5, 31.0; OS, DFS at 8 years were IC: 92.3, 92.3; II: 73.3, 73.3; III: 48.8, 31.7; IV: 33.7, 22.6; relapsed: 37.5, 31.0. There was no difference in survival between patients who received Regimens A and B despite an increase in the total dose of platinum and an increase of more than 1.5- to 3.5-fold in the platinum course of HDC in Regimen B from the equivalence ratio of 4:1 between carboplatin and cisplatin. Among 65 Stage III and IV patients, the best results were obtained for 35 patients with small volume disease: 5-year OS, DFS rates were 74.3, 51.6, and 8-year OS, DFS rates were 66.4, 46.3. CONCLUSIONS: Good long term results were obtained with HDC. Small volume residual disease, platinum sensitivity, and histology excluding mucinous and clear cell adenocarcinoma were important factors for better survival. However, because the results were obtained for selected patients, a prospective, randomized study comparing HDC and standard chemotherapy is necessary if any definitive conclusions are to be drawn.     

50例鼻咽癌调强放疗中内耳受量评价

目的：分析鼻咽癌调强放疗对双侧内耳受量的影响。方法：选择2015年5月至12月就诊于成都军区总医院50例经病理确诊为鼻咽癌的患者,所有患者均接受30次调强放疗。再由一名主治医师在原始的CT图像上勾画出双侧的耳蜗、前庭及内耳道,并在计划的优化过程中对上述结构进行条件一致的剂量限定,最后通过DVH图对上述结构进行剂量分析,包括最大剂量点（Dmax ）、最小剂量点（Dmin ）及平均剂量（Dmean ）。结果：左侧耳蜗的最大剂量点、最小剂量点及平均剂量的均值分别为5366．3cGy、3981．2cGy、4550．1cGy;左侧前庭分别为4323．2cGy、3310．8cGy、3821．1cGy;左侧内耳道分别为5290．8cGy、3828．7cGy、4453．6cGy;右侧耳蜗的最大剂量点、最小剂量点及平均剂量的均值分别为5344．5cGy、3954．2cGy、4550．1cGy;右侧前庭分别为4368．3cGy、3262．9cGy、3796．0cGy;右侧内耳道分别为5165．0cGy、3765．2cGy、4375．2cGy。结论：在鼻咽癌的调强放疗计划设计过程中对内耳结构进行剂量限定,能在不减少靶区受量的同时有效的降低内耳结构的受照射剂量。     

Long-term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy

Ninety ovarian carcinoma patients failing primary intravenous (IV) combination chemotherapy were treated with cisplatin-based combination intraperitoneal therapy. Sixty-five patients had residual disease greater than 2 cm at the start of intraperitoneal therapy. Their median survival was 8 months. Twenty-five patients had disease less than 2 cm; their median survival was greater than 49 months, and the survival curve has an apparent plateau at 69%, with no relapses having occurred after 32 months. The median survival for all 90 patients was 15 months. The median duration of follow-up for all patients was 37 months. These results confirm the critical role of tumor bulk in determining the effectiveness of intraperitoneal therapy, and suggest a role for intraperitoneal salvage treatment in patients with small-volume disease.     

Ten-year outcome of patients with advanced epithelial ovarian carcinoma treated with cisplatin-based multimodality therapy.

PURPOSE: At the end of the 1970s it was thought that advanced epithelial ovarian cancer (EOC) could be cured by multimodality treatment using surgery, cisplatin-based combination chemotherapy, and radiotherapy (RT). Such multimodality treatment was used as standard therapy at our institution. Our long-term results are reviewed. PATIENTS AND METHODS: One hundred ninety-five previously untreated patients with stage III or IV EOC were treated between April 1979 and December 1982. All patients were to have debulking surgery, when feasible, followed by the administration of doxorubicin and cisplatin at 50 mg/m2 every 3 weeks until a total dose of doxorubicin of 450 mg/m2 had been reached. RT was used in addition in patients with disease remaining after the chemotherapy. Maintenance chemotherapy with oral cyclophosphamide and hexamethylmelamine (altretamine) was administered to patients who did not have a documented histologic complete remission. RESULTS: The 10-year overall and failure-free survivals were 4% and 8%, respectively. The median overall survival was 2 years. The achievement of a histologic complete response (n = 32) did not equate to cure because 20 (63%) of the patients eventually relapsed. Multivariate analysis identified residual disease of greater or less than 2 cm as the only independent prognostic factor. CONCLUSIONS: Our multimodality treatment program was noncurative for the majority of the patients. Innovative therapies are needed before we can hope to cure such disease.