Phase I/II study of a combined gemcitabine, etoposide, and cisplatin chemotherapy regimen for metastatic urothelial carcinoma

BACKGROUND: The authors attempted to determine the maximum tolerated dose (MTD) of gemcitabine in combination with etoposide and cisplatin as a chemotherapy regimen and investigated the safety and antitumor activity with the recommended doses of gemcitabine with etoposide and cisplatin for patients with metastatic urothelial carcinoma. METHODS: Patients age 75 years or younger with measurable lesions, creatinine clearance>or=50 mL per minute, and adequate bone marrow and hepatic function were studied. Etoposide and cisplatin were given on Days 1 through 3 at fixed doses of 75 mg/m2 and 25 mg/m2, respectively, and gemcitabine was given on Days 1, 8, and 15. In the Phase I component, gemcitabine was administered at increasing doses from 600 mg/m2. Cycles were repeated every 28 days unless progressive disease was encountered. RESULTS: In Phase I, with the initially fixed doses of etoposide and cisplatin, the MTD of gemcitabine could not be determined because of the occurrence of dose-limiting toxicity at Level 1 in all 3 patients. When the doses of etoposide and cisplatin were modified to 60 mg/m2 and 20 mg/m2, respectively, the MTD of gemcitabine was 1000 mg/m2. Next, 19 additional patients were entered into Phase II with the recommended gemcitabine dose of 800 mg/m2, and 20 patients in all were treated at this dose level. The main toxicity was bone marrow suppression, with Grade 3 or 4 neutropenia and thrombocytopenia recognized in 20 patients (100%) and 14 patients (70%), respectively, although no toxic deaths occurred. In total, all 31 patients at all dose levels had an assessable response, with 6 complete responses and 15 partial responses observed, for an overall response rate of 67.7%. Patients who had visceral metastasis had a significantly worse response rate than patients who had lymph node metastasis alone (50.0% vs. 78.9%; P=.042). The response rate (66.7%) for 21 patients who received prior chemotherapy was not different from that for 10 chemotherapy-naive patients. The median survival for all patients was 13.1 months, and 4 patients survived for >2 years with no evidence of disease. Patients younger than age 65 years had significantly better survival than patients age 65 years or older (P=.026). CONCLUSIONS: Although bone marrow toxicity was considerable, combination chemotherapy with gemcitabine, etoposide, and cisplatin appeared to be very active in patients with urothelial carcinoma and may be especially promising for younger patients, although further study is warranted.     

Renal function after ifosfamide, carboplatin and etoposide (ICE) chemotherapy, nephrectomy and radiotherapy in children with Wilms tumour

We prospectively evaluated tumour response and renal function in 12 newly diagnosed children with high-risk Wilms tumour receiving ifosfamide, carboplatin and etoposide (ICE) chemotherapy. Two cycles of ICE were followed by 5 weeks of vincristine, dactinomycin and doxorubicin (Adriamycin) (VDA), and nephrectomy, radiotherapy, additional VDA, and a third ICE cycle. Carboplatin dosage was based on glomerular filtration rate (GFR) to achieve targeted systemic exposure (6mg/ml min). Mean GFR (measured by technetium 99m-DTPA clearance) declined by 7% after 2 cycles of ICE and by 38% after nephrectomy; the mean carboplatin dose was reduced 32% after nephrectomy. Mean GFR remained stable after the third ICE cycle. Although urinary beta(2)-microglobulin excretion increased during therapy, no patient had clinically significant renal tubular dysfunction at the end of treatment. Treatment with ICE, nephrectomy and radiotherapy significantly reduces GFR, largely as the result of nephrectomy. Adjustment of carboplatin dosage on the basis of GFR and careful monitoring of renal function may alleviate nephrotoxicity.     

Phase I study of high-dose cisplatin,ifosfamide, and etoposide

To test the feasibility of a regimen of high-dose cisplatin, ifosfamide, and etoposide (VP-16; VIPP regimen), we registered 15 patients with advanced non-small-cell lung cancer in a phase I trial of the Northern California Oncology Group. One cycle of treatment consisted of high-dose cisplatin given at 100 mg/m² i.v. on days 1 and 8, VP-16 given at 60–75 mg/m² i.v. on days 1–3, plus ifosfamide given at 1.0–1.2 g/m² i.v. on days 1–3; cycles were repeated every 28 days. There were 13 men and 2 women; the median age was 59 years (range, 47–72 years). The median Karnofsky performance status (KPS) was 90 (range, 70–100). All patients were assessable for toxicity and response. The median number of cycles delivered per patient was two (range, one to four). Hematologic toxicity was dose-limiting and required de-escalation of the ifosfamide and VP-16 doses. Ten patients developed a white blood count of <1000/mm³ and seven patients developed a platelet count of <50,000/mm³. The duration of cytopenia increased progressively with each subsequent cycle of therapy. Two patients required antibiotics for neutropenic fever with documented infections (pneumonia, bacteremia). Seven patients received red blood cell transfusions for a hemoglobin level of <8 gm/dl. Grade III or IV non-hematologic toxicities were uncommon and involved one patient each with grade 3 ototoxicity and grade 3 neurotoxicity. Five patients developed laboratory evidence of renal salt wasting. The overall response rate was 33% (5/15) with a complete response being achieved by two patients (13%) and a partial response being attained by three (20%). The overall median survival was 44 weeks. We conclude that although this regimen demonstrated activity, hematologic toxicity limited its use in the palliative treatment of non-small-cell lung cancer. Using hemopoietic growth-factor support to permit dose escalation, this schedule of VIPP may be of interest in a number of different chemotherapy-sensitive tumor types.     

紫杉醇、卡铂方案与异环磷酰胺、鬼臼乙叉甙、卡铂方案治疗晚期非小细胞肺癌的比较

背景及目的:以铂类为基础的联合化疗已证实对晚期非小细胞肺癌(non-smallcelllungcancer,NSCLC)患者有益。含卡铂的联合化疗方案与含顺铂者相比,前者虽然有效率稍低,但生存期较长、毒性较低。对于姑息治疗而言,较低的毒性及较长的生存期比有效率更有意义,因此我们选择了以卡铂为基础的联合化疗方案犤紫杉醇、卡铂(PC)与异环磷酰胺、鬼臼乙叉甙、卡铂(IEC)犦治疗晚期NSCLC,并比较这两种方案的疗效和毒性。方法:68例晚期NSCLC患者分别接受PC与IEC化疗,PC方案35例,IEC方案33例。两组病人特征具有可比性(P>0.05)。结果:PC组PR14例,NC19例,PD2例,有效率为40.0%(14/35,95%可信区间犤CI犦:23.8%-56.2%),中位生存期9.1个月(95%CI:7.2-11.0个月),1年生存率为25.7%(95%CI:11.2%-40.2%);IEC组PR7例,NC24例,PD2例,有效率为21.2%(7/33,95%CI:7.3%-35.1%),中位生存期7.8个月(95%CI:6.2-9.4个月),1年生存率为20.0%(95%CI:6.0%-34.0%)。PC组的有效率、中位生存期及1年生存率均优于IEC组,但均无统计学差异(有效率:P=0.094,χ2检验;生存期P=0.684,Log-rank检验)。PC组血液学毒性较IEC组低,其中两组白细胞减少(P<0.0005,秩和检验)及血红蛋白减少(P=0.006,秩和检验)差异有统计学意义;血尿及药物热IEC组较高,过敏反应则PC组较     

Dose-intensive chemotherapy in refractory germ cell cancer--a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation

Between September 1986 and March 1988, 33 patients with refractory germ cell cancer were entered on a phase I/II trial of two courses of high-dose carboplatin plus etoposide with autologous bone marrow support. All patients had extensive prior treatment and had either cisplatin-refractory disease (67%) defined as progression within 4 weeks of the last cisplatin dose or failed at least two cisplatin-based regimens (35%) including a cisplatin-ifosfamide salvage regimen. Patients received a fixed total dose of etoposide of 1,200 mg/m2 with each cycle. The carboplatin dose ranged from 900 mg/m2 to 2,000 mg/m2. Twenty of the 33 patients received the second cycle of therapy. Despite extensive prior therapy with cisplatin, neurotoxicity, nephrotoxicity, or hearing impairment with high-dose carboplatin and etoposide was unusual. The most common nonhematologic toxicity was moderate enterocolitis. The hematologic toxicity of this regimen was substantial at each dose level. All 53 courses were accompanied by granulocytopenic fevers. Seven of the 33 patients (21%) died from treatment. All of these deaths occurred during the granulocyte nadir, and five were related to documented sepsis. Overall, 14 of 32 patients (44%) evaluable for response obtained an objective response, including eight complete remissions. Four patients remain in complete remission, with three patients being continuously free of disease in excess of 1 year. Eight responders (including four complete remissions) had progressed while receiving cisplatin. We conclude that carboplatin and etoposide can be administered in combination at high dosages and this regimen may have curative potential for patients with germ cell tumors resistant to conventional-dose cisplatin-based therapies.     

Outpatient regimen rituximab plus ifosfamide, carboplatin and etoposide (R-ICE) for relapsed non-Hodgkin's lymphoma

View this table: [in this window] [in a new window]   Table 1.     

Phase II trial of combination chemotherapy with cisplatin, carboplatin and etoposide in stage IIIB and IV small-cell lung cancer

Purpose: A phase II trial combining cisplatin, carboplatin and etoposide was conducted in previously untreated patients with stage IIIB and IV small-cell lung cancer, in an attempt to increase response rates and prolong survival. Methods: Previously untreated patients with small-cell lung cancer, with measurable disease, aged ≤ 72 years, performance status ≤ 2, and adequate hematologic, hepatic and renal function were enrolled in the study. They were treated with 80 mg/m² cisplatin on day 1, 100 mg/m² carboplatin on days 2, 3 and 8, and 50 mg/m² etoposide on days 1, 2, 3 and 8. Results: A total of 46 patients (20 with stage IIIB and 26 with stage IV disease) were enrolled in the study. A total of 186 courses of chemotherapy were given, and the dose was reduced in 27 courses (15%). The chemotherapy was repeated for four or more courses in 30 patients. There were 10 complete responses and 32 partial responses, for a total response rate of 91% (95% confidence interval, 79% to 98%). The median survival time and 2-year survival rates were 18 months and 22% for stage IIIB disease, and 14 months and 15% for stage IV disease. Major side effects were hematologic: leukopenia, anemia, and thrombocytopenia of grade 3 or more occurred in 48%, 46%, and 43% of patients, respectively. Conclusions: The three-drug regimen of cisplatin, carboplatin and etoposide is feasible and active against small-cell lung cancer. Received: 21 May 1997 / Accepted: 11 September 1997     

Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.

PURPOSE: High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS: Forty-one patients with drug-resistant Hodgkin's and non-Hodgkin's lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS: Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkin's and non-Hodgkin's lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION: High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.     

Neoadjuvant chemotherapy with carboplatin, ifosfamide, and peplomycin in advanced cervical squamous cell carcinoma

Background. To control advanced cervical squamous cell carcinoma more effectively and more easily, we used neoadjuvant chemotherapy, with three drugs carboplatin, ifosfamide, and peplomycin (PIP), in a study performed from July 1990 to October 1994 in nine Institutions. Methods. Sixty-five patients with untreated, inoperable squamous cell carcinoma of the cervix were treated with carboplatin (300 mg/m² IV; low-dose PIP regimen, or 400 mg/m² IV; high-dose PIP regimen) on day 1, ifosfamide (1000 mg/m², IV) on days 1–3, and peplomycin (5 mg/body, IM) on days 1–6. The low-dose PIP was given between July 1990 and April 1992, and the high-dose PIP from May 1992 to October 1994. Results. Response rates for the low- and high-dose PIP regimens were 42.9% (12/28) and 59.5% (22/37), respectively. Measurable lesions were recognized in the cervix, pelvic lymph node (PeN), paraaortic lymph node (PAN), lung, and supraclavicular lymph node. Response rates in these individual lesions to our low- and high-dose PIP regimens were 35.7% (10/28) and 55.6% (20/36), respectively in the cervical lesion and more than 50% for both regimens in the PeN and PAN metastatic lesions, while the supraclavicular lymph node metastatic lesions responded poorly to both regimens. After low-dose PIP, surgery was performed in 2 patients (2/28; 7.1%), while after high-dose PIP, 12 patients (12/37; 32.4%) underwent surgery. The 3-year survival rate of patients with high-dose PIP was significantly higher than that of those with low-dose PIP (P < 0.01). Conclusions. Neoadjuvant chemotherapy with PIP appears feasible and effective. The link between dosage and treatment response and achievable surgery rate and survival rates suggests that results might be further optimized by considering patients' renal function, and utilizing the Calvert formula for dosing analysis. Received: January 21, 1999 / Accepted: July 28, 1999     

Phase II trial of paclitaxel,estramustine, etoposide,and carboplatin in the treatment of patients with hormone-refractory prostate carcinoma

BACKGROUND: Preclinical data suggest that the combination of intravenous (i.v.) paclitaxel, carboplatin, oral etoposide, and oral estramustine (TEEC) has significant activity in patients with advanced, hormone-refractory prostate carcinoma. The authors conducted this clinical trial to evaluate the addition of carboplatin to the three-drug combination of paclitaxel, estramustine, and etoposide (TEE). METHODS: Twenty patients with carcinoma of the prostate that was progressing despite hormone therapy were enrolled on this Phase II trial. Patients were treated with oral estramustine, 280 mg three times daily, and oral etoposide, 50 mg/m2, once daily on Days 1-7, with i.v. paclitaxel, 135 mg/m2, over 1 hour followed by carboplatin (area under the curve, 5) on Day 2 of each 21-day treatment cycle. Patients were evaluated for response after three cycles, and three additional cycles were given to responding or stable patients. RESULTS: Nineteen patients were evaluable for response, and 12 patients had measurable disease at baseline. The measurable response rate was 58% (7 of 12 patients; 95% confidence interval [95% CI], 28-85%), and all of those were partial responses. Eleven patients had decreases >50% from their baseline prostate specific antigen levels during therapy, for a response rate of 58% (95% CI, 34-80%) by this criterion. The median time to disease progression was 5.5 months, with a median survival of 14.2 months. Major toxicities included Grade (according to version 2 of the National Cancer Institute Common Toxicity Criteria) 4 neutropenia in 4 patients, Grade 4 thrombocytopenia in 4 patients, and anemia > or = Grade 3 in 4 patients. One patient had a deep vein thrombosis. CONCLUSIONS: The combination of TEEC was active in patients with hormone-refractory prostate carcinoma. The regimen was tolerable, with primarily hematologic toxicity. The addition of carboplatin to TEE did not appear to add to the efficacy of the three-drug combination of antimicrotubule agents.     

长春新碱+依托泊苷+卡铂静脉化疗方案在视网膜母细胞瘤中的应用分析

目的探讨长春新碱+依托泊苷+卡铂(VEC方案)在视网膜母细胞瘤(RB)中的临床效果和安全性。方法依据治疗方式将80例RB患儿(每例患儿只取1只眼)分为眼动脉灌注化疗(IAC)组(n=43)和IAC+VEC组(n=37),IAC组患儿IAC治疗术前未进行化疗,IAC+VEC组患儿IAC术前进行6周的VEC治疗。治疗前后,比较两组患儿肿块最大径和肿块厚度,记录治疗期间并发症和药物不良反应;采用酶联免疫吸附测定(ELISA)检测两组患儿survivin、血管内皮生长因子(VEGF)、基质金属蛋白酶9(MMP9)水平。结果治疗前,两组患儿的肿块厚度、肿块最大径、VEGE、survivin、MMP9水平比比较,差异均无统计学意义(P﹥0.05)。治疗后,两组患儿肿块厚度和肿块最大径均小于本组治疗前,且VEC+IAC组患儿肿块厚度和肿块最大径均小于IAC组患儿,差异均有统计学意义(P﹤0.05);治疗后,两组患儿血清VEGE、survivin、MMP9水平均低于本组治疗前,且VEC+IAC组患儿血清VEGE、survivin、MMP9水平均低于IAC组患儿,差异均有统计学意义(P﹤0.05)。IAC组患儿眼球内陷和白内障发生率均高于VEC+IAC组患儿,差异均有统计学意义(P﹤0.05)。IAC组患儿不良反应总发生率为32.56%,与VEC+IAC组患儿的51.35%比较,差异无统计学意义(P﹥0.05)。结论VEC静脉化疗+IAC治疗RB患儿,能更有效地缩小肿块体积,抑制survivin、VEGF、MMP9表达,降低眼球内陷和白内障的发生率,且不增加化疗不良反应。     

Phase I and pharmacologic study of sequential topotecan, carboplatin, and etoposide

Inhibition of topoisomerase I by topotecan results in a compensatory increase in topoisomerase II levels associated with increased in vitro sensitivity of tumors to etoposide. Maximum synergy has been observed for the sequence of topotecan followed by etoposide. This is the pharmacologic rationale for the sequence of topotecan 0.4 mg/m(2) per day for 7 days continuous i.v. infusion, carboplatin i.v. on day 8, and etoposide 50 mg per day p.o. days 9 through 20. The carboplatin dosage was escalated from an AUC of 4 to 5 to 6 (Calvert formula). Up to six treatment cycles were administered at 28-day intervals. Eligible patients had metastatic non-small cell lung cancer (NSCLC) or extensive disease small lung cell lung cancer (SCLC), no prior chemotherapy, performance status 0-2, and adequate organ function. Follow-up was twice weekly in the first cycle for CBC and for topotecan and etoposide concentrations. Follow-up, thereafter, was weekly. Tumor response was assessed after two and six cycles and then as clinically indicated. At carboplatin AUCs of 4 and 5, no NCI grade 4 toxicity was observed in cycle 1 in cohorts of three patients each. At the AUC of 5, two patients experienced dose-limiting events after cycle 3, one grade 4 neutropenia lasting >3 days (no fever) and one failure to recover an absolute neutrophil count >1500/microl by day 35. This was, therefore, deemed the maximal tolerable dose. Number of treatment cycles per patient ranged between 1 and 6, and three patients completed six cycles. All patients were male, age 47-71, with NSCLC in one and SCLC in six. The patient with NSCLC had progressive disease after one cycle. One complete and three partial responses were observed in five patients with SCLC. Mean steady-state plasma concentrations during topotecan infusion ranged from 0.73 to 1.69 ng/ml, and mean etoposide concentrations ranged from 60 to 230 ng/ml. This sequence of topotecan, carboplatin, and etoposide appeared tolerable and active. Neutropenia was the dose-limiting toxicity.     

A case of thymic carcinoma responding to combination chemotherapy with nedaplatin, etoposide, and ifosfamide

We described a case of thymic carcinoma that responded remarkably to combined chemotherapy with etoposide (ETP), ifosfamide (IFO) and nedaplatin. A 68-year-old woman was admitted to our hospital because of hoarseness and dysphasia. Chest computed tomographic (CT) scans showed an anterior mediastinal tumor. Using CT-guided needle biopsy, the diagnosis was squamous cell type of thymic carcinoma. We gave her modified VIP therapy with ETP, IFO and nedaplatin. The tumor contraction response was evident after 3 courses of treatment. This case suggested that nedaplatin may be one of the promising agents for thymic carcinoma chemotherapy.     

A phase I clinical, pharmacologic, and biologic study of thrombopoietin and granulocyte colony-stimulating factor in children receiving ifosfamide, carboplatin, and etoposide chemotherapy for recurrent or refractory solid tumors: a Children's Oncology Group experience.

PURPOSE: Ifosfamide, carboplatin, and etoposide (ICE) are associated with grade III/IV dose-limiting thrombocytopenia. The Children's Oncology Group conducted a phase I dose escalation, pharmacokinetic, and biological study of recombinant human thrombopoietin (rhTPO) after ICE in children with recurrent/refractory solid tumors (CCG-09717) to assess the toxicity and maximum tolerated dose of rhTPO administered at 1.2, 2.4, or 3.6 microg/kg per dose. EXPERIMENTAL DESIGN: Children received ifosfamide 1,800 mg/m2 on days 0 to 4, carboplatin 400 mg/m2 on days 0 to 1, and etoposide 100 mg/m2 on days 0 to 4. rhTPO was administered i.v. on days +4, +6, +8, +10, and +12 at 1.2, 2.4, or 3.6 microg/kg per dose.RESULTS: rhTPO was well tolerated and maximum tolerated dose was not reached. Median time to platelet recovery > or =100,000/microL of rhTPO at 1.2, 2.4, and 3.6 microg/kg/d was 24 days (22-24 d), 25 days (23-29 d), and 22 days (16-37 d), respectively. Patients required a median of 2 days of platelet transfusions (0-7 days). Mean (+/- SD) rhTPO maximum serum concentrations were 63.3 +/- 9.7 and 89.3 +/- 15.7 ng/mL and terminal half-lives were 47 +/- 13 and 64 +/- 42 hours after 2.4 and 3.6 microg/kg/d, respectively. There was a significant increase in colony-forming unit megakaryocyte upon WBC count recovery. CONCLUSIONS: rhTPO was well tolerated. Time to hematologic recovery and median number of platelet transfusions seem to be improved compared with historical controls receiving ICE + granulocyte colony-stimulating factor (CCG-0894).     

Phase II study of carboplatin and etoposide as a first line regimen in patients with metastatic breast cancer

BACKGROUND: The data available on the role of carboplatin and etoposidein breast cancer, especially in patients with no or minimalprior therapy are limited. PATIENTS AND METHODS: We performed a phase II study with carboplatin and etoposideas first line treatment in 34 patients with metastatic breastcancer. The treatment regimens was carboplatin 300 mg/m² day1, and etoposide 100 mg/m² days 1, 3 and 5, every four weeks. RESULTS: Of 33 evaluable patients, 2 achieved complete responses (6%)lasting 4 and 5 months, 7 patients (21%) achieved partial responseswith a median duration of 6+ (range 5–8) months, 15 patientshad stable disease, and 9 progressed during treatment. The majortoxicity was myelosuppression. WHO grades 3 or 4 leukocytopeniaor thrombocytopenia were seen in 15 and 10 patients, respectively.One formally ineligible patient with an impaired renal functiondied 14 days after the start of treatment because of a septicaemiain the presence of a grade 4 leukocytopenia. Besides this patientno other patient presented with granulo-cytopenic fever. CONCLUSIONS: In view of the observed response rate of 27% (95% confidenceinterval ll%–43%) we think that carboplatin and etoposidegiven in this dose and schedule has probably no clear advantageover the more commonly used regimens. metastatic breast cancer, chemotherapy, carboplatin, etoposide     

A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas

BACKGROUND: We have previously reported that combination chemotherapy basedon the drugs cytarabine/platinum is effective in recurring lymphomas.In this phase II study, we prospectively studied a combinationregimen of mesna/ifosfamide, mitoxantrone and etoposide (MINE)in patients with recurring lymphoma who had already receivedcytarabine/ platinum but did not respond to the treatment. PATIENTS AND METHODS: 48 patients received MINE at the following doses: mesna 1.33g/m² IV daily x3, and 500 mg p.o. daily 4 hours after each IVdose; ifosfamide 1.33 g/m² IV daily, given concurrently withmesna, x3 d; mitoxantrone 8 mg/m² IV on day 1; and etoposide65 mg/m² IV daily x3. Treatment cycles were 21–28 daysapart, depending on patients' blood counts, with a maximum numberof 6 cycles in responding patients. The histologic grade ofthe lymphomas according to the Working Formulation was low in8 patients and intermediate in 40 patients. In the latter group,12 were transformed from low grade. RESULTS: Overall, 48% of the patients responded, with 21% having a completeresponse (CR), and 27% having a partial response (PR). The mediansurvival time was 9 months, and the median follow-up of survivorsis 51 months at this writing. Median time to treatment failurewas 12 months for patients with complete responses, and 5 monthsfor patients with partial responses. The most serious complicationwas myelosuppression, with 2 deaths resulting from neutropenicinfection. CONCLUSION: The MINE regimen induced responses in a moderate fraction ofpatients after their prior exposure to cytarabine/platinum salvagetherapy, indicating there is no absolute cross resistance betweenthese drug regimens. ifosfamide, salvage therapy, lymphoma     

Phase II trial of carboplatin and etoposide for patients with recurrent high-grade glioma

We present the results of a phase II trial of carboplatin and etoposide (CE) combination as first-line chemotherapy in patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) after surgery and radiotherapy. We assess the activity and the tolerability of this combination. 30 patients with GBM (25) and AA (5) were treated with VP-16 (etoposide) 120 mg m(-2) and CBCDA (carboplatin) 100 mg m(-2) for 3 days every 4 weeks. Moreover, we performed a retrospective analysis of topoisomerase IIalpha gene status using chromogenic in situ hybridisation. The median age was 54 years (21-73 years); Eastern Cooperative Oncology Group performance score was 0-1 in 25 patients and 2 in five patients. All patients had been previously treated with surgical resection (21 radical resections) followed by radiation therapy (40-60 Gy). We observed six (20%) complete responses, three (10%) partial responses and 12 (40%) stable diseases, with a response rate of 30%. The median time to progression was 4 months, while progression-free survival at 6 months was 33.3%. The median survival time was 10 months. Neutropenia occurred in 9 patients: four patients had grade 4, two patients grade 3 and three patients grade 2. In the conclusion of this clinical trial, the CE combination has shown activity in recurrent GBM and AA, with a good toxicity profile. Alterations in the copy number of topoisomerase IIalpha gene seem to be a rare event and in our series do not influence response to the CE combination.     

Treatment of refractory and relapsed non-Hodgkin's lymphoma with ifosfamide,methotrexate and etoposide

Summary The combination of ifosfamide, etoposide and methotrexate was evaluated in 22 patients with non-Hodgkin's lymphoma (NHL) whose disease had relapsed or was resistant to first-line adriamycin-containing treatment. Only 4 of the 22 patients underwent remissions, 3 of which were complete and 1, partial. Two of the complete remissions occurred in patients with high-grade histology who received IMVP-16 after first-line treatment had induced only a partial remission. Bone marrow suppression was the limiting toxicity of this regime, which may be of value in the salvage therapy of selected patients with NHL.     

Risk-adapted chemotherapy of germ cell tumors with carboplatin, etoposide and bleomycin for low-risk and cisplatin, etoposide and ifosfamide for high-risk patients. A single-center study

The prognosis of germ cell tumors treated with chemotherapy depends on the presence of nonseminomatous tumor, clinical parameters based on the tumor volume and site, as well as on the level of the tumor markers AFP, betaHCG and LDH. We report here on the results of a risk-adapted approach to the chemotherapy of germ cell tumors. Patients with low-risk tumors, defined as seminomatous disease and/or nonseminomatous disease with a tumor mass <10 cm, less than 20 lung metastases, no liver, bone, or CNS metastases, and levels of AFP <1,000 IU/ml and betaHCG <10,000 IU/l, were to receive 4 cycles of carboplatin 400 mg/m(2) i.v. day 1, etoposide 120 mg/m(2) i.v. days 1-3 and bleomycin 30 IU i.v. days 1, 8 and 15 during the first 3 cycles (CEB(90)). Patients with high-risk disease were to receive 4 cycles of ifosfamide 1,500 mg/m(2) continuous infusion on days 1-4 together with mesna 1,200 mg/m(2) days 1-5, cisplatin 20 mg/m(2) i.v. days 1-5 and etoposide 100 mg/m(2) i.v. days 1-5 (VIP). Of the 60 patients treated with this risk-adapted approach, 51 had low-risk and 9 had high-risk disease. Forty-five of 51 patiens treated with CEB(90) achieved complete remission (CR), 4 achieved partial remission with marker negativity. Four patients with CR relapsed between 4 to 8 months after the start of chemotherapy. Of the 6 patients failing CEB(90), 3 were treated successfully with surgery or further chemotherapy. With a median follow-up of 52 months, the estimated cause-specific 3-year survival is 93% (95% confidence interval, CI, 80-98%). Seven of 9 high-risk patients treated with VIP achieved a CR and 1 patient relapsed. All 3 patients failing VIP had successful salvage therapy. With a medium follow-up of 63 months all patients remain alive and free of disease. Forty-six patients receiving CEB(90) were retrospectively classified to be in the good prognosis group according to the international germ cell consensus classification. Their estimated 3-year survival was 95% (CI 81-99%). We thus confirm that CEB(90) is a well-tolerated outpatient regimen with good results in good prognosis germ cell tumors. Bleomycin at a cumulative dose of 270 U might contribute substantially to the inferior effect of carboplatin as compared to cisplatin. However, in view of the results of randomized studies favoring cisplatin over carboplatin, it is not recommended to use this regimen outside a clinical trial.