Translocation (11;14)(q13;q32) and overexpression of cyclin D1 protein in a CD23-positive low-grade B-cell neoplasm

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 x ml-1 x 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 (> or = 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.     

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer

PURPOSE: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.     

Effects of risperidone on polydipsia in chronic schizophrenia patients

A total of 34 patients with advanced ovarian cancer, who relapsed 1-72 months after at least one first-line cisplatin-based chemotherapy protocol, were treated with carboplatin, 350 mg/m2 q 4 weeks, with the adjunct of primary prophylactic granulocyte colony stimulating factor (G-CSF; filgrastim), 300 or 480 microg daily, days 5-9. Over 90% of the anticipated dose of carboplatin could be administered. Partial response, defined as a decline in CA-125 of 50% or more on two consecutive samples, occurred in 42%, while 15% of patients achieved a complete response (no clinical signs of disease with normalization of CA-125). Survival from start of carboplatin treatment was 23 months. Myelosuppression was the most important toxicity with 35% of patients experiencing grade 4 thrombocytopenia of short duration. Grade 4 leucopenia occurred in only one patient. It is concluded that single-agent carboplatin, with the adjunct of prophylactic G-CSF, can be administered with adequate dose intensity, and is an effective and acceptable palliative treatment for patients with relapse after first-line cisplatin-based chemotherapy.     

Effectiveness of paclitaxel and carboplatin combination in heavily pretreated patients with head and neck cancers

A phase II study was conducted to evaluate the activity of paclitaxel and carboplatin in advanced head and neck cancer. Twenty-four patients with measurable locoregional squamous cell carcinoma and metastatic disease were entered. All had been heavily pretreated with radiotherapy, surgery and chemotherapy and were at second recurrence or disease progression when they entered the trial. Patients received Paclitaxel 200 mg/m2 with carboplatin 7 AUC once every 3 weeks with premedication with dexamethasone and diphenyldramine and ranitidine. Twenty-three patients were evaluable for response. Four patients (17%) achieved a complete response and 5 (22%) a partial response for an overall response rate of 39%. Duration of response was 3-9 months. Toxicity was tolerable. Four patients showed Grade III (WHO) and 6 Grade II neutropenia. Nineteen (79%) of patients who received more than two courses of chemotherapy presented neurotoxicity. The combination of paclitaxel and carboplatin was effective in heavily pretreated patients with squamous cell carcinoma of the head and neck.     

Phosphatidyl serine-dependent antiprothrombin antibody is exclusive to patients with lupus anticoagulant

In attempt to develop a new chemotherapeutic regimen including carboplatin (CBDCA), epirubicin (EPI), and VP-16 in extensive small cell lung cancer, with a higher dose intensity compared with previous experience of our group, we determined the maximum tolerated dose (MTD) of VP-16 when administered in association with CBDCA (300 mg/ m2, i.v., day 1) and EPI (75 mg/m2, i.v., day 1), recycling chemotherapy every 3 weeks, with the support of granulocyte-colony-stimulating factor (G-CSF). A total of 15 patients received three dose levels of VP-16 (mg/m2, i.v., daily on days 1-3): 100 (three patients), 120 (six), and 140 (six). G-CSF was administered subcutaneously at the dose of 5 micrograms/kg/day on days 6-15 of each chemotherapy course. The MTD was established at 140 mg/m2 and myelotoxicity, grade 4 neutropenia with death for sepsis in one case and grade 3 thrombocytopenia in three cases, was dose limiting. The recommended dose of VP-16 for a phase II study is 140 mg/m2.     

A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer

BACKGROUND: Most patients with advanced ovarian cancer will relapse following platinum-based combination chemotherapy and be considered for second-line treatment. Gemcitabine, a nucleoside analogue, is active against a range of solid tumors. This phase II study investigated the activity of single-agent gemcitabine in patients with recurrent ovarian cancer. PATIENTS AND METHODS: Thirty-eight patients with FIGO stage III (34%) or IV (64%) ovarian cancer who were previously treated with platinum-containing regimens were enrolled. Patients received 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle. RESULTS: Patients completed an average of 3.6 cycles. Two complete and three partial responses were seen in 36 evaluable patients, for an overall response rate of 13.9% (95% CI: 4.7%-29.5%). The median survival time was 6.7 months. Toxicities were generally mild. The most common were grade 3-4 neutropenia and grade 3 leukopenia reported in 23.7% and 10.5% of patients, respectively. One patient had grade 4 pulmonary toxicity. CONCLUSION: Single-agent gemcitabine is active and well tolerated in patients with recurrent ovarian cancer.     

Phase I study of pharmacologically based dosing of carboplatin with filgrastim support in women with epithelial ovarian cancer

PURPOSE: The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA). PATIENTS AND METHODS: A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle. RESULTS: We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level. CONCLUSION: An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.     

Structural thermodynamics: prediction of protein stability and protein binding affinities

It has been demonstrated that the prognosis of ovarian cancer is influenced by the dose intensity of cytotoxic treatment. The impact of received dose intensity of platinum-based combination chemotherapy on disease outcome was analysed in 226 stage III-IV ovarian cancer patients entered into two prospective randomised trials. All patients received either cisplatin or carboplatin and cyclophosphamide with or without doxorubicin for six courses after primary surgery. The impact of the received dose intensity of each drug (RDI), the average received dose intensity of the treatment regimen (ARDI) and the relative total drug dose (RTD) on progression-free survival (PFS) and survival were analysed. In the 198 patients receiving the full six courses of treatment, RDI of cisplatin or carboplatin, ARDI and RTD were > 0.76 in 74.2, 61.1 and 65.1% of cases, respectively. Although the differences were not significant, pathological complete response was more frequently observed in the group of patients with ARDI < 0.75, whereas the partial response rate was higher in the ARDI > or = 0.76 group. Median survival and PFS were 19 and 13 months; 22 and 10 months; 23 and 13 months for the groups of patients receiving chemotherapy at a ARDI of < 0.75, > or = 0.76-0.99 and > 1.00, respectively (P = not significant). It appears that modest dose modifications and brief treatment delays during first-line platinum-based chemotherapy do not affect response rate, survival and PFS in advanced ovarian cancer patients.     

老年乳腺癌术后多西紫杉醇联合环磷酰胺辅助化疗的毒副作用研究

Objective: The aim of this study was to investigate the side effects of docetaxel with cyclophosphamide as postoperative adjuvant chemotherapy for elderly breast cancer patients. Methods: Thirty-six operable elderly breast cancer patients at intermediate risk based on the St Gallen risk classi.cation underwent modified radical mastectomy and then were given four cycles of TC regimen (docetaxel 75 mg/m2 i.v. on day 1; cyclophosphamide 600 mg/m2 i.v. on day 1; every 21 days ). Primary prophylaxis granulocyte colony stimulating factor (G-CSF) 200μg i.h. was administered on day 4-6. Results: The main side effect was neutropenia. Grade 3 neutropenia developed in 36.1% and G4 in 19.4%, respectively. Most of the other side effects were G1-2. Dose reduction occurred in 11.1% patients. The completion rate of chemotherapy was 100%. Conclusion:Docetaxel with cyclophosphamide as postoperative adjuvant chemotherapy regimen with G-CSF primary prophylaxis is tolerable for elderly patients in general good condition.     

Perspectives on the role of the lateral pterygoid muscle and the sphenomandibular ligament in temporomandibular joint function

This is a phase II study to evaluate the efficacy and toxicity of short-course carboplatin in advanced-stage nasopharyngeal carcinoma (NPC). Thirty-three previously untreated stage III-IV NPC patients were studied. Carboplatin was given as a rapid intravenous injection every 3 weeks. The dose of carboplatin was calculated according to the individual patient's creatinine clearance and desired platelet nadir of 75,000/microliter according to the Egorin formula. Response and toxicity were evaluated. Thirty-two patients were evaluated for response. The median age was 54 years, range 30-70 years. Twenty-four patients had local regional disease and 8 patients had metastatic disease. The median dose of carboplatin given was 415 mg/m2 (range 91-791 mg/m2). Fourteen (44%) patients had a partial response with a 95% confidence interval of 26-62%. Fifteen (47%) patients had stable disease and 3 (9%) progressive disease. The overall median survival rate was not reached at 43 months. Overall toxicity was tolerable. Grade III-IV myelosuppression occurred in 4 (12%) patients. There were no other major toxicity- or treatment-related deaths. We conclude that carboplatin has a significant anticancer effect in advanced NPC. Thus carboplatin combination chemotherapy for the treatment of NPC is worthy of future clinical investigations.     

Comparative bioavailability of two oral formulations of ipriflavone in healthy volunteers at steady-state. Evaluation of two different dosage schemes

Because of the relative lack of overlapping toxicity, carboplatin (PPL) and cisplatin (CDDP) can be easily combined for treatment of ovarian cancer to increase total platinum dose intensity. Ifosfamide (IFO), one of the most effective single agents in ovarian cancer, has a low hematological toxicity when administered in continuous infusion. From January 1991 to December 1993, 34 patients with advanced ovarian cancer, previously untreated with chemo- or radiotherapy, were enrolled in a phase I-II study with the aim of determining the maximum tolerated dose (MTD) of CDDP (on day 8 of a 28-day cycle) in combination with PPL (300 mg/m2 on day 1) and IFO (4,000 mg/m2/24 h by continuous infusion on day 1). The initial dose level of CDDP was 40 mg/m2, which was continuously increased by 10 mg/m2 up to the MTD defined as one dose level below that inducing dose-limiting toxicity (DLT) in at least two-thirds of treated patients; no dose escalation was allowed in the same patient. Grade 3-4 leukopenia and thrombocytopenia were observed in 54 and 49% of patients, respectively. The DLT was reached at 70 mg/m2 and therefore the dose recommended for the phase II study was 60 mg/m2. Complete (CR) plus partial response was observed in 88% of patients with a 21% pathological CR. With a minimum follow-up of 32 months (median 40 months), median progression-free survival and overall survival were 21 and 39 months, respectively. In conclusion, the combination of CDDP, PPL, and IFO provides an effective regimen for ovarian cancer with an acceptable toxicity profile.     

Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma

BACKGROUND: The carboplatin-based chemotherapeutic regimen M-CAVI (methotrexate, carboplatin, and vinblastine) is active against bladder carcinoma and can be administered to patients who are ineligible to receive cisplatin or doxorubicin. The authors designed a randomized study to evaluate whether M-CAVI offers a therapeutic advantage over the cisplatin-based regimen M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) in the treatment of patients with surgically incurable advanced bladder carcinoma. METHODS: Patients with surgically incurable advanced bladder carcinoma were enrolled on a randomized trial comparing M-CAVI, which consists of carboplatin (300 mg/m2 on Day 2, adjusted using Calvert's formula for an area under the curve of 5), methotrexate (30 mg/m2 on Days 1, 15, and 22), and vinblastine (3 mg/m2 on Days 2, 15, and 22) administered every 28 days, versus standard M-VAC. The eligibility criteria included histologically proven bladder carcinoma, surgically incurable disease, and no prior chemotherapy. Patients were treated until disease progression or unacceptable toxicity occurred. RESULTS: From January 1989 to January 1994, 47 assessable patients were included. Seventeen patients had lymph node disease and 30 had distant metastatic disease. Twenty-three patients were randomized to receive M-CAVI and 24 to receive M-VAC. Patient characteristics in the two groups were similar. Overall response rates were 39% (95% confidence interval [CI], 20-62%) for M-CAVI and 52% (95% CI, 30-73%) for M-VAC (P = 0.3), with 3 complete responses observed among patients treated with M-VAC and none among those in the M-CAVI group. M-VAC was associated with more gastrointestinal toxicity, stomatitis, alopecia, and Grade 4 neutropenia than M-CAVI. One toxicity-related death occurred in the M-VAC group. There was a statistically significant difference in median disease-related survival time favoring M-VAC (16 months; range, 6 to 22+) versus M-CAVI (9 months; range, 6 to 14+) (P = 0.03). CONCLUSIONS: M-CAVI is less toxic but less active than M-VAC in the treatment of patients with advanced bladder carcinoma. Carboplatin-based regimens in which carboplatin is administered at the dose range used in the current study should be reserved for patients who cannot tolerate cisplatin treatment. Further research is required to assess the impact of high dose carboplatin in the treatment of this disease.     

Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma

PURPOSE: Both paclitaxel and carboplatin have single-agent activity against carcinoma of the urothelium. We evaluated the combination of paclitaxel and carboplatin in the treatment of advanced cancers of the urothelium. PATIENTS AND METHODS: Patients with cancers of the urothelium who had no prior chemotherapy (prior adjuvant chemotherapy > 6 months allowed) were eligible for treatment. Eligibility requirements were performance status of 2 or less, creatinine level less than 2.0 mg/dL, granulocyte count (AGC) 1,500/microL or greater, platelet count 100,000/microL or greater, and total bilirubin level less than 1.5 mg/dL. Paclitaxel 200 mg/m2 followed by carboplatin (area under the curve [AUC] 5, Calvert formula) were administered every 21 days. Patients were evaluated for toxicity weekly and assessed for response every 6 weeks. RESULTS: Thirty-six patients were entered onto the study and 35 patients were assessable for response. A total of 184 cycles were administered (median, six cycles per patient). Nine patients required one dose reduction, and seven patients required two dose reductions for a nadir AGC less than 500/microL, with only one episode of febrile neutropenia and sepsis. Myalgias and arthralgias of grades 1 to 2 occurred in 16 patients and usually lasted 2 to 3 days after treatment. There were no treatment delays because of toxicity. There were 18 responses; seven complete responses (CRs) and 11 partial responses (PRs) (response rate 51.5%; 95% confidence interval, 35 to 68). Median response durations for CR and PR were 6 and 4 months, respectively. Overall median survival was 9.5 months. CONCLUSION: The combination of paclitaxel and carboplatin is an active and well-tolerated regimen for the treatment of advanced urothelial carcinoma. Because of the modest toxicity of this combination, paclitaxel and carboplatin should be considered for addition to other agents with activity in urothelial carcinomas.     

Lack of improved survival plus increase in thromboembolic complications in patients with clear cell carcinoma of the ovary treated with platinum versus nonplatinum-based chemotherapy

BACKGROUND: This study was conducted to evaluate survival rates for patients with clear cell ovarian carcinoma who had platinum-based chemotherapy versus nonplatinum-based chemotherapy and the risk of thromboembolic complications. METHODS: One hundred and eleven evaluable patients with clear cell ovarian carcinoma who underwent primary surgery and postoperative therapy were retrospectively evaluated. Median follow-up was 21.3 months (range, 3-280 months). Patients treated with platinum-based chemotherapy and nonplatinum-based chemotherapy were evaluated according to stage, age, grade, extent of surgery, and development of thromboembolic complications. Patient populations were compared using the chi-square test. Estimated 5- and 10-year survivals for each group were calculated using the method of Kaplan and Meier. Differences in survival rates were calculated using the log rank test. The frequency of thromboembolic complications in the clear cell ovarian carcinoma group was compared with its frequency in a matched-control group of 109 patients with epithelial nonclear cell ovarian carcinoma. RESULTS: Seventy-one patients were treated with nonplatinum-based chemotherapy and 40 patients were treated with platinum-based chemotherapy. There was no statistically significant difference in the characteristics of patient populations treated with platinum-based chemotherapy or nonplatinum-based chemotherapy. The estimated 5-year survival for clear cell ovarian carcinoma patients treated with platinum-based chemotherapy did not differ significantly from the estimated 5-year survival for patients with clear cell ovarian carcinoma treated with nonplatinum-based chemotherapy (36% vs. 32%; P = 0.23). Twelve patients with clear cell ovarian carcinoma developed thromboembolic complications remote from primary surgery, whereas in a matched-control group of patients with nonclear cell ovarian carcinoma treated with platinum-based chemotherapy, no patients developed a thromboembolic complications (P = 0.0004). Eight of 40 patients (20%) with clear cell ovarian carcinoma treated with platinum-based chemotherapy developed thromboembolic complications, whereas 4 of 71 patients (6%) treated with nonplatinum-based chemotherapy developed thromboembolic complications (P = 0.03). Multivariate logistic regression analysis demonstrated that the development of a thromboembolic complication was significantly related to clear cell ovarian carcinoma and platinum-based chemotherapy and had a significant (P = 0.009) negative impact on survival. CONCLUSIONS: Platinum-based chemotherapy did not appear to improve survival compared with nonplatinum-based chemotherapy of patients with clear cell ovarian carcinoma. The combination of platinum-based chemotherapy and clear cell ovarian carcinoma significantly increases the risk for thromboembolic complications and has a significant negative impact on survival.     

Mitomycin C, vinblastine, and carboplatin regimen in patients with nonsmall cell lung cancer. A phase II trial

BACKGROUND: The mitomycin C, vinblastine, and cisplatin (MVP) combination is one of the most frequently used in the palliative setting, but it produces considerable toxicity. Carboplatin and cisplatin have different patterns of toxicity. The goal of this study was to evaluate a combination similar to MVP, using carboplatin instead of cisplatin to render it more feasible in an outpatient setting. METHODS: Inclusion criteria for this study included: inoperable patients or patients relapsing after previous surgery, with nonsmall cell lung carcinoma (NSCLC), a performance status (PS) > 50%, and no previous chemotherapy. The chemotherapy regimen included carboplatin, 300 mg/m2 on Day 1; mitomycin, 8 mg/m2 on Day 1; and vinblastine, 4 mg/m2 on Days 1, 8, and 15 (on Day 15 vinblastine was delivered only in the first cycle) (MVC) every 3 weeks for at least 3 cycles. RESULTS: From August 1991 until August 1994, 70 patients entered the trial. All were evaluable for toxicity and response. The median age was 62 years (range, 40-73 years). The male/female ratio was 60:10 (86%:14%); the ratio of Stage III to Stage IV disease was 26:44 (37%:63%); and the ratio of PS > 70 to < or = 70 was 49:21. A total of 296 cycles (median, 4 [range, 1-6 cycles] per patient) were delivered, 280 of 296 (95%) in an outpatient setting with only 4 patients requiring hospitalization for treatment delivery. Overall response rate (RR) was 38.6% (95% confidence interval [CI], 27-51%) (1 complete response, 1.5%; 26 partial responses, 37.1%). Median duration of response was 9.8 months (range, 2-27 months). In Stage III patients the RR was 42% and in Stage IV patients it was 34%. Overall median survival was 9.5 months (95% CI, 6.8-15.3 months). Survival at 1 year was 39% (standard error [SE] 3.6%) and was 11% at 2 years (SE 3.6%). In Stage III patients median survival was 13 months and the 1-year survival rate was 54% (SE 10%); Stage IV patients had a median survival of 7.4 months and a 1-year survival rate of 28% (SE 7%). Delivered dose intensity was: carboplatin, 71%; vinblastine, 60%; and mitomycin C, 77% of the planned dose intensity. The back calculation of carboplatin area under the curve (AUC) with Calvert's formula and with the Cockcroft-Gault glomerular filtration rate estimation, showed a median AUC value of 4 (range, 2-8). Using the more precise Chatelut formula, AUC was again 4 (range, 2-7). Hematologic toxicity was the major side effect; Grades 3 and 4 leukopenia were observed in 34% and 6% of patients, respectively, and Grades 3 and 4 thrombocytopenia in 25% and 4% of patients, respectively. Grade 2 infection occurred in 10% of patients, with only 1 case of sepsis; severe constipation and Grade 2 alopecia occurred in only 1 patient; and no case of higher than Grade 1 nephrotoxicity was observed. No pulmonary toxicity was observed. Compliance with treatment was good with only one patient refusal after the first cycle. CONCLUSIONS: Chemotherapy for advanced NSCLS is still controversial, because effectiveness in terms of RR and symptom control must be weighed against treatment toxicity and costs. From our study it appears that MVC is easy to deliver in an outpatient setting, and has good patient compliance, low toxicity profile, and promising RR and response duration. The substitution of carboplatin for cisplatin in regimens for advanced NSCLC should be considered.     

Paclitaxel by 96-hour continuous infusion in combination with cisplatin: a phase I trial in patients with advanced lung cancer

PURPOSE: To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 96-hour continuous infusion in combination with cisplatin, to determine if the addition of granulocyte colony-stimulating factor (G-CSF) permits significant paclitaxel dose escalation, and to assess the toxicity and preliminary activity of this combination in patients with advanced lung cancer. PATIENTS AND METHODS: Fifty patients with untreated lung cancer were enrolled: 42 had advanced non-small-cell lung cancer (NSCLC) and eight had extensive-stage small-cell lung cancer (SCLC). Patients received paclitaxel doses of 100 to 180 mg/m2/96 hours and cisplatin doses of 60 to 80 mg/m2 as a single 30-minute bolus injection at the end of the paclitaxel infusion. RESULTS: Two of six patients experienced dose-limiting neutropenia at a dose of paclitaxel 140 mg/m2/96 hours and cisplatin 80 mg/m2. With G-CSF support, one of three patients experienced both dose-limiting mucositis and fatal neutropenic sepsis at a dose of paclitaxel 180 mg/m2/96 hours and cisplatin 80 mg/m2. Significant peripheral neuropathy developed in five patients and occurred after six or more cycles of therapy. Thirty-three of 42 patients with NSCLC had measurable disease; the objective response rate was 55%, with two complete responses and 16 partial responses. For all 42 patients with NSCLC, the median time to progression and median survival duration were 5 months and 10 months, respectively. The actuarial 1-year survival rate was 41%. Of eight SCLC patients, four responded to therapy, and the median survival duration for all SCLC patients was 11 months. CONCLUSION: The MTD without G-CSF is paclitaxel 120 mg/m2/96 hours and cisplatin 80 mg/m2, and the MTD with G-CSF is paclitaxel 160 mg/m2/96 hours and cisplatin 80 mg/m2. Infusional paclitaxel with cisplatin is well tolerated and active in patients with advanced NSCLC.     

Paclitaxel by 3-h infusion and carboplatin in anthracycline-resistant advanced breast cancer. A phase II study conducted by the Hellenic Cooperative Oncology Group

37 patients with advanced breast cancer resistant to anthracyclines were treated with paclitaxel 200 mg/m2 by 3-h infusion and carboplatin at an area under the curve of 7 mg.min/ml every 4 weeks with G-CSF support. There were 5 (14%, 95% CI 3-25%) complete and 11 (30%, 95% CI 15-45%) partial responders. Median duration of response was 11.5 months (range 5.2-16.8+), median time to progression 8 months (range 0.26-16.8+) and median survival 12 months (range 0.5-19.6+). Grade 3-4 leucopenia (27%), thrombocytopenia (10%) and diarrhoea (5%) were noted. In conclusion, the combination of paclitaxel and carboplatin is active and well tolerated in patients with advanced breast cancer resistant to anthracyclines.     

High-dose chemotherapy with autologous peripheral blood stem cell transfusion in the treatment of advanced testis cancer

Four patients with advanced testis cancer were treated by high-dose chemotherapy supporting by autologous peripheral blood stem cell transplantation. High-dose chemotherapy (carboplatin 250 mg/m2 or nedaplatin 200 mg/m2, etoposide 1,500 mg/m2, ifosphamide 7.5 g/m2 was given and peripheral blood stem cell transfusion was performed 72 hours after the last dose of chemotherapy. High-dose chemotherapy. was given followed by 1 or 2 cycles of pre high-dose therapy consisting of cisplatin 100 mg/m2 or carboplatin 500 mg/m2, etoposide 450 mg/m2, ifosphamide 6 g/m2. All 4 patients were evaluable. Three patients obtained a complete response and one showed a partial response. The partial responder was given RPLND. The RPLND specimen showed necrotic tissue.     

Low-dose versus standard-dose lenograstim prophylaxis after chemotherapy: a randomized, crossover comparison

PURPOSE: Granulocyte colony-stimulating factor (G-CSF) administered prophylactically after chemotherapy reduces the duration and severity of neutropenia. This randomized crossover study was designed to assess whether a lower dose of G-CSF is as effective as a standard dose of 5 microg/kg daily. PATIENTS AND METHODS: Patients who received standard-dose chemotherapy regimens expected to cause neutropenia received G-CSF (lenograstim) that started the day after chemotherapy for 14 days or until the absolute neutrophil count (ANC) recovered to greater than 10 x 10(9)/L. The lenograstim dose was randomly allocated to be 2 or 5 microg/kg daily in the first cycle of chemotherapy and crossed over to the alternate dose for the second cycle. The study was designed to accrue 40 assessable patients to provide a power of 80% to detect a difference in duration of neutropenia of 1 day. Fifty-two patients were randomized to treatment and 43 patients completed two cycles of identical chemotherapy. RESULTS: There was little neutropenia irrespective of the dose used. Twenty-three patients (53%) had no grade III or IV neutropenia and 30 patients (70%) had no grade IV neutropenia. Crossover trial methodology was used to assess the difference in outcome caused by the lower dose compared with the standard dose (estimated treatment effect). There was no significant difference in the measures of neutropenia, hospitalization, or other clinical outcomes. The 95% confidence interval (one-sided) for the additional duration of neutropenia caused by the lower dose of lenograstim was 0.43 days or less for grade III or IV neutropenia and 0.34 days or less for grade IV neutropenia. CONCLUSION: Lenograstim 2 microg/kg provides similar protection to 5 microg/kg against neutropenia that complicates standard-dose chemotherapy. The use of a lower dose has important implications for the cost-effectiveness of prophylactic G-CSF therapy.     

Second-line treatment with ifosfamide and carboplatin in patients with ovarian carcinoma relapsing after treatment with carboplatin

20 patients with ovarian carcinoma whose disease had relapsed (1-42 months, median 4 months) after showing either response or stable disease to carboplatin, were treated with ifosfamide (5 g/m2 intravenously over 24 h, day 1) and carboplatin (200 mg/m2 intravenously day 2) as second-line treatment. The mean number of treatment cycles was 3.5 (range 1-6). The major toxicities were thrombocytopenia (WHO grade 3/4, 25%), neutropenia (WHO grade 3/4, 40%) and encephalopathy (WHO grade 3/4, 15%). Overall response rate was 15% [complete response, 0; partial response, 3 (15%); no change, 5 (25%) and progressive disease, 12 (60%)]. The median survival from the date of second-line treatment was 7 months. This combination offers no advantage over either agent used alone.