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J B Vermorken

Publications and source records attributed to J B Vermorken.

At least 19 recordsLinked to original sources
PubMed2000

Quality control in multicentric clinical trials. An experience of the EORTC Gynecological Cancer Cooperative Group.

Data Quality is a central requirement of scientific research and external monitoring is essential in multicentric clinical trials (MCT). A quality control (QC) study was conducted in the main Institutions participating in EORTC-GCCG Protocol number 55863 - randomised phase III trial of vindesine, cisplatin, bleomycin and mitomycin-C (BEMP) versus cisplatin (P) in disseminated squamous cell carcinoma of the uterine cervix - in order to assess the impact of variations in data quality on the conclusions of the trial. The reliability of the different centres in following the protocol was investigated by a questionnaire covering drug prescription, local facilities and the procedure for preparation and administration of chemotherapy. The 'treatment protocol adherence' was evaluated by recalculation of the ideal protocol dose and its comparison with the actual delivered dosage at each cycle of chemotherapy. 'Data quality control' was assessed by comparison of data on case report forms (CRFs) with the corresponding items in the medical records. Eleven centres participating in the trial were visited by the same team of reviewers. Striking differences were noted in the chemotherapy administration procedures and between the type and quality of hospital files. Overall, there was an acceptable level of data quality and protocol compliance. Data accuracy was 81.8% (range: 65. 6-97%) of the 4424 items checked. Incorrect data were found in 7.0% (2.3-14.5%), data were missing on the form in 3.6% of cases (0-12%) and data was on the form but not in the file in 7.6% of cases (0. 7-17.5%). Causes of inaccuracy were analysed. Both problems in data management but also in a lack of clarity of the protocol and/or CRFs were to blame. Training and supervision of data managers, precision in writing protocols, standardisation of some aspects of CRFs and the use of a checklist for chemotherapy data and treatment toxicities would have avoided many of these errors. The need for QC in all collaborative groups performing MCT is emphasised. A literature review on QC in MCT dealing with chemotherapy is included.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Phase II trial of vinorelbine in patients with advanced and/or recurrent cervical carcinoma: an EORTC Gynaecological Cancer Cooperative Group Study.

The objective of this phase II study was to assess the efficacy and toxicity of vinorelbine administered as a single agent in the treatment of chemonaïve cervical cancer patients. 46 patients (41 eligible) with cervical cancer (epidermoid or adenocarcinoma) and measurable metastatic and/or recurrent disease localised outside irradiated areas were treated with weekly intravenous (i.v.) vinorelbine 30 mg/m2 infused over 20 min. No prior chemotherapy was allowed. Median age was 53 years (range: 33-73), and performance status 1 (0-2). 31 patients (76%) had prior radiation therapy. There were 7 partial responders (17, 95% confidence interval (CI) 7-32) and 8 stable diseases (20%). Median duration of response was 5 months (4-11). Granulocytopenia was the major toxicity, with 47% of patients exhibiting grade 3 or 4 toxicity. Dose reduction and/or treatment delay was necessary in 28 patients (78%). Peripheral neuropathy reported in 10 patients was mild (grade 1 in 9 patients and grade 2 in 1 patient). In conclusion, single agent vinorelbine has moderate activity in recurrent or metastatic cervical cancer, but its reduced neurotoxicity warrants further study in combination with cisplatin.

Adult↗
PubMed2000

A phase II study of paclitaxel in chemonaïve patients with recurrent high-grade glioma.

BACKGROUND: The prognosis of malignant gliomas remains poor. In recurrent disease, chemotherapy can be considered. PATIENTS AND METHODS: In this phase II study we determined the anti-tumour efficacy of paclitaxel 200 mg/m2 in a three-hour intravenous infusion every three weeks in chemonaïve patients with recurrent high-grade glioma in terms of response, survival, and quality of life. RESULTS: In 17 patients (14 glioblastoma multiforme, 3 anaplastic astrocytoma) 69 paclitaxel cycles were administered. Partial or complete responses were not observed. Stable disease for four to six months was observed in five patients (29%). Median time to progression and median survival were two and 10 months, respectively. Toxicity due to paclitaxel was as to be expected and minor in most cases. Quality of life and mood estimates appeared rather stable over time. CONCLUSIONS: We conclude that three-weekly 200 mg/m2 paclitaxel chemotherapy for patients with recurrent high-grade gliomas did not lead to major complications or adverse effects on quality of life and mood. However, this therapy is of only very limited value in terms of response and survival in such patients.

Adult↗
PubMed2000

Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature.

Ifosfamide is an alkylating agent used in the treatment of a variety of solid tumours. Ten to 15% of patients treated with ifosfamide develop an encephalopathy. Methylene blue (MB) may be used in the treatment of this encephalopathy. The purpose of this study was to evaluate the neuroprotective effect of MB in these patients and to review the literature. Between 1993 and 1997, 52 patients (age 16-77 years) with solid tumours were treated with ifosfamide in dosages ranging from 3 to 5 g m(-2) q3w when given in combination schedules and up to 12 g m(-2) q4w when given as a single agent. Twelve patients developed central nervous system (CNS) depression, defined as National Cancer Institute Common Toxicity Criteria (NCI-CTC) neurocortical toxicity grade 2 or higher. Eight were treated with MB at a dose of 6 x 50 mg day(-1) intravenously (i.v.). Four recovered fully within 24 h, two recovered partially after 24 h and completely after 48 h while two recovered only after 72 h. Four patients did not receive MB and all recovered only after 48 h. Three patients received prophylaxis with MB at a dose of 4 x 50 mg day(-1) i.v. for the subsequent chemotherapy cycles. Two developed milder encephalopathy; one had no CNS depression at all. We conclude that MB is an effective treatment for ifosfamide-induced encephalopathy. Our findings suggest that it may also be used as a prophylactic agent.

Adolescent↗
PubMed2000

Thoracic wall prosthesis prevents deep invasion by non-small-cell lung cancer.

Chest wall invasion is found in 5% of patients with non-small-cell lung cancer. Treatment for localized non-small-cell lung cancer consists of surgical resection and/or radiotherapy. We report a patient with lung cancer who had a local relapse after a reconstruction of the thoracic wall with a soft-tissue patch. Chemotherapy was given before reresection of the local relapse. Postoperative radiation therapy was performed. Twenty-one months after treatment for recurrent disease, the patient remains in complete remission. The history of this patient shows that a soft-tissue patch may prevent local tumor invasion. A review of the literature is given.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Role of taxoids in head and neck cancer.

Docetaxel and paclitaxel represent a new class of cytotoxic agents having both a specific chemical structure and mechanism of action. They act to promote tubulin polymerization and the formation of stable microtubules. The microtubules produced in the presence of taxoids are resistant to disassembly by physiologic stimuli, and cells exposed to these agents exhibit an accumulation of disorganized microtubule arrays. This affects the normal mitotic process and eventually results in cell death. Both drugs are active as single agents in patients with head and neck cancer with response rates ranging from 20% to 40%. They may be combined with other cytotoxic agents, radiotherapy, or both. A review is given of the presently available data.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Combination chemotherapy studies with gemcitabine and etoposide in non-small cell lung and ovarian cancer cell lines.

Gemcitabine (2',2'-difluorodeoxycytidine, dFdC) and etoposide (4'-demethylepipodo-phyllo-toxin-9-4,6-O-ethylidene-beta-D-g lucopyranoside, VP-16) are antineoplastic agents with clinical activity against various types of solid tumors. Because of the low toxicity profile of dFdC and the differences in mechanisms of cytotoxicity, combinations of both drugs were studied in vitro. For this purpose, we used the human ovarian cancer cell line A2780, its cis-diammine-dichloroplatinum-resistant and VP-16 cross-resistant variant ADDP, and two non-small cell lung cancer cell lines, Lewis Lung (LL, murine) and H322 (human). The interaction between the drugs was determined with the multiple drug effect analysis (fixed molar ratio) and with a variable drug ratio. In the LL cell line, the combination of dFdC and VP-16 at a constant molar ratio (dFdC:VP-16 = 1:4 or 1:0.125 after 4- or 24-hr exposure, respectively) was synergistic (combination index [CI], calculated at 50% growth inhibition = 0.7 and 0.8, respectively; CI <1 indicating synergism). After 24- and 72-hr exposure to both drugs at a constant ratio, additivity was found in the A2780, ADDP, and H322 cell lines (dFdC:VP-16 = 1:500 for both exposure times in these cell lines). When cells were exposed to a combination of dFdC and VP-16 for 24 or 72 hr, with VP-16 at its IC25 and dFdC in a concentration range, additivity was found in both the LL and H322 cells; synergism was observed in the A2780 and ADDP cells, which are the least sensitive to VP-16. Schedule dependency was found in the LL cell line; when cells were exposed to dFdC 4 hr prior to VP-16 (constant molar ratio, total exposure 24 hr), synergism was found (CI = 0.5), whereas additivity was found when cells were exposed to VP-16 prior to dFdC (CI = 1.6). The mechanism of interaction between the drugs was studied in more detail in the LL cell line; dFdCTP accumulation was 1.2-fold enhanced by co-incubation with VP-16, and was even more pronounced (1.4-fold) when cells were exposed to VP-16 prior to dFdC. dCTP levels were decreased by VP-16 alone as well as by the combination of both compounds, which may favor phosphorylation of dFdC, thereby increasing dFdCTP accumulation. DNA strand break (DSB) formation was increased for exposure to both compounds together compared to exposure to each compound separately, this effect being most pronounced when cells were exposed to VP-16 prior to dFdC (38% and 0% DSB for dFdC and VP-16 alone, respectively and 97% DSB for the combination). The potentiation in DSB formation might be a result of the inhibition of DNA repair by dFdC. Provided the right schedule is used, VP-16 is certainly a compound eligible for combination with dFdC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial.

BACKGROUND: Colon cancer is curable by surgery, but cure rate depends on the extent of disease. We investigated whether adjuvant active specific immunotherapy (ASI) with an autologous tumour cell-BCG vaccine with surgical resection was more beneficial than resection alone in stage II and III colon cancer. METHODS: In a prospective randomised trial, 254 patients with colon cancer were randomly assigned postoperative ASI or no adjuvant treatment. ASI was three weekly vaccinations starting 4 weeks after surgery, with a booster vaccination at 6 months with 10(7) irradiated autologous tumour cells. The first vaccinations contained 10(7) BCG organisms. We followed up patients for time to recurrence, and recurrence-free and overall survival. Analysis was by intention to treat. FINDINGS: The 5.3 year median follow-up (range 8 months to 8 years 11 months) showed 44% (95% CI 7-66) risk reduction for recurrence in the recurrence-free period in all patients receiving ASI (p=0.023). Overall, there were 40 recurrences in the control group and 25 in the ASI group. Analysis by stage showed no significant benefit of ASI in stage III disease. The major impact of ASI was seen in patients with stage II disease, with a significantly longer recurrence-free period (p=0.011) and 61% (18-81) risk reduction for recurrences. Recurrence-free survival was significantly longer with ASI (42% risk reduction for recurrence or death [0-68], p=0.032) and there was a trend towards improved overall survival. INTERPRETATION: ASI gave significant clinical benefit in surgically resected patients with stage II colon cancer. ASI has minimal adverse reactions and should be considered in the management of stage II colon cancer.

Adjuvants, Immunologic↗
PubMed1999

Pharmacokinetics of paclitaxel administered as a 3-hour or 96-hour infusion.

AIM: To investigate the pharmacokinetics of paclitaxel (Paxene) administered to patients with advanced breast or ovarian cancer and to document safety and anti-tumour activity in this study population. PATIENTS AND METHODS: Patients with advanced breast or ovarian cancer were accrued to two clinical studies. Paclitaxel (Paxene) was administered as a 3-h 175 mg m-2 or as a 96-h 140 mg m-2(105 mg m-2 in the presence of liver metastases) infusion. Patients not responding to the 3-h schedule were permitted to cross-over to the 96-h schedule. The data were compared to those of five patients who were previously treated with paclitaxel administered as Taxol (140 mg m-296-h infusion) at our Institute. RESULTS: Fourteen patients with breast cancer and five ovarian cancer patients were entered into this study. Seven patients received the 3-h regimen, and 12 were assigned to the 96-h schedule. Five patients originally treated with the 3-h schedule, crossed over to the 96-h arm. For the 3-h 175 mg m-2 dose, the area under the plasma concentration vs time curve (AUC) was (mean+/-SD) 16.9+/-4.8 h x micromol x l-1, whereas the AUCs were 5.5+/-1.2 and 4.3+/-0.9 h x micromol x l-1 for the 96-h 140 mg m-2 and 105 mg m-2 doses, respectively. The clearance of paclitaxel was independent of the dose in the 96-h group, indicating linear pharmacokinetics. Pharmacokinetics of Paxene (96-h 140 mg m-2) were not significantly different from the kinetics after Taxol (96-h 140 mg m-2) administration.

Adult↗
PubMed1999

Current developments in the treatment of newly diagnosed cervical cancer.

The International Federation of Gynecology and Obstetrics (FIGO) staging of cervical cancer relies on physical examination. However, surgical staging, which helps determine the extent of invasion of lymph nodes by cancer, is currently used more widely to define the need for additional therapies. Examples of these additional treatments include high-dose-rate brachytherapy techniques, extension of radiotherapy fields, surgery, concurrent chemotherapy and radiotherapy, and neoadjuvant chemotherapy prior to surgery. Currently there are many ongoing randomized studies that strive to define the risk-to-benefit ratio of these additional therapies.

Female↗
PubMed1999

Scheduling of gemcitabine and cisplatin in Lewis lung tumour bearing mice.

We used the gemcitabine (dFdC) and cisplatin (cis-diamine dichloroplatinum CDDP) resistant murine NSCLC tumour Lewis Lung (LL) in C57/B16 mice to optimise scheduling of both drugs, since in previous in vivo studies no effective combination schedule of both compounds was found to overcome resistance to either drug. dFdC could not be combined at the previously determined maximum tolerated dose (MTD) (120 mg/kg, q3dx4) with CDDP at its MTD (9 mg/kg, q6dx2) (mean weight loss < 15% and < 15% toxic deaths), because of additive toxicity. Therefore, we lowered the dose of dFdC to 60 mg/kg (q3dx4) and of CDDP to 3 mg/kg (q6dx2), which caused an increase in antitumour effect compared with the activity of each compound alone at its MTD (growth delay factor (GDF) = 0.55, 0.13 and 2.56 for dFdC and CDDP alone and the combination, respectively). Changing the CDDP treatment schedule giving the total dose (6 mg/kg) only at day 0 caused unacceptable toxicity. This effect was not seen when mice were treated with the total dose of CDDP on day 9, but, the anti-tumour effect was not enhanced. To decrease toxicity, the dosage of dFdC was lowered to 50 mg/kg and combined with the total dose of CDDP on day 0, which caused a better antitumour effect than the combination of 60 mg/kg dFdC and 3 mg/kg CDDP (q6dx2) with acceptable toxicity. Schedule dependency was found for the combination: dFdC preceding CDDP by 4 h was the best treatment schedule in the LL tumours (GDF: 2.1) with acceptable toxicity. However, when the interval was increased to 24 h, toxicity became unacceptable (> 30% weight loss). The reverse schedule, in which CDDP preceded dFdC, did not lead to an increased antitumour effect or to increased toxicity. Adding amifostine, a selective chemoprotector, to the treatment decreased toxicity of the combination without affecting the antitumour effect. Increasing the CDDP dose to 9 mg/kg (day 0) under amifostine protection led to an improved therapeutic index.

Animals↗
PubMed1999

Cisplatin (P), vinblastine (V) and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa(-theca) cell tumours of the ovary. An EORTC Gynaecological Cancer Cooperative Group study.

The aim of this study was to investigate the clinical activity and toxicity of a modified PVB regimen (cisplatin, vinblastine and bleomycin) in patients with advanced or recurrent, pure granulosa cell tumours (GCTs) or mixed granulosa-theca cell tumours (GTCTs). The PVB regimen consisted of cisplatin (P) 20 mg/m2 intravenous (i.v.) days 1-5, vinblastine (V) 0.15 mg/kg i.v. days 1-2 and bleomycin (B) 30 mg i.v. on day 2, and 15 mg on day 15, for 28 days. 38 eligible patients were entered in this trial. Prior to PVB all patients underwent surgery and 13 received postoperative radio- or other prior chemotherapy. The median number of PVB cycles was 4 in both groups. In the group of 25 patients who had received prior surgery only, 7 and 6 patients had complete and partial responses, respectively (response rate: 52%, 95% confidence limits: 31.3-72.2%). At a median follow-up of 39 months, 6 patients were alive with no evidence of disease, 6 were alive with disease, 12 died due to malignant disease and 1 died due to intercurrent disease. The median time to progression was 13.9 months. The median survival was 25.4 months. 3-year survival was 49% (95% confidence limits: 29-69%). In the group of 13 patients who had previously received postoperative radio- or chemotherapy, 5 complete and 5 partial responses were observed on PVB (response rate: 77%, 95% confidence limit: 46.2-95.0%). At a median follow-up of 50 months, 6 patients were still alive, only 1 without evidence of disease, 6 died due to malignant disease and 1 died due to intercurrent disease. The median time to progression was 19.3 months. The median duration of survival was 41.1 months. Accompanying toxicity was distributed in a similar pattern for both groups. Severe toxicity was mainly documented as haematological toxicity, nausea/vomiting and alopecia. Furthermore cisplatin-related peripheral neurotoxicity and mild/moderate signs of bleomycin-related pulmonary toxicity were observed. The present data confirm the therapeutic activity of the PVB regimen in advanced/recurrent GCTs. The response rate was moderately high compared with previous studies, with a median duration of response of 20 months for both groups.

Adult↗
PubMed1999

Peripheral neuropathy due to biweekly paclitaxel, epirubicin and cisplatin in patients with advanced ovarian cancer.

We assessed the peripheral neuropathic changes induced by biweekly combination chemotherapy including paclitaxel 100-165 mg/m2 (in a 3-h infusion), epirubicin 75 mg/m2 and cisplatin 50 mg/m2 (TEC) in patients with advanced ovarian cancer. Neurologic evaluation, including a standardized questionnaire, bed-side neurological examination, and quantitative determination of vibratory perception thresholds (VPT) and grip strength took place before therapy, after 3 and 6 cycles, and thereafter whenever possible. During chemotherapy all patients received granulocyte colony-stimulating factor from days 2 to 12. Pretreated patients received amifostine two times, before epirubicin and before cisplatin administration. Neuropathic symptoms developed in 11/13 non-pretreated patients and in 7/9 chemotherapy-pretreated patients. Neuropathic signs developed in all patients. Neuropathic symptoms and signs were predominantly sensory in character. VPT changes developed primarily in the feet. According to National Cancer Institute of Canada Common Toxicity Criteria, grade 3 peripheral neuropathy after 6 cycles developed in 1/6 and 2/4 non-pretreated patients who received TEC containing paclitaxel 150 and 165 mg/m2, respectively. We conclude that peripheral neuropathy is dose-limiting in chemonaïve patients treated with biweekly TEC combination chemotherapy, at paclitaxel dose level 165 mg/m2 in a 3-h intravenous administration.

Adult↗
PubMed1999

Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors.

PURPOSE: To determine possible schedule dependent pharmacokinetic and pharmacodynamic interactions between gemcitabine (2',2'-difluorodeoxycytidine, dFdC) and cisplatin (cis-diammine-dichloroplatinum, CDDP) in patients with advanced stage solid tumors in a phase I trial. PATIENTS AND METHODS: A total of 33 patients with advanced stage solid tumors were treated with gemcitabine (30-min infusion, 800 mg/m2) and cisplatin (one-hour infusion, 50 mg/m2). Sixteen patients had a four-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 1 and 8), followed by the reverse schedule and seventeen patients had a 24-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 2 and 9), followed by the reverse schedule. Gemcitabine and cisplatin pharmacokinetics were measured in plasma and white blood cells (WBC), isolated from blood samples taken at several time points after the start of treatment. RESULTS: A four-hour time interval between both agents did not reveal major differences in plasma pharmacokinetics of gemcitabine, dFdU (deaminated gemcitabine) and platinum (Pt), and of gemcitabine-triphosphate (dFdCTP) accumulation and Pt-DNA adduct formation in WBC between the two different sequences of gemcitabine and cisplatin. In the patients treated with the 24-hour interval, cisplatin before gemcitabine did not significantly change peak gemcitabine levels and the AUC of plasma dFdU, but tended to increase dFdCTP AUC in WBC 1.5-fold (P < 0.06). Gemcitabine before cisplatin decreased the plasma AUC of Pt 2.1-fold (P = 0.03). No significant differences in Pt-DNA adduct levels in WBC were found, although gemcitabine before cisplatin tended to increase the 24-hour retention of Pt-DNA adducts. Creatinine clearance on day 28 was related to the peak plasma levels of total Pt (linear regression coefficient (r) = 0.47, P = 0.02, n = 26). Furthermore, the increase in the Pt-GG to Pt-AG ratio 24 hours after cisplatin treatment was related to the overall response of patients (r = 0.89, P < 0.01, n = 8). CONCLUSIONS: Of all schedules the treatment of patients with cisplatin 24 hours before gemcitabine led to the highest dFdCTP accumulation in WBC and total Pt levels in plasma. These characteristics formed the basis for further investigation of this schedule in a phase II clinical study.

Adult↗
PubMed1999

The role of anthracyclines in epithelial ovarian cancer.

This paper provides a survey on anthracycline treatment in ovarian cancer, focusing on toxicity and analysis of treatment results. Meta-analyses and studies in which anthracyclines have been combined with "standard" taxoid regimens are reviewed. The data suggest that the addition of an anthracycline to front-line non-taxoid based therapy is beneficial. The addition of an anthracycline to a combination of a taxoid and platinum derivative is rationale and feasible and randomised trials are on their way to completion. It is important that the final conclusions of these studies are based on long-term survival data, not just on the assessment of median differences in survival.

Antibiotics, Antineoplastic↗
PubMed1999

Randomised trials in ovarian cancer: trial design considerations.

Randomised clinical trials are considered the definitive source of evidence for guiding decisions in clinical practice. The concept of a clinical trial is based on sound scientific, ethical, and practical principles. The strength of evidence that an individual trial provides is assessed on the manner in which these principles are incorporated into the design and execution of the trial. Since the way these principles are incorporated into a trial is judgmental, the strength of evidence from an individual trial is a matter of degree. The purpose of this paper is to present some of the scientific, ethical and practical considerations surrounding the selection of endpoints and determination of sample size for trials in ovarian cancer.

Female↗
PubMed1999

Gemcitabine-cisplatin: a schedule finding study.

PURPOSE: To evaluate the tolerability of four alternating cisplatin-gemcitabine schedules. A secondary aim was to evaluate the clinical efficacy of this combination. PATIENTS AND METHODS: Forty-one patients with advanced solid tumors received alternating sequences with a 4- and 24-hour interval of cisplatin and gemcitabine. Gemcitabine 800 mg/m2 was administered as a 30-min infusion on day 1, 8 and 15, and cisplatin 50 mg/m2 over 1 hour on day 1 and 8; in case of the 24-hour time interval the second drug was administered one day later. Four cisplatin-gemcitabine schedules were studied: gemcitabine four hour before cisplatin (10 patients), or vice versa (14 patients) and gemcitabine twenty-four hours before cisplatin (9 patients) or vice versa (8 patients). The sequence of drug administration was reversed in the second cycle of therapy in each individual patient, enabling the evaluation of sequence-dependent side effects. Twenty-six patients had received prior chemotherapy, of which twenty-one platinum-based. RESULTS: The main toxicity was myelosuppression. Overall, grade 3 and 4 thrombocytopenia was observed in 27 out of 41 patients (66%) and was not schedule dependent. No serious bleeding occurred. Leukopenia was significantly different between the 4 alternating schedules (P = 0.01); gemcitabine 24 hours before cisplatin was significantly less toxic compared to both cisplatin 4 hours and 24 hours before gemcitabine (P = 0.01 and P = 0.003, respectively). Furthermore, paired analysis of the 4-hour and 24-hour data sets showed that leukopenia was significantly more serious when cisplatin preceded gemcitabine (P = 0.005). Although most patients received prior treatment, both prior chemotherapy and radiotherapy were not related to toxicity. Overall, grade 3 and 4 leukopenia occurred in 19 out of 41 patients (46%). Anemia (Hb < or = 6.0 mmol/l) was not sequence dependent and was observed in 63% of patients. Myelotoxicity was cumulative between cycles and caused frequent omission of gemcitabine on day 15. Overall, in 51% of administered cycles there was no omission of gemcitabine. A mean of 3.5 therapy cycles was administered. Non-hematological toxicity was moderate, consisting mainly of grade 1 and 2 nausea/vomiting and fatigue, and was not schedule dependent. Recently, we described that the schedule in which cisplatin was administered 24 hours before gemcitabine produced the best pharmacological profile. Based on this and because toxicity was manageable, the schedule cisplatin 24 hours prior to gemcitabine was chosen for phase II evaluation. Nine out of thirty-six evaluable patients had an objective response. These responses were observed in head and neck squamous-cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, adenocarcinoma of unknown origin, ovarian and esophageal carcinoma. CONCLUSIONS: Myelosuppression was the most important toxicity. Leukopenia was schedule dependent: gemcitabine before cisplatin was less toxic than the reversed sequence, in this respect. Some encouraging responses were seen in patients with esophageal cancer. Currently, a phase II study with cisplatin 24 hours before gemcitabine is ongoing in patients with advanced upper gastro-intestinal tumors.

Adult↗