[Vitamin A derivatives: potential prevention and therapy of solid tumors].
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Animals↗
Biomedical subjects
J Verweij
Publications and source records attributed to J Verweij.
Changing concepts in the systemic treatment of locally advanced or metastatic soft tissue sarcomas.
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Antineoplastic Agents↗
Combination of daily 4-h infusion of 5-fluorouracil and cisplatin in the treatment of advanced head and neck squamous-cell carcinoma: a South-East European Oncology Group study.
Between April 1986 and May 1989 a multicentre study was conducted to evaluate the efficacy of a 4-h intravenous infusion of 1000 mg/m2 5-fluorouracil (5-FU) followed by a 1-h infusion of 25 mg/m2 cisplatin (CDDP) given for 4 consecutive days every 4 weeks to patients with advanced squamous-cell carcinoma of the head and neck. A total of 189 consecutive patients entered the study, including 106 who had previously undergone chemotherapy and 83 who were chemotherapy-naive. Of the 165 evaluable patients, 96 (58%) responded to treatment, including 22 (13%) who achieved a complete remission (CR). In the group of previously untreated patients an objective response (CR+PR) was seen in 78% (CR, 14%) whereas in pretreated patients the response rate (CR+PR) was 40% (CR, 13%). The median survival period was 10 months. No significant difference in the duration of survival or of remission was found between the two groups in relation to previous therapy, tumour localisation, disease stage or performance status. Almost half of the patients (49%) experienced leucopenia but it was severe in only 11% of cases. Anemia (mainly WHO grades 1-2) occurred in 38% of the patients. Nausea and vomiting were common (84%). Nephrotoxicity (23%) was mild and of short duration. Moderate hair loss was seen in 42% of the patients, and phlebitis occurred in 8%. A few cases of cardiotoxicity and neurotoxicity were observed. This regimen is well tolerated and can be given even on an outpatient basis. The resultant response rate and side effects appear to be similar to those previously reported for combination chemotherapy with CDDP and continuous 5-FU infusion.
Adult↗
Phase II study of miltefosine (hexadecylphosphocholine) in advanced soft tissue sarcomas of the adult--an EORTC Soft Tissue and Bone Sarcoma Group Study.
The EORTC Soft Tissue and Bone Sarcoma Group conducted a phase II study with oral miltefosine at a dose of 50 mg thrice daily in patients with metastatic soft tissue sarcomas. No responses were seen in 18 evaluable patients. Toxicity consisted mainly of nausea/vomiting. It is concluded that oral miltefosine has no activity in soft tissue sarcoma.
Administration, Oral↗
Selection of large and objectively measurable target lesions in EORTC phase II trials: impact on recruitment and response rate. EORTC Soft Tissue and Bone Sarcoma Group (STBSG).
The EORTC has recently issued minimum requirements for target lesions in phase II trials, aiming at a decrease in measurement errors [minimum size, computer tomography (CT) scan or ultrasound for deep lesions]. Their impact on recruitment and response has been retrospectively studied in a trial of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), investigating high-dose chemotherapy in patients with advanced soft tissue sarcoma, where 46/103 objective responses were seen, including 10 complete responses. For the 20 patients who did not satisfy the criteria, a similar objective response rate and a significantly higher complete response rate were reported. Among 265 target lesions, the same trends were observed when comparing small to large lesions, for different tumour sites. For deep lesions clinically assessed, significantly higher response rates were reported than for those measured by CT scans or ultrasound. The new stricter EORTC criteria improve the reliability of measurements and have been adopted for future phase II trials of the STBSG. This will not result in the selection of potentially poor responders. Less than 20% of the present recruitment will be lost.
Antineoplastic Combined Chemotherapy Protocols↗
Phase II study of daily oral miltefosine (hexadecylphosphocholine) in advanced colorectal cancer.
34 patients with metastatic colorectal cancer were treated with the ether lipid miltefosine (hexadecylphosphocholine). Most patients received 3 x 50 mg daily, while in 11 patients the dose could be escalated to 4 x 50 mg daily. Nausea and vomiting were the most frequent side-effects occurring in all but 3 patients, nephrotoxicity was observed in 11 patients. Leucocytosis was observed in 24 and thrombocytosis in 17 patients. 28 patients are evaluable for response. 1 patient obtained a partial response of liver metastases for a duration of 8 months. 3 patients had stable disease while 24 progressed during treatment. We conclude that miltefosine in this dose and schedule has limited activity in colorectal cancer.
Administration, Oral↗
Chemotherapy administration and data collection in an EORTC collaborative group--can we trust the results?
As part of a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group, 15 centres took part in a programme to evaluate the quality of treatment delivered and data collected. The centres were visited and facilities for treatment and data management were reviewed. Source data in randomly selected patient hospital records were compared with information which had previously been completed on case record forms and returned to the EORTC Data Centre. The review included 71% of the patients entered into the study and 76% of the treatment cycles. Chemotherapy was prepared by nurses or clinicians in 58% and by pharmacists in 42% of the centres and was administered by specialist nurses in 67% of the hospitals. 8776 items were checked with source data. 3.4% were incorrect, 0.2% were missing and 30% could not be verified as correct (mainly related to the lack of recording of toxicity data in hospital records). The mean doses of chemotherapy delivered and treatment intervals were those stipulated in the protocol but 21% of the cycles were delayed for avoidable reasons. Several modifications to the procedures for running chemotherapy trials were suggested by this survey including the use of a systematic checklist for recording toxicity and chemotherapy administration and the development of quality assurance programmes in other collaborative groups and single centres to ensure that published results are credible.
Adult↗
Phase II study of oral miltefosine in patients with squamous cell head and neck cancer.
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Aged↗
Phase I/II study of a short course of weekly cisplatin in patients with advanced solid tumours.
Twenty-five patients with advanced solid tumours were entered in a phase I/II study of six, weekly cycles of cisplatin. Nineteen patients were chemonaive and six were previously treated. The starting dose was 50 mg m-2 week-1. This dose could be escalated without major toxicity to 70 mg m-2 week-1. At a dose of 80 mg m-2 myelosuppression grade 3 occurred as well as grade 1 nephro- and neurotoxicity. The maximum tolerated dose was 85 mg m-2 with dose limiting thrombocytopenia. Hypertonic saline was effective in preventing nephrotoxicity. Ondansetron was a very effective antiemetic in the first weeks of treatment but its efficacy waned later on. Responses were observed in head and neck cancer, melanoma and mesothelioma. At the dose level of 80 mg m-2 the optimal dose intensity was reached. This schedule will be tested further in phase II studies.
Adult↗
Oral piritrexim, an effective treatment for metastatic urothelial cancer.
Piritrexim is a lipid-soluble inhibitor of dihydrofolate reductase (DHFR) that enters tumour cells rapidly by passive diffusion, cannot be polyglutamated, and is as effective as methotrexate in inhibiting DHFR. Bioavailability after oral dosing is approximately 75%. We performed a phase II study with oral piritrexim in non-chemotherapy pretreated patients with metastatic urothelial cancer. Thirty-three patients were treated with 25 mg three times daily for 5 consecutive days, repeated weekly, with provision for dose escalation or reduction according to the toxicity observed. Of 29 evaluable patients, one patient achieved a complete response of 19+ weeks duration, and ten patients achieved a partial response with a median duration of 22 weeks (range 16-48), for a total response rate of 38%. Piritrexim was generally well tolerated, with myelosuppression as the major toxicity, that frequently required dose modification. We conclude that piritrexim appears to be an active agent in patients with metastatic urothelial cancer when administered as a 5-day, low-dose oral schedule. It would be attractive to investigate the combination of piritrexim and cisplatin.
Administration, Oral↗
Phase I and pharmacokinetics study of topotecan, a new topoisomerase I inhibitor.
PURPOSE: A phase I study with topotecan (SKF 104864-A, NSC 609699), a semisynthetic analog of camptothecin, was performed using a daily-times-5 regimen, given i.v. q 3 weeks, to evaluate the pharmacokinetics and toxicities of the compound. PATIENTS AND METHODS: Patients with a histologically confirmed diagnosis of a solid tumor no longer amenable to established forms of treatment were eligible for the study. Topotecan was given as a 30 min. infusion daily on 5 successive days, repeated every three weeks. In subsequent patient cohorts the dose was escalated from 0.5 to 1.5 mg/m2/day. Weekly evaluations included hematology and biochemistry. Response to treatment was assessed every 2 cycles. Pharmacokinetics were performed using a HPLC method. RESULTS: Forty-eight patients were entered. The maximal tolerated dose was 1.5 mg/m2/day. The dose limiting toxicity was leucocytopenia. Other major toxicities were alopecia and moderate nausea/vomiting. Partial remissions were observed in one patient with pretreated small-cell lung cancer, one with non-small-cell lung cancer and one with no-pretreated pancreatic cancer, lasting 130-240 days. Pharmacokinetics showed a t 1/2 (alpha) of 8.1 +/- 7.6 min., t 1/2 (beta) of 132 +/- 48 min., Vd,ss 72.7 +/- 26.9 L/m2 and Cltot of 0.57 +/- 0.16 L/min/m2. CONCLUSION: Topotecan is an interesting new topoisomerase I inhibitor exerting antitumor activity in this phase I trial. Leucocytopenia is dose-limiting. The recommended dose for phase II studies is 1.5 mg/m2/day for 5 consecutive days every 3 weeks.
Adult↗
Epirubicin in patients with advanced or recurrent adenoid cystic carcinoma of the head and neck: a phase II study of the EORTC Head and Neck Cancer Cooperative Group.
BACKGROUND: Because of the rarity of salivary gland cancer, little is known about the single-agent activity of most anticancer agents in the different histologic types of these cancers. PATIENTS AND METHODS: Twenty patients with advanced or recurrent adenoid cystic carcinoma of the head and neck were treated with epirubicin on a low-dose weekly schedule (30 mg/m2/week) for eight weeks and, in instances of no response, a high-dose three-weekly schedule (> or = 90 mg/m2). Thirteen patients had locoregional disease (12 recurrences), seven of them also had distant metastases and seven had distant metastases only. All had documented progressive disease, and 17 were symptomatic. RESULTS: Two objective responses of 7.5 and 20 months were observed in patients with locally recurrent disease, and ten patients showed disease stabilization. The median time to progression was 16 weeks (range 2-250 weeks) and the median survival 67 weeks (range 13-272+ weeks), with three patients still alive more than five years after the initiation of chemotherapy. Contrary to the rather modest objective response rate, symptomatic improvement occurred more frequently (29.4%) and was evident within 8 weeks of treatment. CONCLUSIONS: This type of chemotherapy should be reserved for patients with rapidly progressive disease or those with symptomatic disease.
Adult↗
Phase II study of oral administration of etoposide for patients with well- and moderately-differentiated adenocarcinomas of unknown primary site.
BACKGROUND: The prognosis of patients with well- and moderately-differentiated adenocarcinomas of unknown primary is poor, as a consequence of chemotherapy resistance. PATIENTS AND METHODS: We performed a phase II study with prolonged oral administration of etoposide in 25 chemotherapy-naive patients with well- and moderately-differentiated adenocarcinomas of unknown primary site. The treatment regimen was 50 mg/m2 for 21 days, every four weeks. RESULTS: Of 24 evaluable patients, two achieved partial responses (8%) lasting 15+ and 17 months, 11 patients had stable disease, and 11 progressed during treatment. The major toxicity was myelosuppression. WHO grades 3 or 4 leukocytopenia was seen in six patients but confined to the first treatment cycle in five of them. Four of these latter five patients already had disease progression after one treatment cycle. A primary tumor site was later identified in four patients, three colon carcinomas and one carcinoma of the pancreas. CONCLUSION: Etoposide given in this dose and schedule has only limited activity in patients with well- or moderately-differentiated adenocarcinomas of unknown primary site.
Adenocarcinoma↗
Piritrexim-induced pulmonary toxicity.
We describe a patient with transitional cell carcinoma of the renal pelvis who developed respiratory dysfunction and an abnormal chest x-ray with diffuse interstitial opacities while on chemotherapy with piritrexim, a methotrexate analog. Drug discontinuation resulted in complete resolution of the clinical and radiographic picture. The pulmonary toxicity is probably induced by piritrexim.
Aged↗
Granulocyte-macrophage colony-stimulating factor allows safe escalation of dose-intensity of chemotherapy in metastatic adult soft tissue sarcomas: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
PURPOSE: This study was designed to test the feasibility of administering doxorubicin at an optimal dose-intensity (> 70 mg/m2 per 21 days) in combination with ifosfamide under recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) cover in patients with metastatic soft tissue sarcomas. PATIENTS AND METHODS: One hundred four eligible patients (of 111 entered) in 16 centers received doxorubicin 75 mg/m2 plus ifosfamide 5 g/m2 every 3 weeks for up to seven cycles. rhGM-CSF (250 micrograms/m2) was administered once or twice daily by subcutaneous injections for up to 14 days between cycles of chemotherapy. RESULTS: Full protocol dose-intensity of chemotherapy was administered to the majority of patients with only 15 of 293 cycles being complicated by febrile episodes that required hospitalization. There were two treatment-related deaths: one from septicemia and one from cardiac failure. The main toxicities attributed to rhGM-CSF were pruritus and rash. A 45% response rate (10% complete remission [CR]) was seen, with a median response duration of 9 months and median survival of 15 months. CONCLUSION: This high-dose regimen of chemotherapy was feasible under rhGM-CSF cover and produced a higher response rate and median survival than previously seen by the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue Sarcoma Group. A randomized phase III study is now underway comparing this regimen with conventional-dose doxorubicin/ifosfamide to test the dose-response relationship.
Adult↗
Cyclophosphamide versus ifosfamide: a randomized phase II trial in adult soft-tissue sarcomas. The European Organization for Research and Treatment of Cancer [EORTC], Soft Tissue and Bone Sarcoma Group.
Ifosfamide (5 g/m2) was compared with its parent analogue cyclophosphamide (1.5 g/m2) in a randomized phase II study. Both drugs were given by 24-h intravenous (i.v.) infusion every 3 weeks along with i.v. bolus infusions of mesna (400 mg/m2), which was given every 4 h for nine administrations. Eligibility criteria included an age of 15-75 years, biopsy-proven advanced metastatic soft-tissue sarcoma, and a World Health Organization performance status of 0-2. Exclusion criteria were prior treatment with classic alkylating agents, a creatinine level of > 150 mumol/l, a bilirubin level of > 20 mumol/l, a leukocyte cell count of < 3.5 x 10(9)/l, and a platelet count of < 100 x 10(9)/l. A total of 171 patients were entered, 24 of whom were ineligible and 12, inevaluable, leaving 135 patients evaluable. In all, 67 patients were treated with cyclophosphamide, and the overall response rate was 7.5%. All responders to cyclophosphamide were patients who had not received prior chemotherapy (13% of 38 patients). Another 68 patients were given ifosfamide, 18% of whom responded to treatment. Of the 28 ifosfamide-treated patients who had received prior chemotherapy, 7% were responders. The response rate for the remaining 40 patients was 25%. The higher overall response rate (P = 0.13) obtained with less myelosuppression in ifosfamide-treated patients suggests that this agent may have advantages over cyclophosphamide in combination therapy.
Adolescent↗
Ifosfamide plus doxorubicin in previously untreated patients with advanced soft-tissue sarcoma.
The objective of this phase II trial was to assess the therapeutic activity and toxicity of doxorubicin plus ifosfamide in previously untreated patients with advanced soft-tissue sarcoma. Treatment consisted of an intravenous bolus injection of doxorubicin at a dose of 50 mg/m2 followed by a 24-h infusion of ifosfamide at 5 g/m2 plus mesna, with therapy being repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Of the 203 patients entered, 175 were evaluable for response. The overall response rate was 35% (95% confidence interval, 28%-42%), with 9% of patients achieving complete responses and 26% showing partial responses. The median time to progression was 29 weeks for all evaluable patients and 67, 40, and 28 weeks for complete and partial responders and patients with stable disease, respectively. The median duration of survival was 58 weeks. Myelosuppression was the dose-limiting toxicity, resulting in leukopenia (World Health Organization grades 3 and 4) in 73% of the evaluable patients. Other side effects were rare and usually well manageable.
Adolescent↗
The use of recombinant human granulocyte-macrophage colony-stimulating factor with combination chemotherapy in the treatment of advanced adult soft-tissue sarcomas: early results from the EORTC Soft-Tissue and Bone Sarcoma Group.
We gave the "optimal" dose of doxorubicin (75 mg/m2) with ifosfamide (5 g/m2), the two most active agents against metastatic soft-tissue sarcomas, in an attempt to determine the feasibility of administration of these doses in combination. To offset complications arising from the myelosuppression associated with this regimen, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF, 250 micrograms/m2 daily) was given by subcutaneous injection during the intervals between courses of chemotherapy. In all, 111 patients with progressive metastatic soft-tissue sarcoma were entered, 104 of whom were eligible for preliminary analysis. Use of rhGM-CSF allowed full doses of chemotherapy to be given to the majority of patients, although cumulative thrombocytopenia became a dose-limiting toxicity during subsequent courses. Two treatment-related deaths occurred, one from presumed septicemia while the patient was at home and one as a result of cardiac failure. An overall response rate of 45% was achieved. The activity of this high-dose combination (with rhGM-CSF) will be compared with that of standard treatment doses in a future phase III randomized trial.
Adult↗