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Biomedical subjects

J Verweij

Publications and source records attributed to J Verweij.

At least 19 recordsLinked to original sources
PubMed1992

A dose-finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumours.

The ether lipid miltefosine (hexadecylphosphocholine) was orally given to patients with various tumours in a dose-finding study. All patients initially received a daily total dose of 100 mg, which in the absence of side-effects was increased to 150 mg and further to 200 mg. A total of 54 patients were entered and were evaluable for gastrointestinal toxicity. Nausea and vomiting were found to be dose-limiting; 22% of patients ultimately tolerated a dose of 100 mg, 59% tolerated a dose of 150 mg and 19% tolerated a dose of 200 mg. In addition 30% of patients developed renal dysfunction, which was thought to be related to the drug. No other toxicities were observed. For further phase II studies it is recommended that one starts with a dose of 150 mg daily, divided over three administrations.

Adult↗
PubMed1992

Weekly low-dose mitoxantrone plus doxorubicin as second-line chemotherapy for advanced breast cancer.

Weekly low dose mitoxantrone (3 mg/m2) plus doxorubicin (8 mg/m2) was administered as second-line chemotherapy to 33 patients with advanced breast cancer. Four out of 28 evaluable patients (14%) obtained a partial response with a median duration of 34 weeks (range 18-67+ weeks), while 8 patients (29%) showed stable disease with a median duration of 28 weeks (range 11+-60 weeks). Gastrointestinal toxicity and alopecia were mild. Grade II and III leukopenia occurred in 63% of the courses without serious infectious disease. Four patients experienced an asymptomatic drop of 16-20% in the left ventricular ejection fraction (LVEF) after relatively low cumulative doses of each drug, and one patient with a history of pericarditis carcinomatosa and mediastinal irradiation developed a heart failure. In conclusion, this second-line combination treatment had moderate activity in breast cancer and caused only few subjective side effects, especially with respect to gastrointestinal symptoms.

Adult↗
PubMed1992

Phase I study of intravenous fosquidone (GR63178A-NSC D611615) using a three times a week schedule.

In a Phase I study fosquidone was administered to 23 patients (15 female, 8 male; mean age 53.6 years) with various solid tumours. Increasing doses (50-325 mg/m2) were given intravenously three times a week for 3 weeks. The MTD was established a 325 mg/m2 dose, the dose limiting factor being phlebitis in two of three patients. The other main side-effects were headache (9 patients), pain (11 patients) and nausea and vomiting (16 patients). The majority of these were mild (WHO grade 1-2), but two patients reported WHO grade 3 and 4 pain. There was no clear relationship between dose, severity and frequency of side-effects. Four tumour regressions (three minor and one partial response) were achieved at varying dose levels (50, 100, 160 and 325 mg/m2) in patients with different tumours (laryngeal, colorectal and lung). The recommended dose for Phase II studies is 250 mg/m2 given intravenously three times a week for 3 week.

Adult↗
PubMed1992

A phase II trial of 10-ethyl-10-deaza-aminopterin, a novel antifolate, in patients with advanced and/or recurrent squamous cell carcinoma of the head and neck. The EORTC Head and Neck Cancer Cooperative Group.

Forty-seven patients with advanced and/or recurrent squamous cell carcinoma of the head and neck were treated with 10-ethyl-10-deaza-aminopterin (10-EdAM), a new analogue of methotrexate. The drug was given as a weekly i.v. bolus injection, starting at 80 mg/m2 with two dose increments of 10% if no toxicity was observed after two weeks. Only patients with tumors of the larynx, oral cavity, oropharynx and hypopharynx were included in the trial. Eighty-two percent of the patients had had prior surgery and/or radiotherapy. Forty-four patients were evaluable for response and toxicity. Five CR (12%) and five PR were obtained, yielding a response rate of 24% (CR+PR). The toxicity was similar to that usually seen with methotrexate; stomatitis and skin toxicity were rather pronounced. The data suggest that 10-EdAM has activity similar to that of methotrexate in patients with head and neck cancer.

Adult↗
PubMed1992

Frequent administration of Dabis Maleate, a phase I study.

Dabis Maleate (1,4-bis(2'-chloroethyl)-1,4-diazabicyclo[2.2.1] Heptane dihydrogen dimaleate) (NSC 262666) is an alkylating quaternary nitrogen compound. In a previous phase I study using a once-every-3-weeks administration the dose-limiting toxicity was neurotoxicity and the recommended dose for phase II studies was 750 mg/m2 iv every 3 weeks. In vitro studies suggested a higher activity after more frequent administration, and in vivo studies a better therapeutic index with prolonged infusion. We studied 11 patients with solid tumors. Dose levels tested ranged from 250-750 mg/m2, either as a day 1-3 regimen or weekly, the latter as bolus administration or as prolonged infusion. The dose-limiting toxicity was neurotoxicity consisting of paresthesias and ataxia. Nausea and vomiting were moderate. No other major toxicity was observed. The dose recommended for phase II studies is 500 mg/m2/week as a 6-hour iv infusion for 6 weeks, followed by a 3-week rest period.

Aged↗
PubMed1992

Phase II trials of fosquidone (GR63178A) in carcinoma of the breast, head and neck, ovary and melanoma.

A total of 91 eligible patients with metastatic cancer have been treated in a series of phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were breast (24), ovary (25), head and neck (21) and melanoma (21). All patients, except those with melanoma had received prior chemotherapy. The drug was given intravenously as a 20 min infusion, at the dose of 120 mg/m2 on days 1 to 5 of a 3 week cycle. Treatment was well tolerated; the only significant side-effects being mild headaches and generalised musculo-skeletal pains. Response was assessed after 2 cycles of therapy. Only one patient (with head and neck cancer) achieved an objective partial response, lasting 6 weeks. A total of 12 patients demonstrated stable disease for a median duration of 15 to 20 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours.

Adult↗
PubMed1992

Phase II study of edatrexate in chemotherapy-naive patients with metastatic breast cancer.

A phase II trial of the new antifolate edatrexate (10-ethyl-10-deaza-aminopterin) was performed in thirty-eight patients with metastatic breast cancer who had never received chemotherapy. Edatrexate was administered as a weekly intravenous bolus injection at a dose of 80 mg/m2. Sites of metastases included visceral (31%), soft tissue/lymph node/bone (51%), and bone only (18%). Thirty-two patients were evaluable for response; there were 3 complete responses (CR) and 8 partial responses (PR), yielding a response rate (CR plus PR) of 34% (95% confidence limits, 17.9% to 50.9%). Responses were seen in soft tissue metastases, in visceral metastases (liver, lung) and in one patient with bone metastases. Median duration of response was 30 weeks (range 12-66 weeks). Substantial toxicity was observed. The dose-limiting toxicities were mucositis, myelo-suppression and skin toxicity. The general toxicity profile was similar to that usually reported for methotrexate, but mucositis and skin toxicity were more pronounced. Edatrexate appears to be an active drug in the treatment of chemotherapy-native patients with metastatic breast cancer.

Adult↗
PubMed1992

Experience with ifosfamide in the EORTC Soft Tissue and Bone Sarcoma Group.

The Soft Tissue and Bone Sarcoma Group of the European Organization on Research and Treatment of Cancer has conducted a number of studies of chemotherapy in advanced disease over the past 15 years. Following the discovery that the CYVADIC regimen (cyclophosphamide/vincristine/doxorubicin/dimethyl imidazole carboxamide) was less active than had been reported originally, the individual components of CYVADIC were studied. This showed that doxorubicin had considerable activity and that ifosfamide 5 g/m2 given over 24 hours was at least as active as cyclophosphamide. Subsequent studies have therefore centered on a combination of doxorubicin and ifosfamide. A large randomized trial showed no significant benefit of doxorubicin/ifosfamide over single-agent doxorubicin, but the doses of doxorubicin were different. More recently, using bone marrow growth factors, it has been possible to increase the doxorubicin dose to that given as a single agent and also maintain the ifosfamide dose. This is now being tested in a randomized trial to determine whether improved response rates and other indicators of outcome will be seen.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

The multidisciplinary approach to treatment of soft tissue sarcomas.

Soft tissue sarcomas are rare tumors including many histological subtypes. They are pre-eminently tumors for which the multidisciplinary approach to treatment is of utmost importance. The two most frequently applied staging systems both require experienced assessment of radiology and pathology, and stage is a prominent prognostic factor for survival that guides the choice of treatment modalities. For primary treatment radical surgery is still the backbone. In many instances postoperative radiotherapy is a valuable and often necessary complementary treatment. The role of preoperative radiotherapy and/or chemotherapy needs to be defined although preliminary results are interesting. Chemotherapy as an adjunct to surgery should still be considered investigational. In metastatic disease "standard" chemotherapy has a definitive though moderate activity, but recent data on dose-intensified chemotherapy suggest that results may be further improved.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

CA 125 in ovarian cancer.

The serum tumour marker CA 125 is useful in the management of ovarian cancer, although it has its limitations. Approximately 85% of the ovarian cancer patients have an increased serum CA 125 at the start of treatment. There is a good correlation between the course of CA 125 and the clinical response of the tumour. Patients with an increasing CA 125 are found to have progressive disease in 97%. In these patients further examinations to document progression should be performed. A decrease in serum CA 125 corresponds in 87% of the patients with tumour regression. A normal serum CA 125, however, does not exclude tumour. More than 40% of the patients with a normal CA 125 still have microscopic or macroscopic tumour at second look surgery. On the other hand, an increased serum CA 125 corresponds in 90% of the patients with the presence of tumour or tumour progression shortly after the second look. The same holds for secondary debulking surgery. Patients with an increasing serum CA 125 before secondary debulking surgery have progressive disease at or shortly after surgery, even if an adequate tumour debulking has been performed. In these patients surgery should be omitted as long as no effective second line therapy is available. The course of serum CA 125 during the first 3 months of treatment is of prognostic value for response rate as well as time to progression and overall survival. Patients with a serum half-life of more than 20 days, or a CA 125 which is still high 3 months after the start of treatment, have a significantly lower response rate and progression-free survival. Whether it is possible to improve the prognosis of these patients by dose-intensification will have to be investigated in randomized trials. Serum CA 125 is not specific for ovarian cancer. High levels can also be found in patients with non-ovarian gynaecological and non-gynaecological tumours as well as patients with benign diseases and even in apparently healthy persons. In view of this aspecificity, serum CA 125 cannot be proposed for mass screening. For the same reason, serum CA 125 and the immunohistochemical staining with OC 125 are of limited value in the differential diagnosis between a primary ovarian tumour and metastatic disease in an ovary, as well as for differential diagnosis of pelvic tumours.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1991

Controlling cancer chemotherapy-induced emesis. An update.

Cytotoxic chemotherapy can induce acute, delayed and anticipatory nausea and vomiting. The efficacy and toxicity data of the available anti-emetics and their role in chemotherapy-induced emesis are reviewed. Moreover, some pitfalls in the methodology of anti-emetic trials as well as factors known to affect the individual sensitivity of patients for the emetic challenge are illustrated. So far, high-dose metoclopramide (3-6 mg.kg-1.d-1) was the most effective single agent in the control of acute emesis. However, extrapyramidal reactions caused by its dopamine antagonism remained a major drawback. The addition of dexamethasone and/or lorazepam decreases the incidence of extrapyramidal reactions, and further improves anti-emetic control. In animals, serotonin type 3 receptor antagonists have demonstrated promising anti-emetic results against chemotherapy-induced and radiotherapy-induced emesis; the results of clinical studies are awaited. Delayed nausea and vomiting have not been studied as extensively. At present, the combination of metoclopramide and dexamethasone offers an optimal protection in approximately 50% of patients on cisplatin chemotherapy. Anticipatory nausea and emesis remain major problems, and an effective pharmacological treatment is lacking. Attempts to control this type of emesis focus on drugs with amnesic properties and on behaviour therapy.

Antiemetics↗
PubMed1991

Pathophysiology of cytotoxic drug-induced emesis: far from crystal-clear.

Both radiotherapy and chemotherapy for cancer are capable of causing severe nausea and vomiting, which formerly often interfered with the patient's compliance to treatment. The basic pathway and pharmacological mechanisms involved in this are still poorly understood. The recent discovery, however, that 5-HT3 receptor antagonists can prevent or greatly reduce chemotherapy-induced emesis led to a re-evaluation of the sequence of events occurring in the protective emetic reflex, which are reviewed in this paper. The vomiting centre co-ordinates the incoming and outgoing information, and is thought to be represented by complex interactions between different adjacent areas in the brainstem. Whether the main role in the emetic reflex arch is accomplished by either the central part (chemoreceptor trigger zone) or the peripheral part (gastro-intestinal tract) needs further confirmation A more important role, however, of the vagal nerve and the gastro-intestinal tract is generally accepted. The neurotransmitter serotonin (5-HT) appears to play a major role in chemotherapy-induced emesis via the 5-HT receptor. These indications could form the basis for further investigations into the involvement of other neurotransmitters, and the character of their interactions.

Animals↗
PubMed1991

Doxorubicin plus ifosfamide with rhGM-CSF in the treatment of advanced adult soft-tissue sarcomas: preliminary results of a phase II study from the EORTC Soft-Tissue and Bone Sarcoma Group.

Doxorubicin and ifosfamide are the two most active agents used in the treatment of advanced inoperable soft-tissue sarcoma, but their use in combination produces dose-limiting myelosuppression. To explore the feasibility of combining optimal doses of both drugs, doxorubicin (75 mg/m2) and ifosfamide (5 g/m2) were given every 3 weeks with recombinant human granulocyte/macrophage-colony-stimulating factor (rhGM-CSF; 250 micrograms m-2 day-1) by subcutaneous injection for up to 14 days after each course. A total of 52 patients with progressive metastatic soft-tissue sarcoma were entered, none having received prior chemotherapy. One patient was ineligible and received no treatment after registration. Preliminary analysis of six cycles of chemotherapy revealed that the full protocol dose intensity had been administered to the majority of patients. Although the median leucocyte and neutrophil counts did not fall with subsequent courses of chemotherapy, the duration of neutropenia increased with each course delivered. Cumulative thrombocytopenia was a major dose-limiting toxicity and was the main reason for any dose modifications that occurred. Although 26 patients experienced infections after one or more courses of treatment, in only 7 was admission required for parenteral antibiotics. One patient died as a result of septicaemia after the first cycle of treatment. To date, there have been 22 responses (43%) with 8% complete remissions. It appears that the administration of rhGM-CSF allows this high-dose regime of chemotherapy to be given safely and the early encouraging response rate adds support to the concept that increasing the dose of doxorubicin improves the outlook for patients with advanced soft-tissue sarcomas.

Adult↗
PubMed1991

Randomised phase II trial of carboplatin and iproplatin in advanced urothelial cancer.

47 patients with advanced urothelial cancer and no prior chemotherapy were randomly assigned to therapy with either carboplatin or iproplatin. Both platinum analogues were administered intravenously every 28 days at doses of 400 mg/m2 carboplatin and 300 mg/m2 iproplatin. None of 14 evaluable patients treated with carboplatin responded. Therefore, this arm was closed and from then on all eligible patients were registered on the iproplatin arm. 5 of 29 evaluable patients treated with iproplatin achieved a partial response (17%) for a median duration of 27 weeks (range 22-37). Iproplatin did not induce renal function disturbance. Gastrointestinal toxicity was mild to moderate. Bone marrow toxicity predominantly consisted of thrombocytopenia and required platelet transfusions in 13% of patients. 2 patients developed hypersensitivity reactions. It is concluded that the bone marrow toxicity and the chance of hypersensitivity render iproplatin an unattractive alternative to cisplatin.

Adult↗