Magnesium hydroxide versus macrogol/electrolytes in the prevention of opioid-induced constipation in incurable cancer patients: study protocol for an open-label, randomized controlled trial (the OMAMA study).

BACKGROUND: Opioid-induced constipation (OIC) is a common symptom in cancer patients treated with opioids with a prevalence of up to 59%. International guidelines recommend standard laxatives such as macrogol/electrolytes and magnesium hydroxide to prevent OIC, although evidence from randomized controlled trials is largely lacking. The aim of our study is to compare magnesium hydroxide with macrogol /electrolytes in the prevention of OIC in patients with incurable cancer and to compare side-effects, tolerability and cost-effectiveness. METHODS: Our study is an open-label, randomized, multicenter study to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. In total, 330 patients with incurable cancer, starting with opioids for pain management, will be randomized to treatment with either macrogol/electrolytes or magnesium hydroxide. The primary outcome measure is the proportion of patients with a score of < 30 on the Bowel Function Index (BFI), measured on day 14. The Rome IV criteria for constipation, side effects of and satisfaction with laxatives, pain scores, quality of life (using the EQ-5D-5L), daily use of laxatives and escape medication, and cost-effectiveness will also be assessed. DISCUSSION: In this study we aim to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. The outcome of our study will contribute to prevention of OIC and scientific evidence of guidelines on (opioid-induced) constipation. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov: NCT05216328 and in the Dutch trial register: NTR80508. EudraCT number 2022-000408-36.

Pharmacological prevention and treatment of opioid-induced constipation in cancer patients: A systematic review and meta-analysis.

BACKGROUND: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients. METHODS: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed. RESULTS: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of oxycodone/naloxone did not show a significant difference in two out of three other studies compared to oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis. Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to oxycodone with laxatives (MD -13.68; 95 % CI -18.38 to -8.98; I2 = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31-0.83; I2 = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64-2.61, I2 = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I2 = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates. CONCLUSIONS: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made.

Impact of integration of clinical and outpatient units on cancer patient satisfaction.

OBJECTIVE: There is an ongoing drive to measure and improve quality of care. Donabedians' quality framework with structure, process and outcome domains provides a useful hold to examine quality of care. The aim of this study was to address the effect of an intervention in hospital structure (integration of three units into one) with the purpose of improving processes (increase meeting, cooperation and communication between professionals and patients) and its effect on the outcome (cancer patient satisfaction). DESIGN: Pre-test-post-test. SETTING: University Medical Center Utrecht, The Netherlands, Department of Medical Oncology. PARTICIPANTS: Cancer patients (n = 174, n = 97). INTERVENTIONS: Physical integration by bringing separately located units (outpatient clinic, day-care clinic, clinical ward) together in one wing of the hospital and adjustments in communication and coordination structures. MAIN OUTCOME MEASURE: Patient satisfaction questionnaire. RESULTS: Satisfaction with care improved for six scales (27%) after integration. Effect sizes (ESs) ranged from 0.36 to 0.80, indicating a small to moderate effect. The most important improvement was found at the day-care clinic on aspects like 'the degree in which the nurses were informed about a patients situation', 'privacy', 'interior design', 'quality of hospital equipment', 'sanitary supplies' and 'waiting periods'. With regard to continuity and coordination of care, satisfaction increased for five items (28% of items concerning continuity and coordination of care). ESs ranged from 0.42 to 0.75. CONCLUSIONS: Integration of three oncology units into one unit had a positive impact on care delivery processes and resulted in improved patient satisfaction concerning care and treatment.

Medical oncology patients' preferences with regard to health care: development of a patient-driven questionnaire.

BACKGROUND: To improve quality of care for cancer patients, it is important to have an insight on the patient's view on health care and on their specific wishes, needs and preferences, without restriction and without influence of researchers and health care providers. The aim of this study was to develop a questionnaire assessing medical oncology patients' preferences for health care based on their own input. PATIENTS AND METHODS: Items were generated using 10 focus group interviews with 51 cancer patients. A preliminary questionnaire was handed out to 681 patients of seven Dutch departments of medical oncology. Explorative factor analysis was carried out on the 386 returned questionnaires (response 57%). RESULTS: Focus group interviews resulted in a preliminary questionnaire containing 136 items. Explorative factor analysis resulted in a definitive questionnaire containing 123 items (21 scales and eight single items). Patients rated expertise, safety, performance and attitude of physicians and nurses as the most important issues in cancer care. CONCLUSION: This questionnaire may be used to assess preferences of cancer patients and to come to a tailored approach of health care that meets patients' wishes and needs.

[The role of consultation in palliative sedation in the central region of the Netherlands]. / De rol van consultatie bij palliatieve sedatie in de regio Midden-Nederland.

OBJECTIVE: To gain insight into the role of consultation in palliative sedation. DESIGN: Retrospective analysis. METHOD: All consultation records of the Palliation Team Midden Nederland (PTMN) from 1 November 2005 to 31 October 2006 were analysed. If palliative sedation was mentioned in the record, the following variables were listed: character of the consultation, data of the questioner, patient data, consultation question, indication for palliative sedation, and character of the advice given. RESULTS: Palliative sedation was a topic in 206 of the 659 consultation records investigated (31%). Intractable delirium, pain, exhaustion, dyspnoea and nausea or vomiting were the most important grounds for palliative sedation. In 47 of the 113 consultations (41%) about starting palliative sedation a negative advice was given, and this was nearly always because there were no intractable somatic symptoms. Existential problems played an important role in 14 of these 113 consultations (12%). In 25 consultations (22%) euthanasia versus palliative sedation was considered explicitly. For these cases there was hardly ever an indication for sedation. CONCLUSION: Palliative sedation was an important reason for consulting the PTMN. The high percentage of negative advice indicates that consultation about palliative sedation has an added value. It gives the questioner the opportunity to check whether all options for treatment have been tried. The question as to whether existential problems are an indication for palliative sedation should be discussed between medical professionals as well as publicly. Palliative sedation rarely is an alternative for euthanasia.

Long-term cardiovascular health in adult cancer survivors.

The number of cancer survivors has tremendously increased over the past decades as a result of aging of the population and improvements in early cancer detection and treatment. Ongoing successes in cancer treatment are expected to result in a further increase in the number of long-term survivors. However, cancer treatment can have detrimental cardiovascular side-effects that impact morbidity and mortality, reducing quality of life in cancer survivors. The spectrum of radiotherapy- and chemotherapy-induced cardiovascular disease is broad, varying from subclinical valvular dysfunction to overt congestive heart failure, and such effects may not be apparent for more than twenty years after the initial cancer treatment. Awareness of these long-term side-effects is of crucial value in the management of these patients, in order to reduce the impact of cardiovascular morbidity and mortality. This review provides a comprehensive overview of the long-term cardiovascular complications of cancer treatments (radiotherapy and chemotherapy) in adult cancer survivors.

Palliative chemotherapy or watchful waiting? A vignettes study among oncologists.

PURPOSE: To determine the preferences of oncologists for palliative chemotherapy or watchful waiting and the factors considered important to that preference. METHODS: Sixteen vignettes (paper case descriptions), varying on eight patient and treatment characteristics, were designed to assess the oncologists' preferences. Their strength of preference was rated on a 7-point scale. An orthogonal main effects design provided a subset of all possible combinations of the characteristics, allowing estimations of the relative weights of the presented characteristics. A written questionnaire was sent to a random sample of oncologists (N = 1,235). RESULTS: The response rate was 67%, and 697 questionnaires were available for analysis. Eighty-one percent of the respondents were male. The mean age was 46 years. We found considerable variation among the oncologists. No major associations between physician characteristics and preferences were found. Of the patient and treatment characteristics affecting treatment preference, age was the strongest predictor, followed by the patient's wish to be treated and the expected survival gain. Other patient and treatment characteristics had a limited effect on preferences, except for psychologic distress, which had no independent impact. CONCLUSION: Patients will encounter different decisions depending on their oncologists' preferences and their own personal background. Therefore, to ensure adequate information for decision-making processes, decision aids are proposed.

Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study.

PURPOSE: To compared the response rates and the toxicity of the new antifolate edatrexate (EDX) with that of methotrexate (MTX) in a randomized trial in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCC) and to compare the durations of response and survival. PATIENTS AND METHODS: Two hundred seventy-three patients with SCC were randomized to receive either EDX or MTX as a weekly intravenous (IV) bolus injection. Doses of EDX were initially 80 mg/m2/wk, but because of the toxicity, this was later reduced to 70 mg/m2/wk. MTX was administered at a dose of 40 mg/m2/wk throughout. In both arms, two dose increments of 10% were scheduled in case of no toxicity. RESULTS: Of 264 eligible patients, 131 were treated with EDX and 133 with MTX. There were five treatment-related deaths: four on EDX and one on MTX. Overall, toxicity was similar in both arms; however, stomatitis, skin toxicity, and hair loss were more pronounced on the EDX arm. The overall response rate was 21% (six complete responses [CRs] and 21 partial responses [PRs]) for EDX and 16% (nine CRs and 12 PRs) for MTX (P = .392). Responses were mainly seen in patients with locoregional disease. Tumors that originated from the hypopharynx responded poorly in comparison to tumors from other sites. The median duration of response was 6.1 months for EDX and 6.4 months for MTX (log-rank P = .262). There was no difference in overall or progression-free survival. The median survival duration was 6 months on both treatment groups. CONCLUSIONS: Both EDX and MTX are moderately active against SCC. In this large phase III study, response rates, time to treatment failure, and overall survival appeared to be similar for both antifolates. However, EDX had more side effects than MTX and therefore cannot be recommended for routine palliative treatment of patients with SCC.

Quality of life in head and neck cancer patients: validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35.

PURPOSE: The aim of this study was to define the scales and test the validity, reliability, and sensitivity of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-H&N35, a questionnaire designed to assess the quality of life of head and neck (H&N) cancer patients in conjunction with the general cancer-specific EORTC QLQ-C30. PATIENTS AND METHODS: Questionnaires were given to 500 H&N cancer patients from Norway, Sweden, and the Netherlands as part of two prospective studies. The patients completed the questionnaires before, during (Norway and Sweden only), and after treatment, yielding a total of 2070 completed questionnaires. RESULTS: The compliance rate was high, and the questionnaires were well accepted by the patients. Seven scales were constructed (pain, swallowing, senses, speech, social eating, social contact, sexuality). Scales and single items were sensitive to differences between patient subgroups with relation to site, stage, or performance status. Most scales and single items were sensitive to changes, with differences of various magnitudes according to the site in question. The internal consistency, as assessed by Cronbach's alpha coefficient, varied according to assessment point and within subsamples of patients. A low overall alpha value was found for the speech and the senses scales, but values were higher in assessments of patients with laryngeal cancer and in patients with nose, sinus, and salivary gland tumors. Scales and single items in the QLQ-H&N35 seem to be more sensitive to differences between groups and changes over time than do the scales and single items in the core questionnaire. CONCLUSION: The QLQ-H&N35, in conjunction with the QLQ-C30, provides a valuable tool for the assessment of health-related quality of life in clinical studies of H&N cancer patients before, during, and after treatment with radiotherapy, surgery, or chemotherapy.

[Palliative sedation]. / Palliatieve sedatie.

Palliative sedation is the intentional lowering of the level of consciousness ofa patient in the last phase of life by means of the administration of sedatives. The objective of palliative sedation is to relieve severe physical or psychological suffering that is otherwise untreatable. Sedation is used in 12% of all patients dying in the Netherlands. Refractory delirium, dyspnoea or pain are the most common indications. If deep palliative sedation is used, the estimated life expectancy should be a few days to at most one week. Midazolam is used most often for continuous sedation, usually by subcutaneous infusion; if the response is insufficient, a combination of midazolam with levomepromazine or phenobarbital or monotreatment with propofol may be used. If continuous infusion is not desired or feasible, intermittent administration of midazolam, diazepam, lorazepam or chlorpromazine may be considered. Provided that it is used under the right circumstances, palliative sedation does not shorten life.

Phase II study of weekly high-dose cisplatin for six cycles in patients with locally advanced squamous cell carcinoma of the head and neck.

In a phase I study of weekly administered cisplatin, we observed a major response in 8 of 9 patients with locally far advanced head and neck cancer. Therefore, a phase II study was initiated to explore the activity and tolerance of this weekly cisplatin regimen. 59 patients with locally advanced head and neck cancer were entered into this phase II study. Cisplatin was administered at a dose of 80 mg/m2 weekly for 6 cycles. Cisplatin was administered in hypertonic saline (3% NaCl) as a 3-h infusion with standard pre- and posthydration. 51 patients were evaluable for response and 55 for toxicity. Only 9 patients were able to complete the treatment with the planned dose intensity of 80 mg/m2/week. Complete disappearance of the tumour was observed in 8 patients and a partial response in 22 (response rate 59%; 51% of all eligible patients 95% CI limits 37-63%). Stable disease was observed in 12 patients, and the tumour progressed in 9 patients. 47 patients subsequently received high-dose radiotherapy, 1 radiotherapy and surgery and 4 patients second-line chemotherapy. The median progression-free survival and median overall survival for all patients were 32 weeks and 56 weeks, respectively. Haematological toxicity consisted of anaemia, leucocytopenia (grade 3 + 4 in 17 patients) and thrombocytopenia (grade 3 + 4 in 17 patients). Because of leuco- and/or thrombocytopenia, treatment was delayed in 30 patients while 13 were taken off the study because of delayed bone marrow recovery. Non-haematological toxicities were: ototoxicity grade 1 in 3 patients, grade 2 in 7 and grade 3 in 3 patients; nephrotoxicity grade 1 in 13 patients, grade 2 in 2 and grade 3 in 1 patient. Neurotoxicity grade 1 was observed in only 8 patients. Cisplatin, as a single agent, administered at high-dose intensity, has an antitumour activity comparable with that of combination regimens in locally advanced head and neck cancer. The pattern of toxicity is different: leuco- and thrombocytopenia jeopardize the dose intensity concept; for patients ototoxicity is the more relevant toxicity. Further studies with weekly cisplatin are of interest particularly with newer measures to reduce toxicity.

Sociodemographic factors and quality of life as prognostic indicators in head and neck cancer.

Pre-treatment quality of life (QOL) has been found to be an independent prognostic factor for survival in cancer patients, in particular in patients with advanced cancer. Sociodemographic factors such as marital and socioeconomic status have also been recognised as prognostic factors. We studied the influence of QOL and mood (measured with the European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) and the Head and Neck Cancer Questionnaire (EORTC QLQ-H&N35), and with the Center for Epidemiologic Studies-Depression Scale (CES-D)) as measured before treatment, the use of cigarettes and alcohol and sociodemographic factors (age, gender, marital status, income and occupation) on recurrence and survival in 208 patients with head and neck cancer prior to treatment with surgery and/or radiotherapy, using Kaplan-Meier and Cox regression analyses. Cognitive functioning and, to a lesser degree, marital status were independent predictors of recurrence and survival, along with medical factors (stage and radicality). Patients with less than optimal cognitive functioning and unmarried patients had a relative risk (RR) of recurrence of 1.72 (95% confidence interval (95% CI) 1.01-2.93) and 1.85 (95% CI 1.06-3.33), respectively, and a RR of dying of 1.90 (95% CI 1.10-3.26) and 1.82 (95% CI 1.03-3.23), respectively. Performance status, physical functioning, mood and global QOL and smoking and drinking did not predict for recurrence and survival. The influence of cognitive functioning might be related to the use of alcohol. Marital status may influence prognosis through mechanisms of health behaviour and/or social support mechanisms.

The content and amount of information given by medical oncologists when telling patients with advanced cancer what their treatment options are. palliative chemotherapy and watchful-waiting.

This study aimed to determine the content and the amount of information given by medical oncologists when proposing palliative chemotherapy and whether this information given is influenced by patient or physician background characteristics. In a prospective study, 95 patients with incurable cancer were interviewed before they consulted their medical oncologist. Their first consultation was audiotaped, and their eventual decision scored. A coding scheme comprised six categories of information given during the consultation. Medical oncologists mentioned or explained the disease course (53%), symptoms (35%) and prognosis (39%). Most patients were told about the absence of cure (84%). Watchful-waiting was mentioned to only half of the patients, either in one sentence (23%) or explained more extensively (27%). Multilevel analysis revealed that the patients' age, patient's marital status, and consulting in an academic hospital explained 38% of the amount of information given. Most of the physicians' attention is spent on the 'active' treatment option. Older patients, married patients and patients in academic hospitals receive more information.

Results of a phase II trial of epirubicin and cisplatin (EP) before and after irradiation and 5-fluorouracil in locally advanced pancreatic cancer: an EORTC GITCCG study.

The objective of the present study was to define the role of chemotherapy, in the form of the EP regimen, consisting of epirubicin (E) and cisplatin (P) in addition to irradiation in combination with 5-fluorouracil (5-FU) for treatment of pancreatic cancer. 53 eligible patients with histologically or cytologically proven locally advanced pancreatic cancer were treated with three cycles of E 60 mg/m2 (if this dose was well tolerated then the dose of E was increased by 10 mg/m2 in the next cycle; 80 mg/m2 was the maximum dose for the following cycles) and P 100 mg/m2 once every 3 weeks, followed after 4 weeks by a split course of irradiation of 40 Gy with 5-FU 500 mg/m2 on each of the first 3 days of each 20 Gy treatment segment. This was followed by another three cycles of EP in patients who achieved stable disease (SD) or a better response after the first three cycles. The treatment given with standard anti-emetics was moderately tolerated. The chemotherapy related toxicity consisted mainly of myelosuppression and the chemoradiotherapy related toxicity of gastrointestinal side-effects. However, due to the long duration of treatment which made the whole treatment difficult to endure, only 18/53 (34%) actually completed the full treatment regimen. Responses were evaluated after the first three cycles and 4 weeks after the completion of the treatment by serial CT-scans using standard criteria. The results in 53 evaluable patients after the first three cycles of EP were as follows: 1 patient achieved a clinical complete response (CR), 7 a partial response (PR) (CR + PR: 15%; 95% confidence interval (CI): 11-33%), 36 patients (68%) had stable disease (SD) and 6 patients progressive disease (PD). There was 1 early PD, 1 toxic death and 1 patient could not be evaluated. The response at the end of the treatment was 3 CR, 11 PR (CR + PR: 14/53 (26%); 95% CI: 15-40%), 30 SD and 6 PD. The median time to progression was 8.9 months and the median duration of response 13.1 months. The median survival of all treated patients was 10.8 months (range 7 days to 41.5 months), of responders 15.1 months and, of the patients with SD 10.3 months. These results are comparable to other combined modality regimens reported in the literature for locally advanced disease. The addition of the systemic treatment with E and P offers no additional advantage to combined modality treatment alone.

A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC Quality of Life Group.

This study tests the reliability and validity of the European Organization for Research and Treatment of Cancer (EORTC) head and neck cancer module (QLQ-H&N35) and version 3.0 of the EORTC Core Questionnaire (QLQ-C30) in 622 head and neck cancer patients from 12 countries. The patients completed the QLQ-C30, the QLQ-H&N35 and a debriefing questionnaire before antineoplastic treatment or at a follow-up. 232 patients receiving treatment completed a second questionnaire after treatment. Compliance was high and the questionnaire was well accepted by the patients. Multitrait scaling analysis confirmed the proposed scale structure of the QLQ-H&N35. The QLQ-H&N35 was responsive to differences between disease status, site and patients with different Karnofsky performance status, and to changes over time. The new physical functioning scale (with a four-point response format) of version 3.0 of the QLQ-C30 was shown to be more reliable than previous versions. Thus, the QLQ-H&N35, in conjunction with the QLQ-C30, appears to be reliable, valid and applicable to broad multicultural samples of head and neck cancer patients.

Hepatic metabolism of paclitaxel and its impact in patients with altered hepatic function.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been demonstrated to be an active anticancer agent, including in platinum-refractory ovarian cancer. The pharmacokinetics of paclitaxel have been extensively described. It displays nonlinear pharmacokinetics in humans, especially when administered in shorter infusion times and at higher doses. Several relationships have been established between pharmacokinetics and pharmacodynamics. In both animal and human studies, hepatic metabolism and biliary excretion have been identified as the main elimination pathways of paclitaxel. It thus can be expected that hepatic dysfunction will have a major impact on the pharmacokinetics of paclitaxel and its main metabolite 6alpha-hydroxypaclitaxel and, thus, on pharmacodynamic outcome (toxicities and responses). Because patients with an altered hepatic function were excluded from most phase I and II studies conducted thus far, little is known about the pharmacokinetics and pharmacodynamics in this group of patients. This report summarizes paclitaxel's metabolism and clinical observations concerning its pharmacokinetics and pharmacodynamics in patients with altered hepatic function. It has been shown that hepatic impairment has a great influence on the systemic exposure of paclitaxel and metabolites with pharmacodynamic consequences. A decrease of biliary elimination is probably the major mechanistic effect that influences paclitaxel metabolism and elimination. Specific dosing guidelines in the treatment of patients with altered hepatic function are required.

Cellular pharmacokinetics of carboplatin and cisplatin in relation to their cytotoxic action.

We have studied the cellular pharmacokinetics of carboplatin (CBDCA), as part of the evaluation of the antitumor activity of CBDCA in cancers limited to the peritoneal cavity in comparison with cisplatin (cDDP). The uptake of CBDCA into L1210 (lymphosarcoma), CC531 (colonic carcinoma), COV413.B (human ovarian carcinoma) and NB1 (human neuroblastoma) cells was 1.5 to 13 times lower than the uptake of cDDP. The uptake of CBDCA into human ovarian carcinoma cells, taken directly from patients, was also 8-20 times lower than cDDP. Platinum concentrations, expressed as a percentage of the total intracellular Pt concentration, were similar for CBDCA and cDDP in cytosol and nucleus/membrane fractions. A second major difference between the drugs was their binding to DNA. Less CBDCA-DNA than cDDP-DNA adducts were formed after incubation at equimolar amounts of drug with isolated salmon sperm DNA (5-25 times less). A 16-69 times higher concentration of CBDCA than cDDP was needed to induce similar changes in cell growth activity (50% [3H]thymidine inhibition) in CC531 and COV413.B cells, indicating that equitoxicity can only be achieved when tumor cells are exposed to higher concentrations of CBDCA than cDDP. Similar toxicity was achieved in CC531 cells after incubation with a 16-fold higher CBDCA dose than cDDP. Comparable intracellular platinum concentrations, however, were obtained with a 10-fold higher CBDCA dose, suggesting that cellular pharmacokinetics of the drugs are different. Regarding drug uptake and pharmacokinetics the mechanism of action of CBDCA differed from cDDP at a cellular level.