Long-term safety of monthly zoledronic acid therapy beyond 1 year in patients with advanced cancer involving bone (LoTESS): A multicentre prospective phase 4 study.

Malignant bone disease can cause significant morbidity. Monthly zoledronic acid (ZOL) reduces skeletal complications; however, limited data are available regarding long-term safety. We aimed to assess efficacy and safety of ZOL beyond 1 year of treatment. We prospectively evaluated 73 patients; breast cancer (n = 29), castrate-resistant prostate cancer (n = 13), multiple myeloma (n = 31) from 2006 to 2008 in 19 cancer centres. All patients were diagnosed with bone disease and had completed 1-2 years of monthly ZOL (4 mg) and received a further 1-2 years of therapy following contemporary guidelines for managing risks of osteonecrosis of the jaw (ONJ) and renal toxicity. Overall rates of skeletal-related events (SREs), renal impairment and ONJ were assessed. Over the additional 1 year of treatment, only 5.5% (n = 4) of patients developed a new SRE. The overall Kaplan-Meier estimate for SRE incidence after 48 weeks on study was 6.75% (95 CI: 2.5-17.3). Although 51% of patients reported serious adverse events, only two cases were suspected as ZOL related. No patients had confirmed ONJ. The observed incidence of new renal impairment was 11% (none due to ZOL). Our study confirms the benefit over risk of continuing monthly ZOL for at least 2 years in patients with advanced cancer involving bone.

Blood-brain barrier disruption and methotrexate in the treatment of a readily transplantable intracerebral osteogenic sarcoma of rats.

An animal model of intracerebral osteogenic sarcoma has been developed to evaluate blood-brain barrier disruption as an adjunct to chemotherapy of intracerebral tumors. Adult Sprague-Dawley rats (n = 225) were inoculated intracerebrally with transplantable, methotrexate sensitive, osteogenic sarcoma cells and 3 days later randomized to receive either no treatment or methotrexate with or without blood-brain barrier disruption using intracarotid mannitol. Methotrexate was administered i.v., i.p., or directly into the carotid artery (i.c.) in doses of 2.5, 10, 20, 50, or 100 mg/kg. Survival was the study's end point. Surgery, anaesthesia, or blood-brain barrier disruption with mannitol did not affect survival. However, there was a significant effect of dose and route of administration of methotrexate on survival. The shortest survival was in rats receiving no treatment in which death occurred reproducibly at 7.6 +/- 0.2 days (n = 29) and the longest survival was 12.7 +/- 0.3 day (p less than 0.001) in those given methotrexate 50 mg/kg i.c. (n = 6). The i.c. route was most effective in prolonging survival followed by i.v. and the least effective was the i.p. route of methotrexate administration. Blood-brain barrier disruption followed by methotrexate (i.v. or i.c.) was deleterious to survival (two-way analysis of variance, p less than 0.003 and p less than 0.011, respectively) and the reduced survival was in part related to early complications such as intratumor hemorrhage or possibly a methotrexate induced encephalopathy. It is concluded that this is a useful model for the study of the chemotherapy of cerebral tumors, that blood-brain barrier disruption did not appear to improve the dose-response curve but resulted in reduced survival. We caution against the use of this procedure in the treatment of cerebral tumor in humans.

Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.

Flare responses in small cell carcinoma of the lung.

Two cases of small cell carcinoma of the lung in which flare responses were demonstrated are discussed. Although the primary tumor and extraskeletal metastases responded to first-line chemotherapy, bone scintigraphs performed 3 months after the start of treatment suggested tumor progression. However, following repeat bone imaging and subsequent clinical evaluation, the interim scintigraphs appeared to represent an unusual flare response, in which the activity of pre-existing hot spots increased and new lesions developed.

The effect of penicillamine and related thiols on cyclophosphamide-induced cystitis and bone marrow suppression.

When adult male Wistar-Kyoto rats had been injected intra-peritoneally with a dose of 100 mg/kg of cyclophosphamide (CP), their urinary bladders showed changes of thickening and haemorrhage visible macroscopically, and oedema, necrosis and haemorrhage of the mucosa visible microscopically. There was an increase in bladder weight from an average of 60 mg in untreated control rats to an average of 125 mg in the CP-treated rats. When in addition they had been given 400 mg/kg of a thiol drug, namely either penicillamine or its disulphide, or N-acetylcysteine (NAC) or its S-carboxymethyl derivative carbocysteine, the increase in bladder weight and the histologic changes of haemorrhagic cystitis were found to be prevented by the co-administration of penicillamine or NAC but not by penicillamine disulphide or carbocysteine. The leucopenia caused by CP was not prevented by co-administration of these thiol drugs. It is concluded that penicillamine, like NAC, is effective in preventing CP-induced cystitis but not at the expense of reducing the cytotoxicity of CP. The inefficacy of penicillamine disulphide and carbocysteine suggests that significant dissociation of the disulphide does not occur in vivo and that the thiol moiety is important in preventing the cystitis. Penicillamine, a thiol compound with anti-rheumatic and possible anti-tumour effects, may thus prove to be a very useful adjunct to CP therapy.

How to assess thinking skills in cancer patients.

This article emphasizes the importance of health care professionals assessing and working with the way cancer patients think. Health care professionals can help cancer patients think more effectively about the organic manifestations of their disease, problems that arise from the cancer experience, and problems unrelated to cancer, but which negatively influence their lives. Nine thinking skills areas are identified and described. Skills that health care professionals can use to assess patients' thinking, and to gain insight into their own thinking, are reviewed. In addition, suggestions are made for how patients can be helped to overcome thinking skills weaknesses and build their strengths so that they can optimize their chances of quality life.

Interaction of epirubicin with other cytotoxics and anti-emetic drugs.

Epirubicin is usually administered in combination with other cytotoxics. Few pharmacological studies address whether relevant clinical interactions occur in vitro between these drugs. This study investigated whether epirubicin interacted with other cytotoxics or anti-emetics. The following drugs were prepared at pharmacological concentrations, etoposide (200 micrograms/ml), 5-fluorouracil (120 micrograms/ml), cisplatin (100 micrograms/ml), vincristine (100 micrograms/ml) and cyclophosphamide (1 micrograms/ml) respectively were admixed with epirubicin (1 micrograms/ml). Epirubicin was analysed by high performance liquid chromatography using in-line UV and fluorescence detectors. Experiments were performed in quadruplicate. No significant interactions were noted. The experiments were repeated for stemetil and maxolon. Maxolon did not interact with epirubicin but stemetil produced an interfering peak in the assay. We conclude that interaction studies are an important step in the workup of chemotherapy regimens.

Comparison of high-performance liquid chromatography and the Abbott fluorescent polarization radioimmunoassay in the measurement of methotrexate.

A modified high-performance liquid chromatographic (HPLC) technique for the assay of methotrexate is described and compared to the Abbott Fluorescence Polarization Radioimmunoassay. The reproducibility (coefficient of variation) at low concentrations was similar for the two assays: 8.1 and 8.5% for the Abbott and HPLC assay, respectively. The limit of detection of the two assays was also similar at 0.01 microM. The correlation coefficient for Abbott versus HPLC was 0.9833 with a gradient of 0.9545. Aspirin was the only drug that interfered with HPLC. Methotrexate's metabolite 7-hydroxymethotrexate did not interfere with the Abbott assay. Plasma half-lives were similar to oncology patients in the two rheumatological patients studied. The 7-hydroxymethotrexate half-life was 15 h.

In vitro binding of MX2 (KRN8602) and epirubicin to human plasma protein.

This study compares the human plasma protein binding characteristics of MX2 and epirubicin. The binding characteristics were determined by equilibrium dialysis at various concentrations of the drugs. The binding dissociation constant (Kd), binding capacity (Bmax) and partitioning constant (Kp) were obtained by Scatchard analysis of the free and bound drugs in the dialysis compartments. Our results have demonstrated that plasma protein binds epirubicin or MX2 in an unsaturable appearance over the concentration up to 150 mumol/l. At the same concentrations, plasma protein binds more epirubicin than MX2. The nature of the interaction may consist of two classes of specific binding, and a partitioning. The binding dissociation constants were 18 and 17.5 mumol/l for the higher binding class (Kd1) and 315.8 and 316.9 mumol/l for the lower binding class (Kd2), respectively, for epirubicin and MX2. The respective maximum binding capacities (Bmax) of plasma protein for epirubicin and MX2 were significantly different, 0.045 and 0.029 mumol/g protein for the higher binding class (Bmax1), and 0.39 and 0.29 mumol/g protein for the lower binding class (Bmax2). The partitioning constants (Kp) were 21.5 x 10(-5) and 20 x 10(-5) litres/g protein for epirubicin and MX2, respectively. The results suggest that plasma protein binds epirubicin or MX2 with a similar affinity, but has less binding sites for MX2. One contributing mechanism to the difference in activity noted between epirubicin and MX2 may be changes in free drug fractions.

Studies on the cytotoxicity of penicillamine in a rat osteogenic sarcoma.

The effect of penicillamine on the growth rate of an osteogenic sarcoma of rats was investigated and compared with cyclophosphamide. Rats were inoculated with a readily transplantable osteogenic sarcoma subcutaneously into the left thigh and treated with penicillamine and cyclophosphamide alone or in combination. Cyclophosphamide inhibited tumour growth. Penicillamine did not delay the appearance or the growth rate of the tumour. Tumour sizes tended to be larger in the penicillamine-treated rats, but there was no evidence that penicillamine interfered with the antitumour effect of cyclophosphamide given in large doses (100 mg/kg).

Prolonged release of morphine alkaloid from a lipophilic suppository base in vitro and in vivo.

The in vitro release characteristics of four suppository formulations of morphine (15 mg) were investigated using the USP rotating basket dissolution apparatus. Morphine hydrochloride in polyethylene glycol (PEG), a hydrophilic suppository base, morphine alkaloid in PEG and morphine hydrochloride in Novata BBC (a lipophilic suppository base) completely released the drug within 25 min whereas, morphine alkaloid in Novata BBC (MAN) released the drug over 10 h. The absorption of the morphine hydrochloride/PEG (MHP) suppository was compared with that of a 15 mg oral solution in eight patients with malignant disease in a crossover design. Time of peak plasma morphine concentration (tmax) was similar for both preparations (1.8 +/- 1.6 h and 1.2 +/- 0.5 h, respectively; p > 0.05), showing that the MHP suppository was rapidly absorbed. The MAN and MHP suppositories were then compared in a further nine patients in a crossover design. Prolonged release of morphine from the MAN suppository was also evident in vivo as tmax (2.5 +/- 1.4 h) was significantly greater than that for the morphine hydrochloride/PEG suppository (0.7 +/- 0.3 h; p < 0.002). There was no significant difference in AUC (0-7 h) (34.5 +/- 19.2 versus 38.9 +/- 16.1 ng.h/ml, respectively; p > 0.05) indicating a similar amount of morphine absorbed. Plasma morphine concentrations were more sustained for 7 h after dosage with the MAN suppository, with lower peak (8.3 +/- 4.9 and 12.3 +/- 6.6 ng/ml, respectively) and higher 6 h plasma morphine concentrations (5.81 +/- 4.85 and 3.30 +/- 1.0 ng/ml, respectively; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood-brain barrier disruption using mannitol: time course and electron microscopy studies.

Blood-brain barrier disruption with a hyperosmolar agent, mannitol, has previously been demonstrated to increase intracerebral methotrexate levels in rats. To determine the optimum conditions for blood-brain barrier disruption without producing neurological sequelae, adult Sprague-Dawley rats were infused with mannitol via the internal carotid artery at rates varying from 0.25 to 0.5 ml.s-1.kg-1. Methotrexate and Evans blue were used as markers of blood-brain barrier disruption. The optimum rate of mannitol that produced blood-brain barrier disruption without neurological sequelae was 0.25 ml.s-1.kg-1 for 20 s. The duration of blood-brain barrier opening was maximal for approximately 5 min and then rapidly reversed. Methotrexate levels on the mannitol-infused side were four to five times that of the noninfused hemisphere. Light microscopy and electron microscopy did not demonstrate any consistent changes that could be attributed to blood-brain barrier disruption nor did it elucidate the mechanism. This model should prove useful in the investigation of the treatment of intracerebral tumors with blood-brain barrier disruption. This study shows that maximal intracerebral methotrexate levels were obtained when methotrexate was infused before or within 5 min of the mannitol infusion.

Interaction of cisplatin with other cytotoxics and non-steroidal anti-inflammatory drugs.

This study investigated a possible interaction between cisplatin, other cytotoxics and non-steroidal anti-inflammatory drugs. Experiments were performed in quadruplicate. Plasma was spiked with cisplatin with or without another cytotoxic or non-steroidal anti-inflammatory drug. The results were analysed by Student's t-test and a p value of less than 0.05 was accepted as statistically significant. No interaction between cisplatin and the other cytotoxics was demonstrated. However, an increase in free cisplatin was noted when mixed with indomethacin (p = 0.019). No interaction with the other non-steroidal anti-inflammatory drugs was demonstrated.

Classical Kaposi's: a rare cause of gastrointestinal haemorrhage.

Classical Kaposi's sarcoma (KS) is an indolent neoplasm involving mucocutaneous sites predominantly in elderly Mediterranean or Jewish persons. Whilst gastrointestinal involvement is common, it is usually asymptomatic. This case report presents a case of massive gastrointestinal haemorrhage in a patient with stable cutaneous disease and outlines options for the investigation and management of this rare complication.

Quality of pharmacokinetic research in oncology.

The usefulness of pharmacokinetically guided individualisation of drug therapy will depend, among other things, on the quality of the analytical and pharmacokinetic methods used. We surveyed the quality of analytical and pharmacokinetics methodology and reporting in a literature search of the oncology literature from 1987 to 1992, using the Medline database. Thirty articles that examined relationships between normal tissue toxicity and area under the plasma concentration-time curve (AUC) formed the study sample. Analytical procedures were adequately described in 77% of the articles, but details of validation of the assay were seriously deficient in the great majority of articles. Methods for calculation of AUC were also deficient in over half of the articles. The findings suggest that greater attention needs to be paid to the quality of pharmacokinetic investigation in oncology, otherwise progress in the use of pharmacokinetically guided individualisation of dosage may be hindered.

Patients' beliefs about cancer management.

The results of a questionnaire answered by 205 medical patients are reported (100 patients with cancer and 105 with other medical conditions). The questionnaire examined beliefs and preferences regarding various aspects of cancer, including expectations of medical management and treatment. The issues examined relate to beliefs and preferences about information giving, trust of doctors' control of decision making, expectations of help, expectations of treatment, the treatment of cancer pain including morphine use, and issues of terminal care. Some patients appear to hold the inconsistent beliefs that doctors should tell them all they want to know, but that doctors do not know a lot of what they would like to be told. They were also ambivalent about who should make decisions, patient or doctor, suggesting a preference for collaborative consensus decision making. It may be important to inform patients more clearly about what doctors can and cannot reasonably be expected to know and do. Some incorrect beliefs about management were related to fear about having cancer. The results suggest the need for better communication between patients and their professional carers and the need for accessible health information about cancer management to be available to the general public.

Lean body mass, body surface area and epirubicin kinetics.

For a number of cytotoxics, a relationship between efficacy and plasma concentrations has recently been demonstrated. Lean body mass has been demonstrated to be a useful parameter for predicting drug clearance for a number of non-cytotoxic drugs. However, the role of lean body mass in predicting drug clearance for any cytotoxic drug has not been previously reported. Our purpose was to investigate lean body mass as a predictor of epirubicin clearance. Pharmacokinetic studies were performed in 10 patients receiving single agent epirubicin. Although preliminary, this study suggests that lean body should be further evaluated and tested in dose optimization studies.

Accuracy of volume measurement using helical CT.

PURPOSE: Our goal was to determine the accuracy of volume estimation using helical CT. METHOD: Helical CT scans were conducted with regularly and irregularly shaped polyvinylchloride bags containing saline of varying volumes immersed in peanut oil during various rates of movement of 0, 10, 15, and 20 cycles/min, using a motorized platform, designed to simulate respiratory motion. Ten cancer patients were scanned with CT to determine optimum upper and lower Hounsfield unit thresholds. The volumes of two human livers and kidneys were also measured in vitro under the same conditions. RESULTS: For all conditions, the accuracy and bias of volume estimation for saline bags ranged from 95.0 to 99.2 and -3.46 to 4.04%, respectively, and the accuracy and bias for the estimation of liver and kidney volumes were 95.6 and 3.12%, respectively. CONCLUSION: This study shows that helical CT is a highly accurate technique for estimating volume, even in the presence of simulated respiratory motion.

Relationships among liver and kidney volumes, lean body mass and drug clearance.

AIMS: To determine whether lean body mass (LBM), a possible surrogate of liver and kidney volumes, correlates with hepatic and renal drug clearances. METHODS: Twenty-one disease-free patients with a history of cancer and with normal hepatic and renal function were studied. Salivary pharmacokinetics of oral antipyrine (1200 mg) and 24 h creatinine clearance were determined following the determination of LBM by dual energy X-ray absorptiometry and the determination of liver and kidney volumes by helical CT scanning. RESULTS: Liver volume correlated with LBM (r2=0.21, P=0.04), body surface area (BSA) (r2=0.54, P<0.001), and total body weight (TBW) (r2=0.61, P<0.001). Kidney volume correlated with LBM (r2=0.49, P<0.001), BSA (r2=0.43, P=0.002) and TBW (r2=0.24, P=0.03). Stepwise multiple regression analysis, incorporating the independent variables of age, height, weight, sex, BSA, LBM, alcohol consumption, smoking status and liver volume and the dependent variable antipyrine clearance, indicated that LBM was the only independent correlate of antipyrine clearance. A stepwise multiple regression analysis with kidney volume in the independent variables, and creatinine clearance as dependent variable, showed that kidney volume and age were the only independent correlates of creatinine clearance. A nomogram using serum creatinine and LBM was comparable with the Cockcroft and Gault nomogram in calculating creatinine clearance. CONCLUSIONS: Of the anthropometric variables tested, LBM was the only determinant of antipyrine clearance, but this was not due to a relationship between LBM and liver volume. By contrast, the relationship between creatinine clearance and LBM appeared to be due to a relationship between LBM and kidney volume.