Palliative radiotherapy for lung cancer: two versus five fractions.

The aim of this prospective randomized trial was to compare the symptomatic effects of two different regimens of palliative radiotherapy for lung cancer. Two hundred and sixteen patients needing palliation were randomized to receive either a 17 Gy mid-point dose in two fractions 1 week apart or 22.5 Gy in five daily fractions. Both toxicity and efficacy were evaluated by postal questionnaires. This small study was intended to identify any clinically important differences in toxicity or efficacy between the two regimens. We detected no such difference, although there was a tendency for iatrogenic dysphagia and improvement in chest pain and cough to be more common with the two-fraction regimen. The only symptom that was improved in over 50% of patients for 8 weeks or more was haemoptysis. Haemoptysis and chest pain appeared to be the best indications for treatment. The relief of other symptoms was disappointing in both degree and duration.

Lack of stereoselectivity in the pharmacokinetics and metabolism of the radiosensitizer Ro 03-8799 in man.

During a clinical toxicity study it was possible to obtain urine samples from six patients receiving either the R-(-)- or S-(+)-stereoenantiomeric forms of the developmental 2-nitroimidazole radiosensitizer Ro 03-8799 (pimonidazole). Paired plasma samples were also obtained from four patients. The pharmacokinetic data were compared with those for the racemic mixture in the same individuals. The results revealed no major differences in the plasma pharmacokinetics, urinary clearance or N-oxidation of the individual enantiomers as compared with the racemic mixture. A similar lack of stereoselectivity with respect to the acute dose-limiting CNS toxicity syndrome suggests that this may not involve a specific CNS receptor interaction.

The combination of multiple doses of etanidazole and pimonidazole in 48 patients: a toxicity and pharmacokinetic study.

The two radiosensitizers etanidazole and pimonidazole, currently in clinical phase 3 trials, have different toxicities. The former produces a peripheral neuropathy after cumulative doses and the latter presents an accurate but transient central nervous system syndrome after each dose. A strategy for improving on the maximum radiosensitization achievable using either drug alone, has been investigated in the study reported in this paper. Escalating doses of the two drugs were given together to determine toxicity up to a maximum of 15 doses of 2.0 g/m2 etanidazole and 0.75 g/m2 pimonidazole/dose. 25 neuropathies were seen in the total of 48 patients (48%). This included 6 grade 2 neuropathies (12.5%) or 15% of those receiving 9 or more infusions. There were no significant correlations between the incidence of neuropathy and various dose and AUC parameters for the 31 patients receiving 10 or more infusions. However, in the selected group of 26 patients planned to receive multiple doses of etanidazole at 2 g/m2/dose with pimonidazole at 0.75 g/m2, significant correlations were seen with the cumulative dose, with single and cumulative AUCs for pimonidazole and also for the cumulative dose and the cumulative AUC for etanidazole, but not its single AUC. In the light of these observations and the recent reports of higher peripheral neuropathy rates than previously reported in studies in the USA, it is concluded that it is not possible at this time to determine whether there is toxicity interaction between the two drugs. There remains the possibility that, on the basis of the combined drug dosage achieved, an increased therapeutic efficacy can be reached with either drug alone.

Abnormal clinical pharmacokinetics of the developmental radiosensitizers pimonidazole (Ro 03-8799) and etanidazole (SR 2508).

The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) are under evaluation as single agents (Phase III) and in combination (Phase I). Ro 03-8799 produces an acute, transient central nervous system syndrome, whereas SR 2508 causes cumulative, peripheral neurotoxicity; both effects are dose-limiting. Pharmacokinetic studies have shown the importance of area under the plasma drug concentration versus time curve (AUC) in predicting the risk of peripheral neuropathy. Most patients have very similar pharmacokinetic parameters. This study reports 2/25 patients receiving 0.75 g/m2 Ro 03-8799 plus 2.0 g/m2 SR 2508 who showed significant discrepancies in drug handling. One patient exhibited a markedly elevated AUC and prolonged t1/2 beta for SR 2508 and this was associated with an unusually rapid onset of peripheral neuropathy. A second patient showed normal handling of SR 2508 but prolonged values for both t1/2 alpha and t1/2 beta for Ro 03-8799 and unusually low levels of its N-oxide metabolite. In addition a low peak Ro 03-8799 concentration combined with a very high volume of distribution was found in this patient, leading to a normal AUC value and toxicity profile. Both patients exhibited a relatively low creatinine clearance. The mechanisms which may underlie these findings are discussed, and the importance of pharmacokinetic monitoring in the use of these agents is emphasized.

Hemolysis associated with hydrogen peroxide at a pediatric dialysis center.

Patients receiving hemodialysis therapy risk exposure to disinfectants used to reduce bacterial burdens in hemodialysis equipment and to reprocess hemodialyzers. From April 29 through May 9, 1988, 3 patients undergoing hemodialysis treatments at a single center were exposed to dialysis fluid that was inadvertently contaminated with hydrogen peroxide (HP). All patients showed a significant decline in blood hemoglobin level and required packed red blood cell transfusions during the 11-day exposure to HP. Contamination of dialysis fluid may have been due to the inadequate rinsing of HP from the water treatment system (WTS) following its disinfection on April 27-28, 1988. The failure to check water at point-of-use stations with a sensitive enough test kit after the disinfection for HP permitted patient exposure to contaminated dialysis fluid. To prevent similar occurrences, we recommend that after each disinfection (or other modifications of the WTS), the WTS be adequately rinsed to remove potentially toxic chemicals. Dialysis center personnel need to be aware of the potential effects that each modification or disinfection of the WTS may have on the product water used.

Estimation of plasma area under the curve for etanidazole (SR 2508) in toxicity prediction and dose adjustment.

The hydrophilic 2-nitroimidazole radiosensitizer etanidazole is currently undergoing clinical evaluation. Although considerably less neurotoxic than misonidazole because of its rapid renal clearance and partial exclusion from the nervous system, total dose is limited by peripheral neuropathy. Monitoring plasma etanidazole concentration in patients to determine the area under the curve (AUC0-infinity) has been proposed as a method of predicting patients at risk, and of providing a quantitative basis for dose reduction in such patients. Successful application of this policy requires accurate assessment of AUC0-infinity. We have analyzed plasma data for 18 patients receiving 2 g/m2 etanidazole to determine the errors introduced in the estimation of AUC0-infinity caused by omitting selected time points from the analysis. A 'baseline' AUC0-infinity value was calculated by integration of the rate equation for the 2-compartment model using data points at 0, 15, and 30 min and 1, 2, 4, 8, 12, and 24 hr after the end of infusion. The mean +/- SD area for AUC0-infinity was 502 +/- 152 micrograms ml-1 h (2.35 +/- 0.71 mM.h). Omitting the zero or the 24 hr time point, the average errors were quite small (2.5% in both cases), but errors of up to 16.4 and 7.3%, respectively, were seen for individual patients. Leaving out both the 8 hr and 12 hr points at the same time gave a similar low average error of 2.9%, with a highest error of 7.3%. Omitting all data points after 4 hr, the mean error was 24.7% and 15 of 18 patients had errors in excess of 10%. In addition, failure to correct for infusion time results in an underestimation of AUC0-infinity averaging 4.5% (range 1.9-8.7%). The choice of sampling times for toxicological monitoring will depend upon the accuracy with which the AUC0-infinity must be known. Including all data points between 0 and 24 hr will minimize errors. Considering the general similarity in the errors introduced by omitting the 8 hr and 12 hr points together compared to those seen with exclusion of the single 24 hr point, the choice between these truncated sampling options would be expected to lie in the relative inconvenience caused to patients and medical staff for the particular dose schedule used. The short sampling schedule (0-4 hr) should not be used.

A multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole).

The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

The multi-dose clinical tolerance and pharmacokinetics of the combined radiosensitizers, Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole).

The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) have differing physico-chemical properties and clinical toxicities. The former is basic, lipophilic and produces an acute but transient central nervous system syndrome; the latter is neutral, hydrophilic and causes cumulative peripheral neuropathy. We therefore investigated the possibility of combining these agents to achieve additive radiosensitization with no enhancement of toxicity, as demonstrated in a rodent tumor model. Following a single dose study which showed a lack of interaction with respect to both toxicity and pharmacokinetics, twenty-one patients have now completed simultaneous drug administration on an escalating, multiple dose schedule. There has been no adverse acute interaction up to 0.75 g/m2 Ro 03-8799 with 2 g/m2 SR 2508 for 15 doses. At this dose-level, however, all patients experienced peripheral neuropathy. There was no adverse pharmacokinetic interaction, or perturbation of plasma pharmacokinetics between initial and final infusions. Tumor concentrations were determined in 48 biopsy samples 0-60 min after administration. Mean values normalized to a dose of 0.75 g/m2 Ro 03-8799 plus 2 g/m2 SR 2508 were 33 micrograms/g Ro 03-8799 and 74 micrograms/g SR 2508. These would be expected to produce a single-dose sensitizer enhancement ratio of around 1.5. The combination is predicted to be around 6.8 times more active than misonidazole, and superior to any single agent tested to date. The current schedules are reaching the limits of clinical tolerance, and an attempt is now being made to define the optimal regimen for use in a randomized clinical trial of the combination.

Hypoxic cell radiosensitizers in the treatment of high grade gliomas: a new direction using combined Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole).

The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) have been evaluated for their simultaneous penetration into human brain tumors and surrounding normal tissue. Thirteen patients received a dose of 1 g of each agent, infused over a 10 minute period during neurosurgery. Samples of glioma (20), brain (10) and cerebrospinal fluid (1) were obtained at a mean time (+/- SD) of 31 +/- 18 min from the end of infusion. A 24 hr plasma time course was measured in six patients. Nitroimidazole concentrations were determined by HPLC. For a mean dose of 0.55 g/m2 of each agent, the mean tumor concentrations (+/- SD) were 17.0 +/- 12.0 micrograms/g for Ro 03-8799 and 13.5 +/- 10.9 micrograms/g for SR 2508. The tumor/plasma ratios were 279 +/- 230% and 47 +/- 34% respectively. For adjacent 'normal' brain tissue, the radiosensitizer concentrations were 29.9 +/- 13.1 micrograms/g for Ro 03-8799, and 4.0 +/- 1.7 micrograms/g for SR 2508, and the brain/plasma ratios were 430 +/- 29% and 14 +/- 8% respectively. There was a significant trend towards increasing accumulation of both agents with time, in both tumor and normal brain. Concentrations in cerebrospinal fluid were very low. Plasma pharmacokinetics for Ro 03-8799 were similar to previous experience, but for SR 2508 the terminal half-life was greater in this series by a factor of 1.3. The results confirm that Ro 03-8799 is distributed widely in the central nervous system, and demonstrate that SR 2508 can achieve high tumor concentrations when the blood-brain barrier is compromised. The concentrations achieved with the combination are indicative of a significant advantage over metronidazole, misonidazole, or either agent alone, and normalized to the therapeutic dose of 0.75 g/m2 plus 2.0 g/m2 SR 2508 are consistent with those giving additive sensitization in an in vivo mouse tumor model.

Small cell lung carcinoma. A phase II evaluation of r-interferon-gamma.

Twelve previously untreated patients with small cell lung carcinoma (SCLC) were treated with r-interferon-gamma (Immuneron, Biogen S.A., Geneva, Switzerland). The planned dose was 1 mg (28 X 10(6) mu)/ms daily for 5 days, followed by 0.5 mg/m2 three times a week for 3 weeks or until progression, whichever was first. Eight patients were fully evaluable, and there were no responses. In four of the eight, the disease remained stable for 1 month, and four progressed before this time. Toxic reactions included pyrexia, headache, and malaise, which were mild to moderate. Ten patients subsequently received conventional chemotherapy, which resulted in three complete and four partial responses. The mean duration of response to chemotherapy was 8 months. It is concluded that r-interferon-gamma, at the dose and schedule used, has no significant clinical activity in small cell lung carcinoma.

New methods for implanting plastic tubes for 192iridium brachytherapy using steel needles.

A revised method for implanting plastic tubes used to carry 192iridium for brachytherapy is described. Solid malleable stainless steel needles are machined at one end with a tapered screw thread, on to which the plastic tubing can be placed for pulling through tissue. The technique has proved to be both simpler and quicker than the standard 'Amersham' method. Since the solid needles may be moulded, it is easier to implant relatively inaccessible areas such as axillary, intrathoracic and paraspinal sites. For sites with no clear exit point for the needles, a large diameter steel needle is described, which enables the plastic tubes to be inserted with less trauma to the tissues.

A comparative study of Ro 03-8799: racemic mixture and enantiomers.

The maximum single dose of the 2-nitroimidazole hypoxic cell radiosensitiser Ro 03-8799 is limited to 1 g/m2 by the occurrence of a well characterised acute syndrome of sweating, nausea and mental changes. In an attempt to increase the tolerable dose, the clinical toxicity of the racemic mixture was compared with that of the R- and S-enantiomers of Ro 03-8799. Twelve patients received escalating alternate doses of racemic mixture and R- or S-enantiomer, the dose levels being 0.25 g/m2, 0.5 g/m2, 0.75 g/m2 and 1.0 g/m2. Careful monitoring of the acute syndrome failed to demonstrate any consistent differences between racemic mixture and either enantiomer. This would suggest that the toxicity is not mediated via any specific central nervous system receptor. It is concluded that separation of Ro 03-8799 into its enantiomers will not enable a clinically useful increase in dosage.

A phase II study of CCNU with benznidazole for metastatic malignant melanoma.

The response of 18 patients with metastatic malignant melanoma to the combination of CCNU (130 mg/m2) preceded 3-4 hr earlier by 20 mg/kg of the 2-nitroimidazole benznidazole has been studied. There were four partial and no complete responses in 16 patients evaluable after 1-6 courses. The median response duration was 14 wk (range 5-33) and for static disease 24 wk (range 10-54). Evidence for chemosensitization is equivocal.

A phase I study of the combination of two hypoxic cell radiosensitizers, Ro 03-8799 and SR-2508: toxicity and pharmacokinetics.

The hypoxic cell radiosensitizer Ro 03-8799 produces acute central nervous system toxicity which limits repeated doses of the drug to 0.75 g/m2, but peripheral neuropathy does not occur. SR-2508 causes no acute effects at doses greater than 3.0 g/m2, but causes peripheral neuropathy at cumulative doses of 30 g/m2. By combining maximum tolerated doses of each agent, it may be possible to increase efficacy, but not toxicity. Escalating single doses of Ro 03-8799 and SR-2508 were administered to 10 patients. The drugs were infused together in 50 ml of 0.9% saline over 10 min, beginning at 0.5 g/m2 of each agent, and proceeding to a fixed dose of 0.75 g/m2 Ro 03-8799 with 0.5, 1.0, 2.0, and 3.0 g/m2 SR-2508. Four patients experienced the expected acute syndrome related to Ro 03-8799, but the incidence was not increased by escalating doses of SR-2508, and no peripheral neuropathy was seen. Plasma and urine pharmacokinetic studies showed that no drug interaction occurred. Six patients have been given a 9-dose regime over a 3 week period, using 0.75 g/m2 Ro 03-8799 and escalating doses of 0.5, 1.0, and 1.5 g/m2 SR-2508. All exhibited the expected acute side effects related to Ro 03-8799, but with no increase at the higher doses of SR-2508. No other toxicity was seen. Plasma pharmacokinetics performed at the beginning and end of the schedule were similar. Biopsies were taken from six superficial tumors following combined radiosensitizer administration. Mean tumor concentrations over the 30 min following the end of infusion were 30 and 72 micrograms/g for Ro 03-8799 and SR-2508, respectively. These values would be expected to translate into an approximate single dose sensitizer enhancement ratio of 1.5 to 1.6, offering a significant gain over the enhancement possible with the drugs given alone. The overall advantage will be determined by the maximum dose levels and number of doses possible; the escalation of both parameters is now in progress.

Metastatic oligodendroglioma presenting as a leukoerythroblastic anaemia.

The clinical course of a patient with oligodendroglioma, treated initially with surgery and radiotherapy, is described. The patient later presented with leukoerythroblastic anaemia due to metastasis to bone marrow. This behaviour had not been previously described in oligodendroglioma.

Erectile dysfunction in diabetes and hypertension.

By direct interrogation and specific questions, the erectile function of 1,128 male adults, aged sixteen to eighty years and over, was elicited. The erectile function was based on ability to develop an erectile angle of 90 degrees and more, and this was used for classification purposes. Three hundred seventeen consecutive, unselected male diabetics and 117 nondiabetic male hypertensives were compared with 635 consecutive adult males with neither diabetes nor hypertension. Our results indicate that erectile dysfunction, partial or complete, is more prevalent in diabetics compared with nondiabetics of the same age groups. An unexpected finding was a meager relationship between hypertension and erectile disability. Antihypertensive drugs were responsible for only 2 cases of erectile dysfunction in our male hypertensive patients. The negative impact of age was noted in all age groups and in those with or without diabetes or hypertension.

Artificial perfusion in impotence.

The physiology of normal erection is contrasted to that induced by artificial perfusion. The diagnostic value of the procedure is limited. Perfusion may be useful in monitoring the effect of drugs instilled into the penis or in choice of procedure.