RF coils for combined MR and hyperthermia studies: I. Hyperthermia applicator as an MR coil.

Combining hyperthermia, an experimental/adjuvant therapeutic modality for cancer, with the non-invasive metabolic studies using Magnetic Resonance (MR) is an interesting area of research. This two parts article discusses the development and testing of a conventional RF hyperthermia applicator for MR studies and vice versa. In this first part, an inductive type applicator known as 'Magnetrode' in RF hyperthermia has been used both as an MR volume resonator and a surface coil. Its concurrent performance as an hyperthermic applicator and an MR transmit/receive coil has been evaluated.

RF coils for combined MR and hyperthermia studies: II. MR coil as an hyperthermic applicator.

Single loop surface coil, often used in MR studies, was evaluated for its performance as an inductive hyperthermic applicator. The heat deposition pattern produced by the surface coil at 84 MHz and 34 MHz was mapped in muscle-mimicking agar phantoms. Temperatures were measured simultaneously at 64 points using multiple-junction thermocouples.

A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy.

BACKGROUND: The role of chemotherapy in the treatment of patients with primary central nervous system lymphoma (PCL) remains unclear, with no randomized trials available to aid in the interpretation of the current data. The Medical Research Council therefore conducted the current randomized trial to assess the impact on survival of postradiotherapy chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in nonimmunocompromised adult patients with pathologically proven PCL. METHODS: After surgery, patients were randomized at a ratio of 1:2 to radiotherapy alone (RT: 40 grays [Gy] in 20 fractions to the whole brain followed by a 14-Gy boost to the tumor plus a 2-cm tumor margin) or to the same radiotherapy followed by six cycles of CHOP chemotherapy given at 3-week intervals (RT-CHOP). The target sample size was 90 patients, which allowed 90% power to detect a doubling of the median survival time. RESULTS: Between 1988 and 1995, 53 patients were randomized: Fifteen patients were randomized to RT, and 38 patients were randomized to RT-CHOP. The trial closed earlier than planned through poor accrual. The median patient age was 57 years, 57% of the patients were male, and 75% of the patients had unifocal disease. The median number of chemotherapy cycles received was 6 (mean, 4 cycles). Forty-three patients have died, and the median follow-up of survivors is 5 years (range, 1-9 years). There was no evidence of a benefit from RT-CHOP with respect to overall survival (hazard ratio [HR], 1.19; 95% confidence interval, 0.51-2.76) after adjustment for prognostic factors (patient age and neurologic performance status) in an analysis in which HR > 1 favored the control (RT) group. CONCLUSIONS: CHOP has no clear role in the postradiotherapy treatment of patients with PCL. Chemotherapy is poorly tolerated and largely palliative in older, less fit patients. In younger patients, initial chemotherapy designed to penetrate the blood-brain barrier warrants further investigation.

Simultaneous evaluation of the effects of RF hyperthermia on the intra- and extracellular tumor pH.

31P-magnetic resonance spectroscopy (MRS) and a fiberoptic pH meter were used simultaneously to follow the changes in intra- (pHi) and extracellular pH (pHe), respectively, of murine RIF-1 tumors with hyperthermia. Hyperthermia was induced at 34 MHz using the same coil used for MR. The study was carried out until 3.5 hr after hyperthermia. In untreated tumors (n = 29), pHi was always higher than pHe. pHi was reduced after hyperthermia (30 min) at both 42 degrees C and 45 degrees C. pHe registered an increase after 42 degrees C and a decrease after 45 degrees C. The reduction in pHi was larger than the initial differential between pHi and pHe, and the change in pHe was relatively small. Hyperthermia changed the acidity of the intra- and extracellular compartments, such that pHe became more alkaline than pHi by 0.15 +/- 0.13 units after 42 degrees C [pHe (7.20 +/- 0.12) and pHi (7.03 +/- 0.05)], and by 0.12 +/- 0.14 units after 45 degrees C [pHe (6.84 +/- 0.24) and pHi (6.72 +/- 0.19)]. Simultaneous measurements of pH from the intra- and extracellular compartments demonstrated reversal in the pH gradient after hyperthermic treatment.

Phase I and pharmacokinetic study of DACA (XR5000): a novel inhibitor of topoisomerase I and II. CRC Phase I/II Committee.

DACA, also known as XR5000, is an acridine derivative active against both topoisomerase I and II. In this phase I study, DACA was given as a 3-h intravenous infusion on 3 successive days, repeated every 3 weeks. A total of 41 patients were treated at 11 dose levels between 9 mg m(-2) d(-1) and the maximum tolerated dose of 800 mg m(-2) day(-1). The commonest, and dose-limiting, toxicity was pain in the infusion arm. One patient given DACA through a central venous catheter experienced chest pain with transient electrocardiogram changes, but no evidence of myocardial infarction. At the highest dose levels, several patients also experienced flushing, pain and paraesthesia around the mouth, eyes and nose and a feeling of agitation. Other side-effects, such as nausea and vomiting, myelosuppression, stomatitis and alopecia, were uncommon. There was one minor response but no objective responses. DACA pharmacokinetics were linear and did not differ between days 1 and 3. The pattern of toxicity seen with DACA is unusual and appears related to the mode of delivery. It is possible that higher doses of DACA could be administered using a different schedule of administration.

A magnetic resonance-compatible experimental set-up for hyperthermia studies.

This study presents the development and testing of an experimental set-up for simultaneous measurements of pH (intracellular by MR and extracellular by fibre-optic pH meter), tumour bio-energetics (by MR), and core/tumour temperatures (by thermocouples) in tumour-bearing mice. Potential sources of measurement errors when using these techniques concurrently in an MR set-up are discussed. Emphasis is placed on simple practical solutions to these problems.

O6-methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma.

Resistance of tumour cells to methylating and monochloroethylating agents in vitro and in vivo has been linked to levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In a clinical trial of temozolomide in advanced malignant melanoma, the relationship between pretreatment MGMT levels in biopsies of cutaneous tumours and involved lymph nodes and clinical response to the drug has been studied. Among 50 evaluable patients, there were three complete responses (CR), four partial responses (PR), six with stable disease (SD) and 37 with progressive disease (PD), with an overall response rate of 14%. In 33 patients in whom MGMT level and clinical response could be evaluated, the tumour MGMT levels (fmol mg(-1) protein) were: CR, 158 +/- 119; PR, 607 +/- 481; NC, 171 +/- 101; PD, 185 +/- 42.3. Thus, measurements of pretreatment levels of MGMT in melanoma did not predict for response to temozolomide.

A phase I study of intravenous RMP-7 with carboplatin in patients with progression of malignant glioma.

RMP-7, a nine amino acid peptide bradykinin agonist, increases the delivery of hydrophilic compounds across the blood-tumour barrier. In this dose ranging study, 14 patients with progressing malignant glioma (9 glioblastoma multiforme, 4 anaplastic astrocytoma, 1 anaplastic oligodendroglioma; age range 31-68 years, baseline Karnofsky range 60-90%, 5 having had prior chemotherapy) were treated with intravenous RMP-7 and carboplatin to assess the safety, tolerability, and side-effect profile of increasing doses of this combination. Carboplatin dosing was by target area under the curve (AUC) according to the Calvert protocol. Patients were allocated to one of five treatment regimes: cohort A (n = 2) received 50 ng/kg RMP-7 and target AUC 5 mg/ml/min carboplatin; cohort B (n = 3) 100 ng/kg RMP-7 + AUC 5; cohort C (n = 2) 100 ng/kg RMP-7 + AUC 7; cohort D (n = 2) 200 ng/kg RMP-7 + AUC 7; cohort E (n = 5) 300 ng/kg RMP-7 + AUC 7. Treatment was given once every 4 weeks with magnetic resonance imaging scans every 2 months. Patients received 37 cycles in total (median 2, range 1-7). The drug combination, as a cancer treatment, was tolerated in all groups. Effects possibly related to RMP-7 included flushing, nausea, headache and mild increase in heart rate, all transient. 3 patients in cohort E experienced grade 3/4 neutropenia and thrombocytopenia. These toxicities are consistent with known effects of carboplatin at this dose range. In cohort E (n = 5) 1 patient improved and another remained stable for > or = 6 months. In summary, the dose was escalated to the maximum dose of RMP-7 given to volunteers without additional related side-effects. The side-effects of the combination were consistent with giving the two drugs alone and would merit further study for efficacy.

A short fractionation radiotherapy treatment for poor prognosis patients with high grade glioma.

Thirty-two patients prospectively identified as having poor prognosis high grade glioma, with a MRC prognostic score >25, were treated with a short palliative course of radiotherapy. A total dose of 36 Gy in 12 fractions was given to the tumour, including oedema and a 2 cm margin, using parallel pair fields prescribed to the midplane with MV photons. Twenty-eight patients completed treatment as planned, while four failed to complete treatment because of clinical deterioration or death. The median survival for the whole group was 16 weeks, with seven patients surviving for more than 6 months. Approximately two-thirds of the surviving patients remained at home after the completion of treatment. A matched case-control comparison with data from patients in previous MRC studies who had received a 6-week course of treatment shows that, for this group of patients, survival is similar (hazard ratio 1.0; 95% confidence interval (CI) 0.57-1.74). The 95% CI for the difference in median survival time excludes a reduction of more than 7 weeks with the 36 Gy course. This shortened radiotherapy regimen may therefore be satisfactory for most poor prognosis patients. However, patients with performance status 3 gained little benefit from treatment, and it is suggested that this group should have a trial period of assessment at home prior to a decision on treatment.

The effects of anesthesia and physical restraint on intra- and extracellular tumor pH, tumor temperature and bioenergetics in murine RIF-1 tumors.

The effects of pentobarbital anesthetic and physical restraint have been evaluated in murine RIF-1 tumors in terms of their suitability in providing minimal temporal variations in core and tumor temperatures, intracellular (pHMR) and extracellular (pHF) tumor pH, and tumor bioenergetics. pHF was measured using a fibreoptic pH probe. The implications of the changes in these parameters on the combined studies of in vivo MRS and hyperthermia have been discussed. The temporal variations of core and tumor temperatures, pHF and pHMR between the anesthetised and restrained mice were statistically significant (p < 0.0001, p < 0.005, and p < 0.0001, respectively). Differences in the temperatures between the two groups varied with time, and were maximum at about 2 h after pentobarbital. In the anesthetised mice, while there was a net increase of 0.28 pH units in pHF, there was a drop by 0.32 pH units in pHMR (p < 0.001). Temporal variations of both pHF and pHMR in the restrained mice were relatively constant. In light of these findings, wherever possible, physical restraint in a suitably designed holder is suggested for immobilizing animals for magnetic resonance spectroscopy studies.

Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma.

PURPOSE: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide. METHODS: The treatment schedule was 150-200 mg/m2 per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging. RESULTS: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity. CONCLUSIONS: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas.

The role of post-operative radiotherapy in non-small-cell lung cancer: a multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease. Medical Research Council Lung Cancer Working Party.

The role of post-operative radiotherapy for patients with non-small-cell lung cancer (NSCLC) is unclear despite five previous randomised trials. One deficiency with these trials was that they did not include adequate TNM staging, and so the present randomised trial was designed to compare surgery alone (S) with surgery plus post-operative radiotherapy (SR) in patients with pathologically staged T1-2, N1-2. M0 NSCLC. Between July 1986 and October 1993, 308 patients (154 S, 154 SR) were entered from 16 centres in the UK. The median age of the patients was 62 years, 74% were male, > 85% had normal or near normal levels of general condition, activity and breathlessness, 68% had squamous carcinoma, 52% had had a pneumonectomy, 63% had N1 disease and 37% N2 disease. SR patients received 40 Gy in 15 fractions starting 4-6 weeks post-operatively. Overall there was no advantage to either group in terms of survival, although definite local recurrence and bony metastases appeared less frequently and later in the SR group. In a subgroup analysis, in the N1 group no differences between the treatment groups were seen, but in the N2 group SR patients appeared to gain a one month survival advantage, delayed time to local recurrence and time to appearance of the bone metastases. There is, therefore, no clear indication for post-operative radiotherapy in N1 disease, but the question remains unresolved in N2 disease.

Nicotinamide and pentoxifylline increase human leucocyte filterability: a possible mechanism for reduction of acute hypoxia.

Transient plugging of microcapillaries by leucocytes is a possible reason for the occurrence of acute hypoxia in tumours. We compared the abilities of nicotinamide at 1000 micrograms ml-1 and 150 micrograms ml-1 and pentoxifylline at 300 micrograms ml-1 to increase the filterability of normal and artificially activated human leucocytes through 8 microns pores, as a model for the capillary bed. Using a St George's filtrometer, filterability of treated leucocyte suspensions was compared with control for three to six sequential 60 microliters samples, normalising control values to unity. Pentoxifylline at 300 micrograms ml-1 halved the ratio of treated to control value to 0.47 +/- 0.13 (2 s.e.), P = 0.001 (i.e. an increase in filterability), and nicotinamide at 1000 micrograms ml-1 reduced it to 0.69 +/- 0.22, P = 0.04, but the clinically achievable 150 micrograms ml-1 was ineffective (0.82 +/- 0.25, P = 0.24). Filterability of artificially activated leucocytes was reduced (3.9 +/- 1.20) but was restored to control values of unity by 1000 micrograms ml-1 nicotinamide and 300 micrograms ml-1 pentoxifylline and partially restored by 150 micrograms ml-1 nicotinamide (1.2 mM), which was isoeffective with 100 micrograms ml-1 pentoxifylline (0.37 mM). Pentoxifylline is therefore more effective on a molar basis and was shown to affect both polymorphonuclear leucocytes and lymphocytes, while nicotinamide only affects lymphocytes. The data are consistent with the hypothesis that both agents modify acute hypoxia by increasing leucocyte filterability.

Expression of apoptosis-regulatory genes in lung tumour cell lines: relationship to p53 expression and relevance to acquired drug resistance.

As a first step towards elucidating the potential role(s) of bcl-2 and bcl-2-related genes in lung tumorigenesis and therapeutic responsiveness, the expression of these genes has been examined in a panel of lung cancer cell lines derived from untreated and treated patients, and in cell lines selected in vitro for multidrug resistance. Bcl-2 was hyperexpressed in 15 of 16 small-cell lung cancer (SCLC) cell lines and two of five non-small-cell lung cancer (NSCLC) lines compared with normal lung and brain, and hyperexpression was not chemotherapy related. Bcl-x was hyperexpressed in the majority of SCLC and NSCLC cell lines as compared with normal tissues, and all lung tumour lines preferentially expressed bcl-x1-mRNA, the splice variant form that inhibits apoptosis. Bax gene transcripts were hyperexpressed in most SCLC and NSCLC cell lines examined compared with normal adult tissues. Mutant p53 gene expression was detected in the majority of the cell lines and no relationship between p53 gene expression and the expression of either bcl-2, bcl-x or bax was observed. No changes in bcl-2, bcl-x and bax gene expression were observed in multidrug-resistant cell lines compared with their drug-sensitive counterparts.

Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and toxicity of PSC 833 infusion administered with etoposide for 5 days in patients with cancer, and to determine the effect of PSC 833 on etoposide pharmacokinetics. PATIENTS AND METHODS: Thirty-five patients were entered onto the study, one of whom was ineligible. Etoposide was delivered from day 1 as a 2-hour infusion over 5 consecutive days at a dose of 75 to 100 mg/m2/d. PSC 833 was administered from day 2 as a 2-hour loading dose and as a 5-day continuous infusion. Doses were escalated from 1 to 2 mg/kg (loading dose) and 1 to 15 mg/kg/d (continuous infusion). RESULTS: Thirty-four patients were treated with 53 cycles of PSC 833 and etoposide. Steady-state blood PSC 833 levels more than 1,000 ng/mL were achieved in all patients treated at PSC 833 doses > or = 6.6 mg/kg/d by continuous infusion. Myelosuppression was the most common toxicity. The major dose-related toxicity of PSC 833 was reversible hyperbilirubinemia, which occurred in 83% of cycles. The dose-limiting toxicity of PSC 833 was severe ataxia, which occurred in two of nine patients treated at 12 mg/kg/d and in both of the single patients treated at 13.5 and 15 mg/kg/d. PSC 833 concentrations more than 2,000 ng/mL resulted in an increase in etoposide area under the curve (AUC) of 89%, a decrease in etoposide clearance (Cl) of 45%, a decrease in volume of steady-state distribution (Vss) of 41%, and an insignificant increase in alpha half-life (t 1/2 alpha) and significant increase of beta half-life (t 1/2 beta) of 19% and 77%, respectively. CONCLUSION: PSC 833 can be administered in combination with etoposide with acceptable toxicity. The recommended continuous infusion dose of PSC 833 for this schedule is 10 mg/kg/d over 5 days. PSC 833 results in an increase in etoposide exposure and etoposide doses should be reduced in patients receiving PSC 833.

Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party.

In patients with non-metastatic but inoperable non-small cell lung cancer that is locally too extensive for radical radiotherapy (RT), but who have good performance status, it is important to determine whether thoracic RT should be the minimum that is required to palliate thoracic symptoms or whether treatment should be more intensive, with the aim of prolonging survival. A total of 509 such patients from 11 centres in the UK between November 1989 and October 1992 were admitted to a trial comparing palliative versus more intensive RT with respect to survival and quality of life. They were allocated at random to receive thoracic RT with either 17 Gy in two fractions (F2) 1 week apart (255 patients) or 39 Gy in 13 fractions (F13) 5 days per week (254 patients). Survival was better in the F13 group, the median survival periods being 7 months in the F2 group compared with 9 months in the F13 group, and the survival rates 31% and 36% at one year and 9% and 12% at 2 years, respectively (hazard ratio = 0.82; 95% CI0.69-0.99). There was a suggestion of a trend towards greater benefit in fitter patients. Metastases appeared earlier in the F2 group. As recorded by patients using the Rotterdam Symptom Checklist, the commonest symptoms on admission were cough, shortness of breath, tiredness, lack of energy, worrying and chest pain. These were more rapidly palliated by the F2 regimen. Psychological distress was generally lower in the F13 group. Three patients (two F13, one F2) exhibited evidence of myelopathy. As recorded by patients using a diary card, 76% of the F2 compared with 81% of the F13 patients had dysphagia associated with their RT. This was transient, lasting for a median of 6.5 days in the F2 group compared with 14 days in the F13 group. In conclusion, the F2 regimen had a more rapid palliative effect. In the F13 group, although treatment-related dysphagia was worse, survival was longer.

Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party.

Radiation myelopathy (RM) is an uncommon but serious late effect of thoracic radiotherapy (RT), which oncologists try to avoid by careful planning and dose selection. Five patients with RM are described from among 1048 with inoperable non-small cell lung cancer treated with palliative RT in three randomized trials conducted by the Medical Research Council Lung Cancer Working Party. Seven RT regimens were used in these trials: 10 Gy in a single fraction on one day (10/1/1) (114 patients), 17/2/8 (524 patients), 27/6/11 (47 patients), 30/6/11 (36 patients), 30/10/12 (88 patients), 36/12/16 (86 patients) and 39/13/17 (153 patients). Of the five instances of RM, three occurred in the 524 patients treated with 17 Gy in two fractions, and two in the 153 treated with 39 Gy in 13 fractions. The estimated cumulative risks of RM by 2 years were 2.2% for the 17 Gy group, 2.5% for the 39 Gy group, and 0% for the remainder, but the annual risks had wide 95% confidence intervals, indicating that the distribution of episodes among the seven regimens could have been random. Nevertheless, calculation of cord doses in terms of the total doses that would have an equivalent biological effect if given in 2 Gy fractions (LQED2 values) from our data for different values of the ratio of the linear quadratic parameters of the cell survival curve (alpha/beta), suggest that the best estimate of alpha/beta is less than 3 Gy, and possibly close to 2 Gy. This emphasizes the sensitivity of human spinal cord to changes in fraction size. We recommend that, when the computed LQED2 for a schedule of treatment that includes the thoracic spinal cord (assuming alpha/beta = 2 for cord) exceeds 48 Gy, oncologists should consider reducing the dose to the cord.

Phase II trials of rhizoxin in advanced ovarian, colorectal and renal cancer.

Rhizoxin is a tubulin-binding anti-neoplastic agent which is active in a range of murine tumour models. The recommended schedule, of intravenous (i.v.) bolus administration at a dose of 2 mg m-2 every 3 weeks, has been assessed in three phase II trials of ovarian, renal and colorectal cancer. In general terms the drug was fairly well tolerated, but the response rate was disappointing: 0/18, colorectal cancer; 0/18, renal cancer; 1 partial response (PR)/17, ovarian cancer.

A phase II study of oral piritrexim in recurrent high-grade (III, IV) glioma.

Piritrexim is a lipid-soluble drug which is as effective an inhibitor of dihydrofolate reductase as methotrexate. Phase I and II studies have indicated activity in some tumour types. Because of its lipophilicity we have conducted a phase II study in recurrent high-grade malignant glioma (grades III and IV). Twenty-seven patients were treated with 25 mg p.o. three times daily for five consecutive days, repeated weekly, with provision for dose escalation or reduction according to toxicity. Five patients received less than 4 weeks' treatment because of disease progression or death. Twenty-two patients were evaluable for response. One complete and one partial response was seen (duration 262+ and 241+ weeks) and 13 patients had static disease for a median duration of 13 weeks (range 7-35). The major toxicity was myelosuppression. This response rate of 9% of evaluable patients is much lower than that seen for some conventionally used drugs and we conclude that piritrexim is unlikely to be of value in the management of high-grade gliomas.