New treatments for advanced cancer: an approach to prioritization.

The allocation of funding for new anticancer treatments within the UK has not kept pace with demand. Clinicians find themselves restricted in the use of licensed drugs which they feel are in the best interests of individual patients. Against this, health authorities have a duty to ensure that scarce resources are used equitably to meet the needs of the local population as a whole. Differential levels of funding for new treatments across the country have led to concerns about rationing by postcode. This paper outlines an approach to the prioritization of new treatment for advanced cancer developed jointly by clinicians and health authorities in South London. The approach involves evidence reviews and consensus meetings. Existing and new treatments are rated on a four-point 'relative effectiveness scale', which takes account of the impact of the treatment on quality of life and on survival. The strength of evidence supporting each effectiveness rating is also classified. Health Authorities have used these ratings to determine overall funding levels, while leaving decisions on individual patients to the relevant Trusts.

Iododoxorubicin in advanced breast cancer: a phase II evaluation of clinical activity, pharmacology and quality of life.

Iododoxorubicin 80 mg m-2 i.v. was given 3 weekly for a maximum of six cycles as first-line chemotherapy to 14 evaluable women with metastatic breast cancer. The response rate was 14% (95% confidence intervals 4-40%); median time to progression was 3.5 months (range 0.7 to > 9.3) and median survival was 10.2 months (range 2.3 to > 20.4). Neutropenia was the main toxicity but was not associated with severe sepsis. Two patients had a significant (> 10%) but asymptomatic fall in cardiac ejection fraction; other toxicities were mild. Plasma pharmacokinetics was studied during the first cycle of treatment. Iododoxorubicin was extensively metabolised to iododoxorubicinol. Neutropenia and thrombocytopenia were both significantly correlated with the area under the concentration-time curve (AUC) for iododoxorubicin and the total AUC for iododoxorubicin and iododoxorubicinol. Quality of life (QOL), evaluated by self-report questionnaire and interview, showed little evidence of benefit in terms of physical symptom relief, level of activity, psychological symptoms or global evaluation of QOL during treatment. Iododoxorubicin is subjectively less toxic than standard anthracyclines, but at the dose and schedule used has limited activity in metastatic breast cancer, possibly because iododoxorubicinol is not clinically active.

Brain dopamine activity following intranigral or intrathalamic drug injections in the rat.

Stereotaxic injection of muscimol into a restricted region of one substantia nigra of the rat provoked robust circling and a concomitant rise in ipsilateral nigrostriatal dopamine activity, as revealed by a greater accumulation of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the caudate-putamen together with depleted nigral dopamine concentrations. Considered with earlier evidence, these data are taken to indicate that dopamine may be involved in the mediation of this particular rotational behaviour. On the other hand, focal application of bicuculline to the substantia nigra or ventromedial thalamus, or intrathalamic kainate, all evoked a closely similar and vigorous hypermotility (not circling) that could not be correlated with the assorted changes in dopamine utilisation occurring in the substantia nigra, caudate-putamen or nucleus accumbens, either uni- or bilaterally. These changes were therefore probably casually rather than causally related to the mechanisms underlying the behaviour of the animals. Whilst the regional concentrations of noradrenaline were unaltered by these focal drug treatments, the induction of halothane anaesthesia coupled with a unilateral intranigral saline injection produced bilateral elevations in regional dopamine utilisation when assessed 15 min after injection. Such changes were not apparent in tissue taken 30 or 60 min post-injection. We conclude that dopamine cell activity and/or other indices of dopamine utilisation cannot be used to predict the behavioural state of the individual and that an imbalance between the dopamine systems in the two hemispheres does not per se lead to postural or locomotor asymmetry.

Dysfunction of the midbrain angular complex can accentuate or attenuate circling behaviour in the rat.

The role of the midbrain angular complex (AC) in the execution of motor behaviours was investigated in the rat. In an automated holeboard apparatus bilateral AC electrolesions attenuated exploration and increased locomotor performance of drug-free rats on the first and second test occasions respectively; the latter result may signify a retarding of between-session habituation. Apomorphine also decreased locomotion and almost abolished head dipping and rearing in the holeboard; bilateral AC lesions reinstated locomotion to a normal level without modifying the other behavioural parameters. An electrolesion of one AC did not affect the animal's posture or spontaneous locomotion in the open field, but gave rise to pronounced ipsiversive circling when coupled with systemic administration of apomorphine. In unilaterally 6-hydroxydopamine (6-OHDA) treated rats subcutaneous injection of apomorphine evoked robust contraversive circling. A concomitant lesion of the ipsilateral AC introduced an additional ipsilateral bias to these animals' movements; contraversive circling was initially curtailed and posture reduced (or reversed), while stereotyped activities (particularly grooming) were suppressed. Contralateral orientation and circling were restored by subsequently lesioning the contralateral AC as well; bilateral AC lesions significantly potentiated circling to systemic apomorphine. Contralateral locomotor asymmetry was also produced by depositing apomorphine stereotaxically into the supersensitive caudate, or by microinjecting one substantia nigra zona reticulata with muscimol (in naive rats). Both rotational responses were facilitated by injury to the ipsilateral AC. The effects of electrocoagulating the AC were generally duplicated by discrete microinjection of muscimol or gamma-vinyl GABA into this area, suggesting GABA-mediated synapses are normally operative in this part of the brain. These results do not support the claim that the AC is specifically engaged in mediating postural asymmetry in the unilaterally 6-OHDA denervated rat. Instead, we believe that impairment of neurotransmission through one AC imposes an independent and reciprocal tendency to move towards that side of the brain, as well as attenuating stereotypy and facilitating locomotion. The resultant behavioural response to systemic apomorphine shown by animals bearing these two types of lesion embodies these separate actions.

Role of the ventromedial nucleus of the thalamus in motor behaviour--I. Effects of focal injections of drugs.

An assortment of drugs was injected into one or both ventromedial nuclei of the thalamus, to see how these influenced stereotypy, locomotion and posture in spontaneously behaving and actively rotating rats. Unilateral intrathalamic muscimol promoted weak ipsiversive circling, while bilateral treatment gave catalepsy. Similar injections of 4-amino-hex-5-enoic acid, which inhibits gamma-aminobutyrate metabolism, raised gamma-aminobutyrate levels in the ventromedial nuclei more than three-fold yet had none of these behavioural effects. The indirectly acting gamma-aminobutyrate agonists flurazepam and cis-1,3-aminocyclohexane carboxylic acid had little effect on posture and locomotion and, like muscimol and 4-amino-hex-5-enoic acid, elicited only very weak stereotypies. Procaine behaved like the gamma-aminobutyrate antagonist bicuculline, provoking vigorous locomotor hyperactivity and teeth chattering if given uni- or bilaterally. Pretreatment of one ventromedial nucleus with muscimol or 4-amino-hex-5-enoic acid, and to a lesser extent flurazepam or cis- 1,3-aminocyclohexane carboxylic acid, gave rise to pronounced ipsilateral asymmetries when combined with a large systemic dose of apomorphine. Contraversive rotations were initiated by unilateral stereotaxic injection of muscimol into the substantia nigra pars reticulata, or with apomorphine from the supersensitive striatum in unilaterally 6-hydroxydopamine lesioned rats. Drug treatments in the ipsilateral ventromedial nucleus showed a similar rank order of potency at inhibiting these circling behaviours, seemingly by reducing apomorphine-induced posture and muscimol-induced hypermotility. The suppression of circling by muscimol in these tests was highlighted by introducing the compound into the ventromedial nucleus at the height of circling activity. Both types of circling stimulus lost the capacity to increase locomotion, but still caused head turning and stereotypy in rats made cataleptic with bilateral ventromedial muscimol. Treating one ventromedial thalamus with muscimol greatly intensified any pre-existing posture directed towards that side, and vice versa. These data suggest that the ventromedial nucleus is not involved with the expression of stereotyped behaviours, but can profoundly influence posture and locomotion, especially in the presence of some other motor stimulus. The recovery of circus movements in rats with impaired ventromedial nucleus function implies this nucleus is not essential for the execution of circling in these models.

Role of the ventromedial nucleus of the thalamus in motor behaviour--II. Effects of lesions.

Rotational behaviour was initiated in naive rats by injecting muscimol into one substantia nigra pars reticulata, or in unilaterally 6-hydroxydopamine-treated rats with systemic or intracaudate apomorphine. Electrolytic or kainic acid lesions were made in one or both ventromedial nuclei of the thalamus and their effects on the components of circling studied. A unilateral ventromedial electrolesion imposed a weak ipsilateral posture and occasionally elicited weak ipsiversive circling acutely, but not chronically. Challenging these rats with a large subcutaneous dose of apomorphine invariably provoked ipsiversive circling, however old was the lesion. Bilateral electrolesions caused slight hypoactivity. Kainic acid treatments of one or both ventromedial thalami produced uncontrolled hypermotility initially, with subsequent loss of ventromedial neurones and recovery of normal motor behaviour. No form of ventromedial lesion affected the incidence of stereotypy. Acute (but not chronic) contralateral or ipsilateral ventromedial electrolesions, or both, slowed muscimol and apomorphine-induced circling (often in different ways) through complex changes in posture and/or locomotor drive. Animals lesioned during the course of a circling episode often showed the biggest changes in circling to begin with, only to recover minutes later. Rapidly circling rats were sometimes more readily inhibited than slowly circling rats. Toxin injury of the ventromedial nucleus appeared to suppress muscimol and not apomorphine circling. Any ventromedial lesion (electrical or chemical, acute or chronic), if positioned opposite a contraversive circling stimulus, intensified the associated posture. Ipsilateral lesions tended to abolish posture altogether or, like bilateral treatments, to suppress locomotion. Sham operations had none of these effects. Acute electrical lesions and drug-induced inhibition of one or both ventromedial thalami were more or less identical in their effects on rat circling behaviour, save that bilateral muscimol injection caused profound catalepsy while lesions did not. It is suggested that the ventromedial thalamus is more concerned with the registration of striatal dopamine-mediated behaviours in drug-stimulated than in spontaneously behaving rats, and that other output pathways may rapidly compensate for any impairment of function in the ventromedial nuclei.

Interactions between dopamine and gamma-aminobutyrate in the substantia nigra: implications for the striatonigral output hypothesis.

Experiments employing a rodent circling model were conducted to test the predictive capacity of the theory which states that striatonigral gamma-aminobutyrate neurones transmit striatal information influencing the animal's locomotion and orientation. In agreement with this proposal, blocking nerve conduction in one substantia nigra with procaine, or nigral gamma-aminobutyrate receptors with bicuculline administered stereotaxically, frequently forced rats to move ipsiversively to systemic apomorphine, as though the treatment had impaired striatonigral transmission on that side of the brain. Attempts to reverse the direction of apomorphine circling by stimulating gamma-aminobutyrate receptors with muscimol, by facilitating the amino acid's action with flurazepam, or by increasing its synaptic concentration either with a breakdown inhibitor (ethanolamine O-sulphate or 4-amino-hex-5-enoic acid) or an uptake blocker (cis-1,3-aminocyclohexane carboxylic acid) in one nigra, proved unsuccessful. In fact, ethanolamine O-sulphate, flurazepam and muscimol all gave the appearance of hindering rather than enhancing the passage of striatal-derived motor information through the nigra. Broadly speaking, these drugs gave predictable behavioral responses from the ventromedial thalamus, suggesting they were acting in accordance with known mechanisms. The anomalous behaviour with ethanolamine O-sulphate may be attributed to its elevating gamma-aminobutyrate levels in other brain areas, since similar ipsiversive rotations occurred if gamma-aminobutyrate catabolism was prevented at a wide variety of extranigral sites. A simple explanation for the paradoxical ipsiversive behaviours produced by intranigral flurazepam or muscimol in combination with systemic or intracerebral injection of dopamine agonists, is that they act via presynaptic receptors to inhibit the release of endogenous gamma-aminobutyrate and thereby impede striatonigral outflow ipsilaterally.

Multifocal brain sites for apomorphine-induced circling and other stereotyped motor behaviour in the 6-hydroxydopamine-lesioned rat.

Rats pretreated with 6-hydroxydopamine (6-OHDA, 8 micrograms in 4 microliters) in one medial forebrain bundle exhibited an assortment of stereotyped activities and pronounced circling towards the unlesioned side when apomorphine was administered either subcutaneously (0.5 mg/kg), or by discrete stereotaxic injection (5 micrograms in 0.2 microliter) into the caudate nucleus, nucleus accumbens, amygdala, lateral habenula, ventromedial thalamus, substantia nigra zona reticulata, periaqueductal grey or superior colliculus (but not a variety of other areas) ipsilateral to the lesion. These rotational responses were absent in unlesioned animals and, where tested, were attenuated by intraperitoneal haloperidol (0.5 mg/kg). It is suggested that multiple brain sites become sensitive to apomorphine following dopamine depletion by 6-OHDA.