Imatinib: new indication. Efficacy in gastrointestinal stromal tumours must be confirmed

(1) Gastrointestinal stromal tumours are rare and have highly variable malignant potential. (2) Available cytotoxic agents have so far failed to reduce tumour burden of inoperable or metastatic gastrointestinal stromal tumours. Only a minority of such patients survive beyond two years. (3) Imatinib, a tyrosine kinase inhibitor, is now approved for use in this indication. (4) A trial lasting nine months and involving 147 patients showed that oral imatinib 400 mg or 600 mg daily led to partial tumour regression in about 50% of cases. The results of ongoing trials should show whether or not this translates into a tangible increase in survival. (5) The main known adverse effects of imatinib are oedema (74% of patients), gastrointestinal, cutaneous and haematological reactions, and muscle pain. One in five patients had adverse effects that the investigators considered severe. (6) Imatinib has the potential to interact with many other drugs. (7) In practice, given the lack of alternatives, patients should be offered imatinib and be enrolled in follow-up cohorts, in order to determine the optimal treatment regimen (especially duration) and the real benefits.     

Rituximab: new indication. In aggressive non Hodgkin lymphoma: benefits must be confirmed

The first-line treatment for diffuse large-B-cell non Hodgkin's lymphoma, a highly malignant lymphoma, is CHOP chemotherapy (cyclophosphamide + doxorubicin + vincristine + prednisone). Rituximab, a monoclonal antibody targeting certain B cells, has received a new indication in the treatment of this type of lymphoma, in combination with the CHOP protocol. In late 2002, the only available evaluation data came from one comparative, unblinded trial in patients over 60 years of age. Addition of rituximab to the CHOP protocol increased both the overall two-year survival rate (70% versus 57%), and the two-year event-free survival rate. Other trials are underway. In this trial, 9% of patients had major systemic reactions during the first rituximab infusion (respiratory disturbances, chills, fever and hypotension). These reactions did not occur during subsequent infusions. About 6% of patients had serious cardiac arrhythmias. In practice, the CHOP protocol remains the standard treatment for aggressive non Hodgkin's lymphoma. Pending further information, addition of rituximab to the CHOP protocol may be justified for patients who meet the inclusion criteria used in the only available clinical trial.     

Flurbiprofen: new indication. Lozenges: NSAIDs are not to be taken like sweets!

In practice, flurbiprofen lozenges have a negative risk-benefit balance in the treatment of sore throat; it is better to suck real sweets and, if necessary, take oral paracetamol.     

Olanzapine: new indication. New indication in acute mania: just another neuroleptic

(1) Lithium is the first-line treatment for patients with acute mania. For patients with psychosis or intense agitation, an oral neuroleptic can be added (haloperidol or chlorpromazine, the best-assessed drugs of this class). (2) The licensed indications for oral olanzapine, a neuroleptic, explicitly mention the treatment of acute mania. (3) The clinical evaluation dossier on olanzapine in this setting (10 mg to 15 mg/day) is not particularly impressive. In particular, clinical trials included patients with a variety of associated psychotic symptoms. (4) The only comparative trial against another neuroleptic, haloperidol at a high starting dose (10 mg), showed that olanzapine was no more effective. The same applies to a trial comparing olanzapine with disodium valproate. (5) One placebo-controlled trial tested olanzapine as an additional treatment in patients who did not respond adequately to lithium or valproate disodium. Olanzapine potentiated the antimanic effects of the original treatment but also increased the incidence of adverse effects. (6) In patients with acute mania, the main adverse effects of olanzapine are drowsiness, weight gain, dizziness, and dry mouth. In the trial comparing olanzapine with haloperidol, olanzapine caused fewer extrapyramidal side effects but more weight gain than haloperidol. (7) Olanzapine costs 20 times more than haloperidol in France. (8) In practice, olanzapine is just another neuroleptic approved for the treatment of acute mania in patients with psychotic symptoms and agitation. There is no evidence that olanzapine has the best risk-benefit ratio in this category.     

Citalopram: new indication. No advantage

(1) Citalopram, a serotonin reuptake inhibitor antidepressant, now has a new licensed indication, in the preventive treatment of panic attacks. In France, clomipramine, a tricyclic antidepressant, and paroxetine, another serotonin reuptake inhibitor, are already approved for this use. (2) In the only available comparative trial the efficacy of citalopram (20-60 mg/day) was similar to that of clomipramine (60-90 mg/day). (3) The safety profile of citalopram is different from that of clomipramine. (4) There are no data clearly comparing citalopram with paroxetine in terms of efficacy, safety, drug interactions, or convenience. (5) Clomipramine is much cheaper than citalopram.     

Imatinib: new indication. Chronic myeloid leukaemia, first-line option: favourable findings to be confirmed

(1) For many years the reference first-line treatment for patients with chronic myeloid leukaemia who do not qualify for bone marrow transplantation was interferon alfa-2, possibly combined with cytarabine. (2) Imatinib, a tyrosine kinase inhibitor, was initially approved for second-line treatment of adults with chronic myeloid leukaemia and in the accelerated phase or blast crisis. This indication has now been extended to cover first-line treatment and children. (3) An unblinded trial in 1106 adults compared imatinib (400 mg/day by mouth) as a first-line treatment with the combination of interferon (5 MIU/m2/day) and cytarabine (20 mg/m2/day, 10 days a month) subcutaneously. After 18 months, imatinib significantly increased progression-free survival rate (92.1% versus 73.5%) and quality of survival, but not overall survival. (4) In the paediatric setting, there are follow-up data from only 17 children who received imatinib as a first- or second-line treatment. The results were similar to those obtained in adults. (5) In the only available trial in adults, the number of treatment withdrawals for adverse events was lower among patients taking imatinib. Fatigue and depression were the two serious adverse events reported more commonly by people taking interferon + cytarabine. (6) Imatinib is given by mouth, which is more convenient than subcutaneous route required for interferon + cytarabine. (7) In practice, pending a second comparative trial and further follow-up, imatinib seems a therapeutic advance in the first-line treatment of chronic myeloid leukaemia.     

Verteporfin: new indication. New indication in complications of high myopia: no sustained benefit

(1) High myopia can lead to subfoveal choroidal neovascularisation with a marked loss of central vision. There is no satisfactory treatment. (2) Marketing authorisation has been granted for verteporfin in this indication. Intravenous verteporfin injection is followed by cold red laser therapy, in one or several sessions. (3) In a multicentre comparative randomised double-blind trial involving 120 patients, verteporfin + cold red laser therapy stabilised visual acuity in 72% of patients after one year of follow-up, compared to 44% of patients who received a placebo + cold red laser therapy. This advantage was lost at two years of follow-up. (4) This trial revealed no new side effects of verteporfin. (5) In practice, for want of anything better, verteporfin-based photodynamic therapy may be helpful, but patients should be told of its limitations.     

Iloprost: new indication. Not adequately assessed

(1) Iloprost, a vasodilatory prostacyclin analogue administered by infusion, is indicated for second-line therapy in patients with severe ischaemia of the lower limbs, when surgical revascularisation fails or is contraindicated. (2) In thromboangiitis obliterans the clinical file on iloprost has remained inadequate since the product was first released. (3) A meta-analysis of 6 clinical trials giving conflicting results in patients with stage III or IV lower-limb arterial disease favoured iloprost. But the results of this meta-analysis are uninterpretable because of methodological biases. It is not known what effects iloprost has in the short term (on pain and skin damage) or in the long term (on the risk of amputation). (4) The iloprost dose must be adjusted individually according to adverse effects linked to vasodilation.     

Modeling addiction: trusted experimental approaches are tried in new applications

The EuroConference/Neurochemistry Winter Conference on Modeling Addiction, held on 6-11 April 2002 in Soelden, Austria(1) explored the question of how various experimental approaches, ranging from those at the level of molecular biology to human behavior, reflect human patterns of drug abuse and dependence and whether these various approaches constitute suitable predictive or homologous models to test novel pharmacotherapies.     

Gabapentin monotherapy: new indication. Sometimes helpful

(1) Gabapentin is now licensed for first-line or replacement monotherapy of partial epilepsy, in patients over 12 years of age. (2) The assessment file concurs with current recommendations of medicines agencies. (3) One comparative trial of first-line monotherapy showed a similar efficacy/adverse effects ratio of gabapentin and carbamazepine. Gabapentin has not been compared with valproate sodium. (4) In one trial, involving patients with refractory epilepsy, various doses of gabapentin were added to an ongoing inadequately effective treatment, which was then gradually stopped. Gabapentin monotherapy was considered satisfactory in a minority of patients. (5) The adverse effects of gabapentin are limited to neuropsychological disorders, namely dizzy spells, drowsiness, fatigue and headache. The risk of interactions is also limited. (6) The optimal dose regimen of gabapentin is not yet established.     

Albendazole: new indication. Useful adjunct in hydatid disease

(1) Albendazole, an antiparasitic drug belonging to the benzimidazoles, is indicated in France for the treatment of hydatid disease and alveolar echinococcosis. (2) According to non comparative data and a small comparative trial, albendazole is helpful when surgical removal and percutaneous drainage of a hydatid cyst are impossible. The best ways to use this treatment are not, however, known. One comparative trial showed the value of albendazole before surgery. Two other comparative trials showed the benefit of combining albendazole with percutaneous drainage, an approach that can replace surgical excision. (3) In the absence of comparative trials we do not know if the prognostic improvement seen in alveolar echinococcosis in recent years can be ascribed to albendazole. (4) Transaminase activity and blood cell counts should be checked regularly (there may be a small risk of neutropenia).     

Palivizumab: new indication. Moderate reduction in hospitalisation rate

(1) Respiratory syncytial virus (RSV) infection is common in infants; it is usually mild except in high risk children. (2) Palivizumab, a monoclonal antibody against RSV, was the first preventive treatment to be marketed in France. The licence was recently extended in France to cover children under 2 years of age who have haemodynamically significant congenital heart disease. (3) Follow-up data from Spanish cohorts of premature infants and infants with bronchopulmonary dysplasia are now available. The data tend to agree, albeit with different levels of evidence, that palivizumab reduces the risk of hospitalisation for RSV infection (3.95% of infants treated with palivizumab, 13.25% of untreated infants), but has no impact on the need for intensive care or on overall mortality. There are no data on the overall risk of hospitalisation. (4) In a randomised double-blind placebo-controlled trial in 1287 infants under 2 years of age with haemodynamically significant heart disease, palivizumab had no effect on mortality. But it did reduce the rate of hospitalisation both for RSV infection (5.3% versus 9.7%) and for all causes (54.9% versus 62.3%). (5) Few adverse effects have been reported after five years of use. The estimated risk of anaphylactic reactions is less than 1 per 100 000 infants. The risk of adverse effects when an infant is treated during a second season is poorly documented. (6) Treatment costs about 5000 euros per season for a 6 kg child. (7) In practice, palivizumab seems useful for the following categories of infants: those aged less than 6 months who were born with a gestational age of less than 32 weeks and who had bronchopulmonary dysplasia at birth; formerly premature infants under 2 years of age who are receiving long-term treatment for pulmonary sequelae; and infants with haemodynamically significant heart disease.     

Caspofungin: new indication. No progress in invasive candidiasis

(1) The reference treatment for invasive candidiasis in patients without neutropenia is standard amphotericin B. If this treatment fails or is too nephrotoxic, second-line alternatives are liposomal amphotericin B and fluconazole. Voriconazole is a third-line option. (2) Caspofungin, an antifungal drug belonging to the echinocandin class, is now approved for use in this indication in France. (3) The clinical evaluation dossier contains no data from comparative trials with fluconazole or voriconazole. It only gives the results of a double-blind trial in 239 patients, designed to show simply that caspofungin was not inferior to standard amphotericin B. Most of the patients did not have neutropenia. About one-third of the patients died. There was no difference in mortality between the two groups. No data are available from trials versus other forms of amphotericin B. (4) In this trial, caspofungin had fewer adverse effects (especially nephrotoxicity) than standard amphotericin B. However, in other trials in other indications, caspofungin had more adverse effects than fluconazole. (5) In France, caspofungin costs nearly 100 times more than standard amphotericin B. (6) In practice, caspofungin has no proven advantages over existing options for the treatment of invasive candidiasis in patients without neutropenia.     

Vigabatrin: new indication. An advance in infantile spasms

In children with infantile spasms, vigabatrin monotherapy has been assessed in three published comparative trials. The small numbers of patients make it impossible to draw precise conclusions on effectiveness. However, a few days' treatment with a dose of about 100 mg/kg/day clears infantile spasms in a larger proportion of cases than a placebo or steroids. Vigabatrin seems to be more effective in Bourneville disease. The effect is sometimes transient: despite continued treatment, spasms or other types of epilepsy occur in approximately 50% of patients who are initially improved. In a trial versus ACTH, the lesser initial efficacy of vigabatrin was partly offset by a lower incidence of relapse and other types of seizures. Vigabatrin is effective in some children who are resistant to ACTH or steroids. As with steroids and ACTH, there is no proof that vigabatrin improves the long-term psychomotor development of these children. In comparative trials the incidence of adverse events was statistically lower on vigabatrin than on steroids. Most of the events were relatively mild neuropsychological effects, but a question mark still hangs over the possible neurotoxicity or oculotoxicity of vigabatrin during long-term administration.     

Octreotide and bleeding oesophageal varices: new indication. Nothing new

(1) Octreotide, a synthetic somatostatin analogue, is now also indicated for emergency treatment of ruptured oesophageal varices pending endoscopic treatment. (2) The assessment file in this indication is limited. (3) The two available comparative trials show no difference in efficacy compared with terlipressin, but their statistical power was low. Octreotide has not been compared with somatostatin, the efficacy of which is not clearly established either. (4) A placebo-controlled trial, published only as an abstract, showed no specific activity of octreotide on bleeding oesophageal varices. (5) There are few reports of adverse effects with octreotide. There is nothing to suggest that its adverse effects differ from those of somatostatin, when the drug is used in patients who cannot tolerate terlipressin. Octreotide is no easier to administer than somatostatin or terlipressin.     

Fluvoxamine: new indication. No progress in obsessive-compulsive disorder

(1) Four drugs are approved in France for patients with obsessive-compulsive disorders, namely clomipramine and three selective serotonin reuptake inhibitors (SSRIs): fluoxetine, paroxetine and sertraline. None of the four has emerged as a reference treatment. For children with obsessive-compulsive disorder, the treatment hierarchy is as follows: psychotherapy; behaviour therapy; clomipramine; sertraline. (2) Fluvoxamine, another SSRI, has now been approved in France for the treatment of obsessive-compulsive disorder in patients aged at least 8 years, after European harmonisation of SPCs for fluvoxamine-based preparations. (3) In adults, two placebo-controlled trials and the six trials versus clomipramine show that fluvoxamine, like clomipramine, is only partially effective (about one-third of patients "respond"). (4) In the only placebo-controlled trial in 120 children and adolescents aged from 8 to 17 years, who were treated for 10 weeks, efficacy was even more modest (response rate 15%, compared to 10% with placebo). (5) The safety profile of fluvoxamine is the same as that of all SSRIs but it has a potential for more drug interactions. (6) In practice, approval of fluvoxamine in adults or children with obsessive-compulsive disorder will have no impact on their management.     

Alteplase: new indication. Inadequately assessed in ischaemic stroke

(1) Alteplase is the first thrombolytic drug to be approved in France for the treatment of ischaemic stroke within three hours of symptom onset. (2) The clinical evaluation dossier contains nine placebo-controlled trials, of which six were relatively large. In the two NINDS trials (624 patients in total), treatment was started within the first three hours and it showed no survival benefit. Near-complete functional recovery was more frequent in the alteplase group than in the placebo group. In the two ECASS trials (620 and 800 patients) and the ATLANTIS trials (142 patients and 613 patients), treatment was started within the first six hours and it showed no significant benefit in terms of survival or functional recovery. (3) There are two meta-analyses of these trials. They confirm the lack of a survival benefit with alteplase. Using a combined endpoint, one meta-analysis showed that treating 1000 patients with alteplase prevented death or major disability (dependency) in 55 patients. The other meta-analysis underlined the importance of a short interval between the onset of symptoms and the beginning of treatment. (4) Intracranial haemorrhage is the most important adverse effect. One meta-analysis showed that alteplase caused 62 additional symptomatic intracranial haemorrhages (including 25 deaths) per 1000 treated patients. (5) Various retrospective subgroup analyses have tentatively identified subgroups of patients at a particularly high risk of adverse effects, but subgroup analyses provide only weak evidence. The patients most likely to benefit from alteplase, started within three hours of symptom onset, remain to be defined. (6) The current health infrastructure in France would allow only a small number of stroke patients to be treated with alteplase under the kind of conditions prevailing in clinical trials (imaging to confirm ischaemic stroke, and treatment very soon after the onset of symptoms). (7) In practice, there is a narrow margin between the wanted and unwanted effects of alteplase. This treatment should be used only by specialised teams and for strictly selected patients. Research must continue, particularly to identify those patients most likely to benefit from alteplase, and those most likely to be harmed in whom thrombolysis is contraindicated.     

Thalidomide: new indication. A last resort in myeloma

(1) There is no reference treatment for patients with multiple myeloma who have relapsed, or not responded to first-line treatment. (2) Thalidomide has been granted temporary authorization in France for patients with multiple myeloma who have no other therapeutic option. (3) A non comparative trial of thalidomide therapy in 169 patients showed an increase in the survival time of a few months with an oral dose of 200 mg to 800 mg/day. In other trials the main endpoint was a fall in the circulating level of monoclonal immunoglobulin. (4) Three non comparative trials of the thalidomide + dexamethasone combination failed to show a survival advantage relative to thalidomide alone. There is no evidence that adding one or several cytotoxic agents to this combination improves outcomes, but assessment is limited to three small non comparative trials. (5) Thalidomide has many adverse effects, including neuropathies (often irreversible) and venous thromboembolism. It is highly teratogenic, and its use by men and women of childbearing potential is subject to strict conditions. (6) In practice, thalidomide monotherapy is justified for patients with multiple myeloma who have no other therapeutic option. All patients should be given comprehensive information on the risk-benefit ratio of this drug.