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About one-quarter of cases of non- small cell lung cancer are diagnosed sufficiently early, i.e. at stages I to lIlA, to envisage surgical resection. Despite this surgery, the prognosis remains poor. In 2016, what is the harm-benefit balance of chemotherapy in addition to surgical resection of early-stage non-small cell lung cancer? We con- ducted a review of the literature using the standard Prescrire methodology. In 38 trials including about 11 000 patients, the 5-year survival rate rose from 60% to 64% when surgery was followed by chemotherapy in patients who mainly had stage IB or I disease, and from 29% to 33% in patients with mainly stage Ill disease who also received radiation therapy. The chemo- therapy regimens used in most of these trials consisted of cisplatin plus a vinca alkaloid such as vinorelbine. In 15 trials including more than 2000 patients, most of whom had resectable stage IB, IIB or lIlA disease, platinum-based chemotherapy given before surgery raised the 5-year sur- vival rate from 40% without chemo- therapy to 45%. There are too few data to assess the impact of chemotherapy on sur- vival among patients who undergo surgery for stage IA disease. About two-thirds of patients who receive platinum-based chemotherapy experience serious adverse effects, and at least 1% of patients die from toxicity. The most common adverse effects are haematological disorders. Tyrosine kinase inhibitors and angiogenesis inhibitors have not been shown to improve survival among patients with resectable non-small cell lung cancer. Clinical guidelines published since 2010 recommend cisplatin-based chemotherapy for patients with resect- able stage IIB or lIlA disease. There is some disagreement concerning stage IB and IIA disease. In practice, clinical trials show that adjuvant chemotherapy improves the 5-year survival rate by a few percent- age points among patients who under- go surgical resection for non-small cell lung cancer. Adjuvant chemother- apy with cisplatin and a vinca alkaloid is thus a reasonable choice for surgi- cal patients (except those with a local- ised tumour measuring ≤ 3 cm), who accept its toxicity, with the hope of a slightly longer survival. It is also a reasonable option for patients to forgo chemotherapy.

Diethylstilbestrol(DES) is a synthet- ic nonsteroidal oestrogen and endo- crine disruptor that was used in the 1950s-1970s to prevent spontaneous abortion, despite its lack of proven efficacy. Millions of women worldwide took DES during pregnancy. In France, between 1951 and 1981, about 160 000 children were exposed to DES during the first trimester of their intrauterine life, and in some cases almost throughout the entire pregnancy. They are referred to as "DES daughters" and "DES sons". In 2010, in France, about 25 000 DES daughters were aged 33 to 40 years: pregnancies among these women are foreseeable until about 2020. In utero exposure to DES can have harmful effects. In particular, DES daughters have an increased risk of cancer and structural abnormalities of the uterus that can adversely affect their pregnancies. What are the consequences of tak- ing DES during pregnancy for the third generation, i.e. the children of DES children? To answer this question, we reviewed the available data in mid- 2016 using the standard Prescrire methodology. According to a retrospective study conducted in France by Réseau DES France, published in 2016, which included 4409 DES grandchildren (2228 girls and 2181 boys) and about 6000 controls, about one-quarter of DES grandchildren are born prematurely. Preterm delivery exposes neonates to serious neonatal complications, including neurosensory disorders, disabilities and increased neonatal mor- tality. The more premature the baby, the greater the risk of complications. In the Réseau DES France study, cerebral palsy was more frequent in the DES grandchildren group: 59/10 000, versus 6/10 000 in the control group. A study conducted in the United States in about 4500 DES daughters found that preterm delivery occurred at a frequency of about 26%, much higher than that reported in controls. Neonatal mortality was 8 times higher among DES grandchildren, and the risk of stillbirth was twice as high. Other smaller studies have also shown an increased risk of preterm birth. A cohort study conducted in about 5000 DES grandchildren found that the risk of malformations of any type was higher than in the unexposed control group. Epidemiological studies, conduct- ed in several countries, found an increased frequency of hypospadias in DES grandsons. The relative risk was about 5 in the largest study. Other, less robust studies found no statistically significant difference. Several studies in several countries have shown a twofold increase in the risk of oesophageal atresia or tracheo- oesophageal fistula in DES grandchildren. The data on congenital heart defects or musculoskeletal malformations are limited and uninformative. Epidemiological studies have not identified a significant increase in the risk of gynaecological anomalies or cancers in DES granddaughters. Limited data are available on the risk of malformations in the children of DES sons. The data obtained in rodents exposed to DES (and other endocrine disruptor

Existing drugs are poorly effective in patients with inoperable or meta- static melanoma without a mutation in the BRAF gene at position V600. The first-line treatment of choice for patients with BRAF V600-positive melanoma is a combination of dabrafenib (a BRAF inhibitor) and trametinib. Nivolumab is a human monoclonal antibody designed to block receptors for PD-1 (programmed cell death-1) and thus to enhance T lymphocyte activity, especially against tumour cells. Nivolumab has been authorised in Europe as monotherapy for patients with inoperable or metastatic melanoma, regardless of BRAFV600 status. Nivolumab has not been compared with the dabrafenib + trametinib combination in patients with BRAF V600-positive melanoma. A randomised double-blind trial ver- sus dacarbazine involved 418 patients with inoperable or metastatic BRAF V600-negative melanoma who had not yet received medication for this stage of the disease.The trial was halted prematurely when an unscheduled analysis showed an improvement in one-year survival with nivolumab compared to dacarbazne(73% versus 42%, p<0.0001). A double-blind trial compared first-line treatment with nivolumab, ipili- mumab or a combination of the two drugs.The mortality results are not yet available in mid-2016.The median time to melanoma aggravation or death was 6.9 months in the nivolumab group, 2.9 months in the ipilmumab group, and 11.5 months with the com- bination (p<0.001). A comparative, randomised, unblinded trial included 405 patients with metastatic or inoperable melanoma in whom at least one drug had failed. An interim analysis conducted after about two years showed no stat- istically significant difference in medi- an survival between patients who received nivolumab and those who received cytotoxic drugs. As expected, given its protein structure and mechanism, the adverse effects of nivolumab are mainly due to immunological mechanisms.They are numerous and affect many organs: skin rash and toxic epidermal necrolysis, thyroid dysfunction, hepatitis, pneumonia, colitis and encephalitis. Adverse effects were serious in 9% of patients, and a few cases were fatal. In practice, first-line nivolumab monotherapy was significantly more effective than dacarbazine in a trial in patients with BRAF V600-negative inoperable or metastatic melanoma. Although its evaluation must continue, nivolumab already seems to be a better option than dacarbazine and ipilimumab for treatment-naive patients, provided they receive detailed and balanced information on the uncertainties, efficacy and adverse effects of this new drug. For other patients, there is no evidence that nivolumab monotherapy represents an advantage over other available treatments.

In 2014, Prescrire launched a new distance-learning practice improve- ment programme for subscribers to our French edition, called M6dicaments en Questions (Medicines in Question).The aim of this programme is to help healthcare professionals take greater account of the harmful effects of drug treatments in their daily practice, manage adverse effects better, and help to reduce their inci- dence and severity. This programme is based on a reflexive approach: participants describe, analyse and compare their practices; update and improve their knowledge base; exchange ideas with other health professionals; and devel- op strategies for improvement. The results of the first session (2014-2015) have been encouraging: participants took greater account of adverse effects, exposed fewer patients to the harms of drugs that have an unfavourable harm-benefit balance, communicated better with other healthcare professionals, found it easier to discuss adverse effects with patients, and were encouraged to report adverse effects to the public pharmacovigilance system.

About 50% of patients with meta- static or inoperable melanoma carry a tumour with BRAF V600 mutation.The drug of first choice for these patients is vemurafenib, a BRAF inhibitor, which appears to prolong survival by a few months. Dabrafenib is a vemurafenib me-too with a slightly different known profile of adverse effects. Trametinib, a MEK inhibitor, is now authorised in the European Union for use in this setting, either as monotherapy or in combination with dabrafenib (marketed by the same company). Trametinib monotherapy has not been compared to BRAF inhibitor monotherapy. In a randomised, unblinded trial versus cytotoxic drugs in 322 patients, the median survival time did not differ statistically between the groups (15.6 versus 11.3 months; p = 0.09), but 65% of patients in the chemotherapy group received trametinib after disease pro- gression, making it more difficult to detect a difference between the groups. In an unblinded randomised controlled trial in 704 patients who had never received treatment for metastatic or inoperable disease, the trametinib + dabrafenib combination prolonged median survival by about 8 months more than vemurafenib. In another double-blind randomised controlled trial in 423 patients, median survival was about 6 months longer with trametinib + dabrafenib than with placebo + dabrafenib. The trametinib+ dabrafenibcombination was poorly effective after BRAF inhibitor failure in non-comparative trials including a few dozen patients in which the only endpoint was tumour response. Trametinib has many adverse effects, some of which can be life-threatening, such as heart failure, deep vein thrombosis, bleeding (including intracranial haemorrhage), neutropenia, and gastrointestinal perforation. Trametinib also causes retinal disorders and pneumonitis. Combining trametinib with dabrafenib reduces the risk of hyperkeratosis and skin cancer associated with dabrafenib, but increases the frequency of fever (including very high fever). Trametinib interactions mainly involve additive effects or antagonism. In practice, when a patient with metastatic or inoperable BRAF V600-positive melanoma is willing to accept the significant toxicity of trametinib in the hope of gaining several extra months of life, the trametinib + dabrafenib combination is a first-line option.