Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper.

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.

[Management of the cardiovascular complications of treatment in thoracic oncology]. / Prise en charge des complications cardiovasculaires des traitements en oncologie thoracique.

The management of patients suffering from bronchial and lung tumors depends on conventional chemotherapy and/or targeted molecular therapies. The prescription of these chemotherapies may be accompanied by cardiovascular complications, principally congestive heart failure, arterial hypertension and arterial or venous thrombo-embolism, the frequency of which varies with the molecule administered. The management of these complications is currently poorly standardized and should take account of the patient's oncological prognosis.

No evidence for relevant QT interval prolongation in mitotane-treated patients with adrenocortical carcinoma.

OBJECTIVE: We designed a single-center retrospective study to assess the QT interval duration and to describe cardio vascular events among patients treated with mitotane for a adrenocortical carcinoma (ACC). DESIGN: We selected 14 patients (6 males and 8 females) that met the following criteria: ACC treated with mitotane, for whom an electrocardiogram (ECG) at baseline (before mitotane initiation) was available and for whom at least one ECG was available during the course of mitotane therapy together with a concomitant mitotane plasma level determination. RESULTS: Mean mitotane plasma level at baseline and after treatment showed a significant increase (mean level increased from 0 to 14.9±2 mg/l). At baseline and before mitotane was initiated all QTc intervals were <450 msec for men and <460 msec for women. During the treatment phase with mitotane, no QTc>470 msec was found in any patients respectively for men and women. In addition, no patient showed any significant QTc prolongation (>5% or >10 msec) at any time during mitotane treatment. During a mean follow-up of 15.9±3.5 months (range 2-45 months). No cardiovascular deaths or hospitalization for cardiovascular events was documented. No torsades de pointes were documented on ECG. No syncope, dizziness, heart failure were observed during follow up. Six out of 14 patients died during the follow-up, in five cases due to the progression of the disease, one patient died suddenly at home during followup. CONCLUSION: This short and retrospective series shows no evidence that mitotane induce any QT prolongation, even when plasma levels are well above the therapeutic window.

[Use of sorafenib in patients with hepatocellular or renal carcinoma]. / Bon usage du sorafénib chez les patients pris en charge pour un carcinome hépatocellulaire ou un cancer du rein.

Therapeutic approaches of cancers have been recently improved by the development of targeted therapies. Amongst these new drugs, some anti-angiogenic molecules have been approved by either the EMEA or the Food and Drug Administration. Sorafenib, one of these inhibitors of angiogenesis, has been established as the standard of care for advanced hepatocellular and renal carcinoma. This paper reviews the safety profile of sorafenib and presents guidelines for the prevention and the treatment of the main side effects associated with this molecule.

Management of hypertension in angiogenesis inhibitor-treated patients.

BACKGROUND: Hypertension (HTN) is one of the most frequent side-effects of systemic inhibition of vascular endothelial growth factor (VEGF) signaling. Its incidence and severity are dependent on the type of drugs, dose, and schedule used. The recognition of this side-effect is an important issue because poorly controlled HTN could lead to serious cardiovascular events. On another hand, HTN induced by anti-VEGF agents maybe a predictive factor of oncologic response. Knowledge of this clinical toxicity and/or therapeutic target or novel biomarker of drug activity can aid clinicians choosing the optimal and least toxic regimen suitable for an individual patient. METHODS: A Medline search was carried out using the following criteria: (i) all Medline listings as of 1 January 2000 with abstracts, (ii) English language, and (iii) Humans. The following phrases were used to query the database: ('hypertension', OR 'blood pressure') AND ('anti-VEGF' OR 'VEGF inhibition' OR 'bevacizumab' OR 'sunitinib' OR 'sorafenib' OR 'VEGF Trap'). The references of each article identified were carefully reviewed for additional reference. RESULTS: Lifestyle modification should be encouraged. However, these nonpharmacologic strategies are not always suitable to patients with altered performance status related to metastatic cancer necessitating early drug intervention. Only one randomized study showed a beneficial effect of a calcium channel blocker use to prevent or minimize HTN secondary to antiangiogenic therapy. Nitrates looks as effective in controlling such side-effect. CONCLUSIONS: No clear recommendation for an antihypertensive agent can be made in this context because there is a lack of controlled studies addressing the subject. Blood pressure-lowering drugs should be individualized to the patient's clinical circumstances and angiogenic inhibitors should be withheld only from patients who experienced hypertensive crisis.

Coronary artery bypass graft in HIV-infected patients: a multicenter case control study.

Coronary artery disease (CAD) is an emerging complication in HIV-infected patients treated with highly active antiretroviral therapy. Immediate results and long-term outcome after coronary artery bypass graft (CABG) have not been yet evaluated in this population. Between January 1997 and December 2005, we compared baseline characteristics, immediate results and clinical outcome [Major Adverse Cardiac Events (MACE): death for cardiac cause, myocardial infarction (MI), coronary revascularization] at 41 months in 27 consecutive HIV-infected (HIV+) patients and 54 HIV-uninfected (HIV-) controls matched for age and gender (mean age of the cohort, 49+/-8 years; 96% male) who underwent CABG. Cardiovascular risk factors were well-balanced and nearly identical in both groups. In HIV+ group, mean preoperative CD4 was 502+/-192/mm(3) compared with 426.2+/-152.6/mm(3) postoperatively (p=0.004) without clinical manifestations at follow-up. At 30-day, the rate of post-operative death, MI, stroke, mediastinitis, re-intervention was identical in both groups. At follow-up [median: 41-months (range: 34-60)], rate of occurrence of 1(st) MACE was higher in HIV+ group compared with HIV- group (11, 42% versus 13, 25%, p=0.03), mostly due to the need of repeated revascularization using percutaneous coronary intervention of the native coronary arteries but not of the grafts in the HIV+ group [9 (35%) versus 6 (11%), p=0.02]. CABG is a feasible and safe revascularization procedure in HIV+ patients with multivessel CAD. Immediate postoperative outcome was similar compared to controls. However, long-term follow-up was significantly different, due to an increased rate of repeated revascularization procedure in the native coronary arteries of HIV+ patients.

[Low molecular weight heparin and non valvular atrial fibrillation]. / Héparines de bas poids moléculaire et fibrillation auriculaire non valvulaire.

Low molecular weight heparin (LMWH) are obtained through chemical or enzyme depolymerisation of unfractioned heparins (UFH). LMWHs present several advantages over UFH: they exhibit a smaller interindividual variability of the anticoagulant effect, they have a greater bioavailability, a longer plasma half-life and do not require monitoring of the anticoagulant effect. LMWH have restrictive indications in AF patients, cardioversion (II level C and TEE for ACC/AHA/ESC and 2C for ACCP guidelines) or use as a bridge therapy (IIB, level C for ACC/AHA/ESC). The ACE study (Anticoagulation for cardioversion using enoxaparin), showed a reduction, though not statistically significant, of 42% of the composite end point (embolic event, major bleeding and death) 2.8% under enoxaparin vs. 4.8 % under conventional treatment, relative risk 0.58, CI 95% 0.23-1.46). Other studies, using dalteparin, confirmed that an anticoagulant treatment using LMWH followed by warfarin was at least as good as conventional management. ACUTE II (Assessment of cardioversion using transesophageal echochardiography), a randomized multicenter trial, compared the efficacy and tolerance of enoxaparin (1 mg/kg every 12 hours) and UFH in 155 patients eligible for a TEE-guided cardioversion. These patients were administered LMWH or UFH for 24 hours before TEE or cardioversion. There were no significative differences regarding the incidence of the study end points, in particular stroke and bleeding, and no death occurred. HAEST (Heparin in acute embolic stroke trial), a randomized, placebo-controlled, double blind trial failed to show the LMWH superiority over aspirin in patients with acute ischemic stroke and atrial fibrillation. Finally, LMWH have been proposed as a bridge therapy in patients under chronic VKA prior to surgery or invasive procedures. This strategy resulted in a low rate of thromboembolic events and major bleedings.

Clinical characteristics and mid-term prognosis of acute coronary syndrome in HIV-infected patients on antiretroviral therapy.

OBJECTIVES: Acute coronary syndromes (ACSs) and coronary artery disease are emerging complications in HIV-infected patients on highly active antiretroviral treatment. The aim of this study was to determine the mid-term prognosis of ACS in HIV-infected patients. METHODS: We evaluated the clinical characteristics and follow-up profile [38+/-15 months; mean+/-standard deviation (SD)] of ACS in 20 HIV-infected patients (mean +/-SD: age 44+/-8 years; range 35-65 years). All had coronary angiograms performed mean time 3+/-48 h after the onset of symptoms. RESULTS: Eighteen patients were on antiretroviral therapy, of whom 13 patients were on regimens including protease inhibitors (mean duration+/-SD: 19+/-13 months). Fifteen patients had a first episode of ST segment elevation ACS and five had non-ST segment elevation ACS. Tobacco consumption (80%) and hypercholesterolaemia (50%) were the most frequent cardiovascular risk factors. During initial hospitalization, four patients were treated with thrombolysis, two had primary coronary angioplasty and seven had secondary coronary angioplasty. At follow up, 10 patients (50%) had had 18 cardiovascular events: one cardiovascular death, seven episodes of recurrent myocardial ischaemia in four patients, three pulmonary oedemas in two patients, and seven revascularization procedures in five patients. CONCLUSIONS: This preliminary report highlights the risk of ACS and related complications in HIV-infected patients and raises questions regarding the implications of antiretroviral treatment.