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Practice Changing UpDates
Authors:
H Nancy Sokol, MD
April F Eichler, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2018. | This topic last updated: Apr 03, 2018.

INTRODUCTION — This section highlights selected specific new recommendations and/or updates that we anticipate may change usual clinical practice. Practice Changing UpDates focus on changes that may have significant and broad impact on practice, and therefore do not represent all updates that affect practice. These Practice Changing UpDates, reflecting important changes to UpToDate over the past year, are presented chronologically, and are discussed in greater detail in the identified topic reviews.

ONCOLOGY (March 2018)

Durvalumab in non-small cell lung cancer

For patients with unresectable stage III non-small cell lung cancer whose disease has not progressed following concurrent platinum-based chemotherapy and radiation, we suggest the programmed death-ligand 1 (PD-L1) antibody durvalumab (Grade 2B).

Despite administration of chemoradiotherapy, the prognosis for unresectable stage III non-small cell lung cancer (NSCLC) remains poor. In a phase III trial, over 700 patients with stage III NSCLC without progression after at least two cycles of platinum-based chemoradiotherapy were randomly assigned to the programmed death-ligand 1 (PD-L1) antibody durvalumab or to placebo [1]. Durvalumab increased the median duration of progression-free survival (16.8 versus 5.6 months), with comparable rates of severe adverse events. Overall survival results are immature. In February 2018, based on these data, the US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemoradiotherapy [2], and we now suggest its use in this setting. However, some experts may reasonably opt to avoid this additional treatment, given the lack of mature overall survival data and the potential for toxicity associated with immunotherapy. (See "Management of stage III non-small cell lung cancer", section on 'Immunotherapy'.)

ADULT PRIMARY CARE, FAMILY MEDICINE, GERIATRICS, INFECTIOUS DISEASES (October 2017, Modified February 2018)

Vaccination to prevent herpes zoster

For most patients who meet criteria for zoster vaccination, we suggest the recombinant zoster vaccine (RZV) rather than the live attenuated zoster vaccine (ZVL) (Grade 2B). For patients who previously received ZVL, we suggest revaccination with RZV (Grade 2C).

Two vaccines are available to prevent herpes zoster and postherpetic neuralgia in patients ≥50 years of age: a recombinant glycoprotein E vaccine (recombinant zoster vaccine [RZV], approved for use in the United States in October 2017) and a live attenuated vaccine (zoster vaccine live [ZVL]). We suggest RZV rather than ZVL for most patients who meet criteria for vaccination. RZV appears to provide greater protection against herpes zoster, and there is less concern for waning immunity. The choice of RZV as the preferred type of vaccine is consistent with recommendations from the Advisory Committee on Immunization Practices [3]. Disadvantages of RZV are the need for two doses (versus one with ZVL), and an increased risk of mild to moderate side effects (pain at the injection site, myalgia, fatigue, headache, fever) that typically resolve in one to three days. These factors rarely prevent patients from completing the RZV series. For patients who previously received ZVL, we suggest revaccination with RZV. The optimal use of RZV in immunocompromised patients is still to be determined. (See "Vaccination for the prevention of shingles (herpes zoster)".)

NEUROLOGY (February 2018)

Time window for mechanical thrombectomy after acute ischemic stroke

For patients with ischemic stroke caused by a large artery occlusion in the proximal anterior circulation who cannot start treatment within six hours of the time they were last known to be well, intra-arterial mechanical thrombectomy from 6 to 24 hours is recommended if there is evidence of a mismatch between specific clinical and imaging criteria (Grade 1B).

Randomized trials have established that intra-arterial mechanical thrombectomy improves neurologic outcomes when started within six hours of symptom onset for patients with ischemic stroke caused by a large artery occlusion in the proximal anterior circulation. Newer evidence from the DAWN and DEFUSE 3 trials shows that the benefit of mechanical thrombectomy for stroke due to occlusion of a proximal large artery in the anterior circulation extends to patients who are selected by imaging criteria and can be treated within 6 to 24 hours of the time last known to be well [4,5]. This includes patients with "wake-up" strokes who were well before going to bed but had stroke symptoms upon awakening.

The DAWN trial selected patients within 6 to 24 hours of the time they were last known to be well who had a clinical deficit that was disproportionally severe compared with the volume of infarction on diffusion-weighted magnetic resonance imaging (MRI) or perfusion computed tomography (CT) [4]. At 90 days, the rate of functional independence was greater for the thrombectomy group compared with standard care (49 versus 13 percent).

The DEFUSE 3 trial selected patients within 6 to 16 hours of the time they were last known to be well who had a mismatch between the volume of hypoperfused tissue and the volume of infarction on diffusion-weighted MRI or CT perfusion imaging [5]. At 90 days, the percentage of patients who were functionally independent was higher with mechanical thrombectomy compared with medical therapy alone (45 versus 17 percent).

These data support the use of mechanical thrombectomy from 6 to 24 hours for selected patients who present to a stroke center with expertise in both mechanical thrombectomy and infarct volume determination using MRI or perfusion CT. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Benefit of later treatment'.)

CARDIOVASCULAR MEDICINE (February 2018)

Catheter ablation for atrial fibrillation with heart failure

For selected patients with symptomatic atrial fibrillation (AF) and heart failure with reduced ejection fraction, in whom antiarrhythmic drug therapy has failed, we suggest catheter ablation of AF rather than continued attempts with antiarrhythmic drug therapy or no antiarrhythmic drug therapy (Grade 2B).

For many patients with heart failure (HF) and atrial fibrillation (AF), we prefer a rhythm to a rate control strategy for AF management. Rhythm control can be achieved with medical therapy (eg, antiarrhythmic drugs) or catheter ablation (CA). The strongest evidence supporting the use of CA in many of these patients comes from the CASTLE-AF randomized trial that compared CA with medical therapy (rate or rhythm control) in 363 patients with symptomatic paroxysmal or persistent AF; New York Heart Association class II, III, or IV HF; a left ventricular ejection fraction of ≤35 percent; failure or unwillingness to take antiarrhythmic drug therapy; and an implanted cardioverter-defibrillator [6]. CA significantly reduced the primary composite end point of death from any cause or hospitalization for worsening HF. Based on the results of CASTLE-AF, we now suggest CA as an appropriate treatment for selected patients with AF and HF for whom initial attempts at antiarrhythmic therapy were ineffective. (See "The management of atrial fibrillation in patients with heart failure", section on 'Catheter ablation'.)

ONCOLOGY (January 2018)

Adjuvant therapy for cutaneous melanoma

In most patients with BRAF wild type or unknown stage III cutaneous melanoma or stage IV disease who have undergone definitive resection of all sites of disease, we recommend adjuvant nivolumab rather than ipilimumab (Grade 1B). In patients whose tumor contains a BRAF V600 mutation, we suggest adjuvant nivolumab rather than targeted therapy (Grade 2C).

Patients with cutaneous melanoma and positive lymph nodes (stage III) at initial definitive surgery and those with distant metastases (stage IV) who undergo definitive resection of all sites of metastatic disease stage are at increased risk for recurrence and subsequent death due to metastatic melanoma (table 1A-B). In a phase III trial, nivolumab, a checkpoint inhibitor targeting programmed cell death protein 1 (PD-1), increased progression-free survival compared with ipilimumab and was associated with decreased toxicity [7]. Based upon these results, nivolumab was approved by the US Food and Drug Administration as adjuvant therapy for cutaneous melanoma [8]. Nivolumab is now our preferred agent for adjuvant therapy in most patients with stage III cutaneous melanoma and those with stage IV disease who have undergone definitive resection of all metastatic sites; targeted therapy is also an option in patients with BRAF-mutant melanoma. (See "Adjuvant therapy for cutaneous melanoma", section on 'Nivolumab'.)

INFECTIOUS DISEASES, ADULT PRIMARY CARE, PEDIATRICS (September 2017, Modified January 2018)

Third dose of MMR for prevention of mumps in an outbreak setting

For individuals who are part of a group identified by public health authorities as being at increased risk for mumps because of an outbreak and who previously completed a two-dose series of mumps virus-containing vaccine prior to outbreak onset, we suggest a third MMR dose (Grade 2C).

In January 2018, the Advisory Committee on Immunization Practices (ACIP) recommended that, in the setting of a mumps outbreak, individuals who have been previously vaccinated with two doses of the measles, mumps and rubella (MMR) vaccine receive a third dose of mumps virus-containing vaccine [9]. We are in agreement with this approach, which is supported by a study performed during a mumps outbreak at a university with over 20,000 enrolled students [10]. Almost all students had previously received two MMR doses; nearly 5000 received a third dose following the outbreak onset. In an adjusted analysis, the third MMR dose was associated with a 60 percent lower risk of mumps at seven days after vaccination. In subgroup analysis, the mumps attack rate was lowest for students who had received their second dose of MMR within two years of the outbreak, compared with those who completed the two-dose MMR series more than two years earlier. Given that the benefit of a third MMR dose increases with time since receipt of the second MMR dose, it is reasonable to prioritize booster vaccination to those who have had longer intervals since their previous MMR immunization. (See "Mumps", section on 'Prevention'.)

PEDIATRICS, ADULT PRIMARY CARE, PULMONARY AND CRITICAL CARE MEDICINE (December 2017)

Tezacaftor-ivacaftor approved for cystic fibrosis

For patients 12 years and older with cystic fibrosis who are homozygous for the F508del mutation, we recommend treatment with tezacaftor-ivacaftor (Grade 1B). We also suggest tezacaftor-ivacaftor for patients who have one of several specific residual function mutations (Grade 2B).

Cystic fibrosis transmembrane regulator (CFTR) modulators are a new class of drugs that improve production, intracellular processing, and/or function of the defective CFTR protein. Tezacaftor-ivacaftor, a new combination of CFTR modulators, was approved by the US Food and Drug Administration (FDA) in February 2018 for patients 12 years or older who have homozygous mutations of F508del (the most common CFTR genotype and associated with severe disease), or who have at least one "residual function" mutation as listed in the table (table 2). The approval for F508del homozygotes was based upon a randomized trial that reported modest improvement in pulmonary function and lower risk of pulmonary exacerbations over the duration of the trial, and a good safety profile [11]. Similar findings were reported in a second trial in patients with compound heterozygosity for F508del and a residual function mutation [12]. Expansion of the FDA approval to include patients with a residual function mutation was based upon in vitro data [13]. Selection of CFTR modulators depends upon the patient’s genotype and age, as summarized in the table (table 3). (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Tezacaftor-ivacaftor for homozygous F508del and residual function mutations'.)

INFECTIOUS DISEASES; OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (November 2017)

Elvitegravir-cobicistat use during pregnancy

For HIV-infected women who become pregnant while on an elvitegravir-cobicistat-containing regimen, we suggest switching to a different regimen (Grade 2C).

Preferred antiretroviral regimens for pregnant women differ somewhat from those for the general HIV-infected adult population, in part because of altered pharmacokinetics during pregnancy. Recently updated Department of Health and Human Services perinatal guidelines now state that elvitegravir-cobicistat should not be selected as part of an initial antiretroviral regimen for treatment-naïve pregnant women because of emerging data suggesting decreased drug levels during pregnancy and an associated risk of loss of virologic suppression [14,15]. Furthermore, if an HIV-infected woman is already receiving a suppressive elvitegravir-cobicistat-containing regimen when she becomes pregnant, we suggest switching to a different regimen; if elvitegravir-cobicistat is continued, the potential risks and need for close viral monitoring should be discussed. (See "Antiretroviral and intrapartum management of pregnant HIV-infected women and their infants in resource-rich settings", section on 'On ART with viral suppression'.)

NEPHROLOGY AND HYPERTENSION (November 2017)

Acetylcysteine does not prevent contrast nephropathy

For patients undergoing angiography who are at increased risk for contrast nephropathy, we suggest that acetylcysteine not be given, either orally or intravenously (Grade 2B).

Radiocontrast media may cause acute kidney injury (AKI) among high-risk patients. Earlier studies have been inconsistent but indicated that the administration of oral acetylcysteine may decrease the risk of AKI, and led to our previous suggestion to administer acetylcysteine before and the day of angiography to patients at risk of contrast nephropathy. A recent randomized trial in over 5000 patients at increased risk for nephropathy who were undergoing scheduled angiography found that oral acetylcysteine, compared with placebo, did not prevent death, need for dialysis, or decline in kidney function [16]. The trial was a 2 by 2 factorial design and also compared intravenous sodium bicarbonate with isotonic saline, finding no benefit for sodium bicarbonate. UpToDate recommends giving isotonic saline rather than sodium bicarbonate and now suggests not giving acetylcysteine prior to angiography. (See "Prevention of contrast nephropathy associated with angiography", section on 'Acetylcysteine'.)

HEMATOLOGY, ADULT PRIMARY CARE, FAMILY MEDICINE AND GENERAL PRACTICE, GASTROENTEROLOGY AND HEPATOLOGY (November 2017)

Frequency for dosing of oral iron

For individuals with iron deficiency who are treated with oral iron, we suggest that the dose be taken every other day rather than every day (Grade 2C).

For many years, iron deficiency has been treated with oral iron given at least once per day, despite significant gastrointestinal side effects in the majority of individuals. A small, unblinded randomized trial has now demonstrated that giving oral iron every other day rather than every day resulted in greater iron absorption and fewer gastrointestinal side effects [17]. Alternate-day dosing is also supported by mechanistic studies that showed favorable effects on hepcidin, a negative regulator of intestinal iron absorption and iron release from macrophages. We now suggest that patients treated with oral iron for iron deficiency take the iron every other day rather than daily. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)

GASTROENTEROLOGY AND HEPATOLOGY, ADULT PRIMARY CARE, FAMILY MEDICINE AND GENERAL PRACTICE (November 2017)

Revised recommendations for endoscopy in the evaluation of dyspepsia

Patients ≥60 years of age with new onset dyspepsia should undergo an upper endoscopy. For patients <60 years, upper endoscopy is reserved for those with clinically significant weight loss, overt gastrointestinal bleeding, more than one alarm feature, or rapidly progressive alarm features. Patients <60 years of age should be tested and treated for H. pylori infection.

The American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) have published guidelines on the evaluation and management of dyspepsia [18]. The recommended age threshold for routine upper endoscopy in patients with dyspepsia, to exclude upper gastrointestinal neoplasia, has been raised to ≥60 years, in contrast to earlier guidelines advising ≥55 years. The new guidelines also recommend that patients <60 years with dyspepsia be tested for Helicobacter pylori and treated if positive. For patients <60 years, upper endoscopy is reserved for those with significant weight loss, overt gastrointestinal bleeding, more than one alarm feature (table 4), or rapid progression of one or more alarm features. The rationale for these revised recommendations is the low risk of gastric cancer in younger patients, the low positive predictive value of any single alarm feature in detecting gastrointestinal neoplasia, and the inherent risk and cost of performing upper endoscopy. Our management approach is generally consistent with these guidelines (algorithm 1). (See "Approach to the adult with dyspepsia", section on 'Diagnostic strategies and initial management'.)

HEMATOLOGY (November 2017)

Cross-sectional imaging for suspected multiple myeloma

For patients with suspected multiple myeloma, we prefer cross-sectional imaging (low-dose CT, PET/CT, or MRI scan), rather than a skeletal survey, as the imaging modality to detect bone involvement.

Imaging is a key part of the evaluation of all patients with suspected multiple myeloma (MM). Until recently, a skeletal survey using plain radiographs had been the preferred modality for detecting bone lesions that would trigger the institution of therapy. Low-dose computerized tomography (CT), FDG positron emission tomography (PET)/CT, and magnetic resonance imaging (MRI) are all more sensitive than plain radiographs for the detection of most skeletal lesions in myeloma. Accumulating data suggest that patients who previously would have met criteria for smoldering myeloma based on negative skeletal surveys, but who have lesions detected by one of these modalities, have a shorter time to progression than similar patients with negative cross-sectional imaging [19]. We now prefer cross-sectional imaging with one of these modalities for patients with suspected MM. The preferred modality depends upon availability, cost, institutional preference, and clinical features. (See "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma", section on 'Choice of modality' and "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma", section on 'CT, MRI, and PET'.)

NEUROLOGY, CARDIOVASCULAR MEDICINE (October 2017)

Patent foramen ovale (PFO) device closure for prevention of recurrent ischemic stroke

For patients age ≤60 years with an embolic-appearing cryptogenic ischemic stroke who have a patent foramen ovale (PFO) with a right-to-left shunt detected by bubble study, we suggest percutaneous PFO closure in addition to antiplatelet therapy, rather than antiplatelet therapy alone (Grade 2B).

Treatment for patients with a cryptogenic stroke who have a patent foramen ovale (PFO) has been controversial. In earlier randomized controlled trials, point estimates suggested that percutaneous device closure of a PFO in patients ≤60 years of age was more effective than antiplatelet therapy for reducing recurrent stroke, but the findings did not reach statistical significance. However, the results of three recent randomized trials, RESPECT extended follow-up [20], REDUCE [21], and CLOSE [22], provide stronger evidence that device closure of a PFO plus antiplatelet therapy is more effective than antiplatelet therapy alone for preventing recurrent ischemic stroke in such patients, with absolute risk reductions ranging from 2.2 to 6 percent. Based upon these results, we now suggest percutaneous PFO closure in addition to antiplatelet therapy for patients who meet all of the following criteria: age ≤60 years, embolic-appearing cryptogenic ischemic stroke (ie, no evident source of stroke despite a comprehensive evaluation), and a PFO with a right-to-left interatrial shunt detected by bubble study. (See "Treatment of patent foramen ovale (PFO) for secondary stroke prevention", section on 'Our approach'.)

ONCOLOGY (October 2017)

Anti-EGFR therapy and primary tumor location in metastatic colorectal cancer

For patients with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) and a left-sided primary tumor, we suggest treatment with an antibody targeting the epidermal growth factor receptor (EGFR), rather than bevacizumab, when a biologic agent is chosen as a component of first-line therapy (Grade 2A). For most patients with RAS/BRAF wt mCRC and a right-sided primary tumor, we suggest bevacizumab rather than an anti-EGFR antibody in conjunction with first-line chemotherapy (Grade 2C).

Accumulating data suggest that the site of the primary tumor influences the effectiveness of first-line treatments for metastatic colorectal cancer (mCRC) that target the epidermal growth factor receptor (EGFR). In a meta-analysis of trials comparing anti-EGFR with anti-vascular endothelial growth factor (VEGF) agents when added to standard first-line chemotherapy, patients with RAS wild-type (wt) mCRC and a left-sided primary tumor had longer survival with anti-EGFR treatment, while there was a trend toward longer survival in patients with right-sided tumors who received bevacizumab [23]. Given these data, when a biologic agent is chosen as a component of first-line therapy, we suggest treatment with an anti-EGFR antibody rather than bevacizumab for patients with RAS/BRAF wt mCRC and a left-sided primary tumor. For most patients with RAS/BRAF wt mCRC and a right-sided primary tumor, we suggest bevacizumab rather than an anti-EGFR antibody in conjunction with first-line chemotherapy, although anti-EGFR agents could be used for later lines of therapy. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy'.)

PSYCHIATRY, ADULT PRIMARY CARE (August 2017)

Management of treatment resistant depression in adults

For patients with mild to moderate treatment resistant major depression, we suggest augmenting the initial antidepressant with a second drug and/or psychotherapy, rather than other strategies such as switching antidepressants or switching from pharmacotherapy to psychotherapy (Grade 2C).

For patients with treatment resistant depression, there has been little comparative evidence to guide the choice between add-on therapy (augmentation) and switching to a different antidepressant drug. In an open label trial, more than 1500 patients with treatment resistant depression were randomly assigned to one of three treatment strategies: augment the current antidepressant with aripiprazole, augment with bupropion sustained release, or switch to bupropion [24]. At 12 weeks, remission was more likely in the augment-aripiprazole group than the switch group, but the clinical difference was small (29 versus 22 percent). Akathisia, somnolence, weight gain, and laboratory abnormalities were more common with aripiprazole, and anxiety occurred more often in the other groups. Based on these results, we now favor augmentation for managing treatment resistant depression; however, switching remains a reasonable alternative, especially for patients who want to avoid medication side effects. (See "Unipolar depression in adults: Treatment of resistant depression", section on 'Efficacy of augmentation compared with switching'.)

INFECTIOUS DISEASES, GASTROENTEROLOGY AND HEPATOLOGY, ADULT PRIMARY CARE (August 2017)

Glecaprevir-pibrentasvir and sofosbuvir-velpatasvir-voxilaprevir for chronic HCV infection

For patients with chronic HCV genotype 1 infection who have not been previously treated with sofosbuvir or an NS5A inhibitor, we suggest ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, or glecaprevir-pibrentasvir (Grade 2B).

For patients with chronic HCV genotype 2 or 3 infection who have not been previously treated with a DAA regimen, we suggest sofosbuvir-velpatasvir or glecaprevir-pibrentasvir (Grade 2B).

Treatment options for patients with chronic hepatitis C virus (HCV) continue to grow. Two new combination therapies, glecaprevir-pibrentasvir and sofosbuvir-velpatasvir-voxilaprevir, were recently approved by the Food and Drug Administration in the United States and are expected to be approved in Europe this year. Glecaprevir-pibrentasvir is highly effective for patients with genotypes 1 through 6 infection, offers the possibility of an eight-week regimen for most patients without cirrhosis, and can be used in patients with renal impairment (including those on dialysis) [25-28]. It is now one of our preferred regimens for all genotypes; regimen duration depends on the genotype, the presence of cirrhosis, and the treatment history (algorithm 2 and algorithm 3 and algorithm 4 and algorithm 5). Sofosbuvir-velpatasvir-voxilaprevir is highly effective in patients with genotypes 1 through 6 infection who have failed a prior direct acting antiviral (DAA) regimen and is now the main treatment option for those who have failed an NS5A inhibitor-containing regimen [29]. Like other contemporary DAA regimens, these new combinations are well tolerated, with common but mild side effects. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Selection of treatment regimens' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Selection of treatment regimen' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults", section on 'Selection of treatment regimens'.)

HEMATOLOGY, ALLERGY AND IMMUNOLOGY (August 2017)

Midostaurin for advanced systemic mastocytosis

For patients with advanced systemic mastocytosis, we suggest midostaurin for initial systemic therapy rather than imatinib or other cytoreductive therapies (Grade 2B).

Cytoreductive treatment of advanced systemic mastocytosis (SM) can mitigate organ dysfunction, improve quality of life, and limit disease progression until a suitable donor for allogeneic hematopoietic cell transplant is identified. Midostaurin is a multikinase inhibitor that is effective against SM with wild type or mutant KIT (eg, KIT D816V). A recent phase II study found that midostaurin was associated with improved measures of organ damage (eg, cytopenias, liver function studies) in two-thirds of patients with advanced SM, with median overall survival >3 years [30], confirming similar findings from an earlier trial [31]. The drug was well tolerated, with primarily grade 1 to 2 nausea/vomiting or modest cytopenias. The US Food and Drug Administration approved midostaurin for treatment of advanced SM earlier this year. We now suggest midostaurin for initial systemic therapy of advanced SM. (See "Systemic mastocytosis: Management and prognosis", section on 'Choice of therapy'.)

HEMATOLOGY (August 2017)

Rituximab in acquired TTP

For patients with a presumptive diagnosis of acquired TTP, we suggest administration of rituximab as a component of initial therapy (Grade 2C).

Acquired thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening condition; standard treatment includes plasma exchange (PEX) and glucocorticoids. The role of additional up-front rituximab in acquired TTP is evolving, as evidence continues to accumulate suggesting that rituximab may reduce the risk of relapse and refractory disease and may hasten initial response. The latest evidence comes from a retrospective study from the United Kingdom TTP Registry, which found low rates of relapse in patients treated with rituximab as part of initial therapy, although patients were only observed for a median of 15 months [32]. Based on this and other studies, we now use rituximab as a component of initial therapy for acquired TTP. Some experts may reasonably omit rituximab due to concerns about toxicity, pending additional data. Other considerations for rituximab use In TTP include the optimal dose, timing relative to PEX, and risk of hepatitis B reactivation. (See "Acquired TTP: Initial treatment", section on 'Rituximab'.)

ONCOLOGY (June 2017)

Management of a positive sentinel lymph node biopsy in patients with cutaneous melanoma

For patients with cutaneous melanoma and a positive sentinel lymph node biopsy, we suggest clinical observation and ultrasound surveillance of the positive nodal basin rather than immediate completion lymph node dissection (Grade 2B).

Historically, completion dissection of all involved nodal basins was considered the standard treatment approach for patients with cutaneous melanoma and a positive sentinel lymph node biopsy (SLNB). In the phase III Multicenter Selective Lymphadenectomy Trial II (MSLT II), patients with a positive SLNB were randomly assigned to either completion lymph node dissection or observation that included ultrasound evaluation of the appropriate lymph node basins at each follow-up visit [33]. Melanoma-specific survival at three years was the same for both groups, although the incidence of recurrence in regional lymph nodes was higher in patients managed with observation and ultrasound surveillance. The incidence of lymphedema was higher in patients who underwent immediate lymph node dissection. For patients with a positive SLNB, we suggest clinical observation coupled with ultrasound surveillance of the positive nodal basin. Completion lymph node dissection is indicated if, in the absence of distant metastases, there is evidence of regional lymph node recurrence. (See "Evaluation and treatment of regional lymph nodes in melanoma", section on 'Multicenter Selective Lymphadenectomy Trial II'.)

ONCOLOGY (June 2017)

Next-generation ALK-inhibitors in crizotinib-naive ALK-positive NSCLC

For patients with newly diagnosed ALK-positive NSCLC, we recommend alectinib as first-line treatment (Grade 1B). For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib.

For patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), crizotinib has been administered as frontline therapy. However, newer agents have shown promising efficacy in advanced ALK-positive NSCLC:

In a global trial of 303 patients randomly assigned to frontline crizotinib versus the next-generation inhibitor alectinib (ALEX), those receiving alectinib experienced a longer progression-free survival (PFS, not reached versus 11.1 months), with fewer toxicities, at a median follow-up of approximately 18 months [34]. These results are consistent with an earlier Japanese trial [35].

In a phase III trial of 376 patients comparing ceritinib, another next-generation ALK inhibitor, with pemetrexed and a platinum agent, ceritinib improved progression-free survival (17 versus 8 months) [36]. Ceritinib has not been compared with crizotinib in the frontline setting.

For patients with newly diagnosed, ALK-positive NSCLC, we now recommend frontline therapy with alectinib. For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)

PULMONARY AND CRITICAL CARE MEDICINE, ADULT PRIMARY CARE, FAMILY MEDICINE AND GENERAL PRACTICE (June 2017)

Revised follow-up for a solitary pulmonary nodule

For patients with an asymptomatic solid or subsolid (pure ground glass or part-solid) solitary pulmonary nodule (SPN) <6 mm, no routine follow-up is required. For patients with solid SPNs that have been stable on serial CT over a two year period, or with subsolid SPNs that have been stable over a five year period, we suggest no further diagnostic testing.

Fleischner Society guidelines have been updated to reflect the accumulating data on the malignancy risk of incidental pulmonary nodules and growth rates of lung cancer [37]. Important changes include guidance on identifying benign nodules with minimal follow-up imaging. For patients with a solid or subsolid (ground glass or part-solid) solitary pulmonary nodule measuring <6 mm, follow-up computed tomography (CT) is optional, but no longer required. A solitary pulmonary nodule that is solid and unchanged on serial CT over a two-year period, or subsolid and unchanged over a five-year period, is likely benign and does not need further diagnostic evaluation. Recommendations in UpToDate have been revised to reflect these new guidelines. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Management' and "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Solid nodule ≤8 mm'.)

OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (May 2017)

Tranexamic acid for management of postpartum hemorrhage

For women with postpartum hemorrhage diagnosed within three hours of delivery, we recommend administration of tranexamic acid as a component of overall treatment (Grade 1B). When more than three hours have elapsed since delivery, we still suggest tranexamic acid (Grade 2C), but the benefit of treatment is less clear.

Tranexamic acid, an antifibrinolytic drug, reduces bleeding in surgical and trauma patients. In a pragmatic randomized trial involving over 20,000 women with postpartum hemorrhage in over 20 countries (the World Maternal Antifibrinolytic Randomized Trial [WOMAN]), tranexamic acid, compared with placebo, reduced the relative risk of death due to bleeding by 20 to 30 percent, reduced the incidence of laparotomy to control bleeding, and was not associated with an increase in adverse effects [38]. Overall mortality was not reduced. We now recommend administration of tranexamic acid as a component of the treatment for postpartum hemorrhage. (See "Postpartum hemorrhage: Medical and minimally invasive management", section on 'Administer tranexamic acid'.)

NEUROLOGY (May 2017)

Edaravone for amyotrophic lateral sclerosis

For patients with ALS who have a disease duration of two years or less, are living independently, and have an FVC ≥80 percent, we suggest treatment with edaravone (Grade 2B). We also suggest edaravone for patients with more advanced ALS (Grade 2C).

Edaravone is a free radical scavenger that is thought to reduce oxidative stress, which has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone may slow functional deterioration in some patients with ALS. An earlier trial found no benefit for edaravone compared with placebo, but a post-hoc analysis showed a possible treatment effect in a subgroup of individuals with early-stage ALS. A subsequent trial enrolled 137 Japanese patients within two years of ALS diagnosis who were living independently and had a forced vital capacity (FVC) of ≥80 percent [39]. Compared with placebo, functional decline at 24 weeks was smaller in the edaravone group, and the difference was considered clinically meaningful. Edaravone was approved in 2015 for the treatment of ALS in Japan and Korea and has now received regulatory approval to treat patients with ALS in the United States [40]. We now suggest edaravone for patients with early-stage disease as well as for those with more advanced disease, although the data are less compelling for the latter group. (See "Disease-modifying treatment of amyotrophic lateral sclerosis", section on 'Edaravone'.)

HEMATOLOGY (May 2017)

Eltrombopag for adults with acquired severe aplastic anemia unable to undergo HCT

For adults with acquired severe aplastic anemia who are not candidates for allogeneic hematopoietic cell transplantation, we suggest eltrombopag plus standard immunosuppressive therapy (IST) rather than IST alone (Grade 2C).

Acquired aplastic anemia (AA) has a high morbidity, and allogeneic hematopoietic cell transplantation (HCT) is suggested as therapy for patients healthy enough to tolerate HCT who have a suitable donor. Immunosuppressive therapy (IST) is offered to those for whom HCT is not an option but is often ineffective in improving outcomes over the long term. A prospective cohort study in adults with acquired severe AA evaluated the effectiveness of IST plus eltrombopag, a thrombopoietin receptor agonist that acts on platelet precursors and hematopoietic stem cells [41]. Eltrombopag plus IST produced higher rates of overall hematologic response at six months compared with responses in a historical cohort (80 to 94 percent versus 66 percent for the historical group). Based on these findings, we now suggest administration of eltrombopag plus IST for individuals with acquired severe AA who are not candidates for allogeneic HCT. (See "Treatment of aplastic anemia in adults", section on 'Evidence for efficacy'.)

NEUROLOGY (April 2017)

Ocrelizumab for primary progressive multiple sclerosis

For patients with primary progressive multiple sclerosis, we suggest treatment with ocrelizumab (Grade 2B).

Ocrelizumab is the first drug to reduce the risk of disability progression among patients with primary progressive multiple sclerosis (PPMS), as shown by the multicenter ORATORIO randomized trial [42]. Compared with placebo, ocrelizumab modestly reduced the proportion of patients with disability progression at 24 weeks (30 versus 36 percent). In addition, ocrelizumab slowed deterioration from baseline to week 120 on the timed 25-foot walk and led to improvements on other endpoints. While the long-term risks of infection and neoplasm with ocrelizumab are uncertain, there are no other disease-modifying therapies for PPMS. Therefore, we suggest treatment with ocrelizumab for most patients with PPMS. Ocrelizumab has also been approved by the US Food and Drug Administration for use in relapsing-remitting MS (RRMS), although its role in the early treatment of this form of the disease remains to be determined. (See "Treatment of progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)

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