To update a clinical practice guideline (CPG) for the empirical management of fever and neutropenia (FN) in children with cancer and hematopoietic stem-cell transplantation recipients.

The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group of experts in pediatric oncology and infectious diseases that includes a patient advocate. For questions of risk stratification and evaluation, we updated systematic reviews of observational studies. For questions of therapy, we conducted a systematic review of randomized trials of any intervention applied for the empirical management of pediatric FN. The Grading of Recommendation Assessment, Development and Evaluation approach was used to make strong or weak recommendations and to classify levels of evidence as high, moderate, low, or very low.

Recommendations related to initial presentation, ongoing management, and empirical antifungal therapy of pediatric FN were reviewed; the most substantial changes were related to empirical antifungal therapy. Key differences from our 2012 FN CPG included the listing of a fourth-generation cephalosporin for empirical therapy in high-risk FN, refinement of risk stratification to define patients with high-risk invasive fungal disease (IFD), changes in recommended biomarkers and radiologic investigations for the evaluation of IFD in prolonged FN, and a weak recommendation to withhold empirical antifungal therapy in IFD low-risk patients with prolonged FN.

Changes to the updated FN CPG recommendations will likely influence the care of pediatric patients with cancer and those undergoing hematopoietic stem-cell transplantation. Future work should focus on closing research gaps and on identifying ways to facilitate implementation and adaptation.

Fever and neutropenia (FN) is a common complication of cancer treatment. In 2012, we published a clinical practice guideline (CPG) focused on the management of FN in children with cancer and in recipients of hematopoietic stem-cell transplantation (HSCT).1 Like all CPGs, it is important that the systematic reviews that inform the recommendations are timely, typically considered every 5 years in the absence of important new studies. Consequently, we updated the systematic reviews and present the 2017 pediatric FN CPG.

The International Pediatric Fever and Neutropenia Guideline Panel includes representation from pediatric oncology, infectious diseases, nursing, and pharmacy, as well as a patient advocate and a guideline methodologist from 10 different countries (Data Supplement).

The methodology applied to our CPG update mirrored our 2012 FN CPG. We followed previously validated procedures for creating evidence-based guidelines2 and used the Appraisal of Guidelines for Research & Evaluation II instrument as a framework.3 Each member completed a conflict of interest form (Data Supplement). The funding agencies had no role to play in the recommendations or editing of the manuscript. The Grading of Recommendation Assessment, Development and Evaluation approach was used to generate recommendations. Details of methodology may be found in the Data Supplement.

Members were divided into working groups that focused on the three major sections addressed in the initial CPG: initial presentation, ongoing management, and empirical antifungal therapy. Given the paucity of pediatric data at the time of initial CPG development, none of the original systematic reviews were restricted to randomized controlled trials (RCTs). For the guideline update, we decided to focus on pediatric RCTs for questions related to therapy because we believed that clinical practice was unlikely to change on the basis of additional observational studies alone. For questions related to risk stratification and evaluation, the original systematic reviews were updated. The Data Supplement contains details of the search strategies, flow diagrams of study identification and selection, and eligibility criteria.

Table 1 presents the 2017 recommendations, highlights changes from the 2012 FN CPG, and provides key remarks. The associated evidence profiles are illustrated in the Data Supplement when data were not published in separate manuscripts. Research gaps are presented in Table 2.

Table

Table 1. Overall Summary of Recommendations, Changes, and Remarks

Table

Table 2. Research Gaps

SECTION A: INITIAL PRESENTATION OF FN

Question

What clinical features and laboratory markers can be used to classify pediatric patients with FN as being at low risk or high risk of poor outcomes?

Recommendation

A1. Adopt a validated risk stratification strategy (Table 3) and incorporate it into routine clinical management (strong recommendation, low-quality evidence).

Table

Table 3. Validated Pediatric Risk Stratification Strategies for Low-Risk Patients

Literature update and analysis.

The 2012 recommendation was derived from a systematic review16 that demonstrated a number of schemas that varied by patients included, definitions of FN, and outcomes measured. Updating the systematic review (Data Supplement) demonstrated further validation of previously published schemas, and more small studies deriving new rules. Six clinically based low-risk stratification schemas that rely on a single assessment at presentation have been validated in different pediatric populations (Table 3). Even with further information, we remain unable to clearly recommend any single prediction rule. There remains evidence of geographical and temporal variation; thus, all schemas require local validation before use. The choice of strategy should be determined by an institution’s ability to implement more complex rules and the timeliness of receipt of required components of the rule, such as C-reactive protein. Two additional risk stratification schemas including repeated measurement of biomarkers have been derived and successfully validated in their originating groups.17,18 These use clinical assessment and IL-8 measurements for all pediatric patients17 or IL8 and C-reactive protein for a high-risk group.18

Question

What clinical, laboratory, and imaging studies are useful at the initial presentation of FN to assess the cause of the episode and guide future treatment?

Recommendations

  • A2. Obtain blood cultures at the onset of FN from all lumens of central venous catheters (strong recommendation, low-quality evidence).

  • A3. Consider obtaining peripheral blood cultures concurrent with central venous catheter cultures (weak recommendation, moderate-quality evidence).

  • A4. Consider urinalysis and urine culture in patients in whom a clean-catch, midstream specimen is readily available (weak recommendation, low-quality evidence).

  • A5. Obtain chest radiography (CXR) only in patients with respiratory signs or symptoms (strong recommendation, moderate-quality evidence).

Literature update and analysis.

The value of peripheral blood cultures has been addressed in nine studies,19-27 two of which were published after 2011.19,20 The updated estimate of the proportion of true bacteremia episodes detected by peripheral blood cultures alone, when central venous catheter cultures are negative, was 12% (95% CI, 8%–17%). Thus, peripheral cultures consistently increase the identification of true bacteremia compared with central cultures alone, which may be related to timing or volume. It is a weak recommendation because the impact of increased yield is unknown and it should be balanced against pain and isolation of contaminants.

In terms of urinalysis and urine culture to detect urinary tract infections in pediatric FN, in one study, all patients with positive urine cultures were asymptomatic,28 strengthening the conclusion that restricting urine culture to those with symptoms is not adequate. The use of abnormal urinalysis to triage culture is also not recommended because pyuria was present in only 4% of urinary tract infection episodes during neutropenia29 and nitrite testing in younger children (without cancer) is less discriminatory than in older patients.30

Two additional studies have been added to the initial systematic review16 of the use of routine CXR during the initial assessment of pediatric FN. One was undertaken in a broad cohort of patients with FN31 and one in children undergoing HSCT.32 Both demonstrated rates of pneumonia of < 3% in an asymptomatic child. Asymptomatic children who did not undergo CXR had no significant adverse clinical consequences.33 Thus, no change was made to the strong recommendation to obtain CXR only in patients with respiratory signs or symptoms.

Question

What empirical antibiotics are appropriate for children with high-risk FN?

Recommendations

  • A6. In high-risk FN:

  • A6a. Use monotherapy with an antipseudomonal β-lactam, a fourth-generation cephalosporin, or a carbapenem as empirical therapy in pediatric high-risk FN (strong recommendation, high-quality evidence).

  • A6b. Reserve the addition of a second gram-negative agent or a glycopeptide for patients who are clinically unstable, when a resistant infection is suspected, or for centers with a high rate of resistant pathogens (strong recommendation, moderate-quality evidence).

Literature update and analysis.

In the systematic review of RCTs of pediatric FN, we compared monotherapy with aminoglycoside-containing combination therapy, and the results are presented in Table 4.34 In this comparison, a rate ratio > 1 indicates that monotherapy is better than combination therapy. No significant differences in failure rates, infection-related mortality, or overall mortality were observed. Three studies were conducted solely in patients with high-risk FN,35-37 and among these studies, no difference in treatment failure was observed (rate ratio, 1.14; 95% CI, 0.54 to 2.39; P = .73). However, it is important to note that these three RCTs did not evaluate monotherapy with a β-lactam against the same β-lactam plus an aminoglycoside, thus highlighting the importance of the specific monotherapy β-lactam antibiotic used. This analysis confirmed the efficacy and safety of monotherapy without the addition of aminoglycosides in treatment settings in which resistance rates were low enough to permit random assignment between monotherapy and combination therapy. Consequently, the updated CPG continues to have a strong recommendation to use empirical monotherapy in high-risk FN. However, local epidemiology and resistance patterns should be evaluated regularly.

Table

Table 4. Synthesized Outcomes for Comparisons of Different Antibiotic Strategies

Table 4 also demonstrates the comparison between antipseudomonal penicillin monotherapy and fourth-generation cephalosporin monotherapy.38-42 Five studies were included; one study42 was identified in the updated search after publication of the FN systematic review.34 No differences in treatment failure, infection-related mortality, or duration of fever were observed, and the point estimate for mortality was in favor of the fourth-generation cephalosporin, thus arguing for its inclusion in the empirical antibiotic recommendation. The 0.81 day increase in duration of antibiotics associated with cephalosporin therapy was not considered clinically meaningful.

Question

In children with low-risk FN, is initial or step-down outpatient management as effective and safe as inpatient management? Is initial or step-down oral antibiotic management as effective and safe as management with parenteral antibiotics?

Recommendations

  • A7. In low-risk FN:

  • A7a. Consider initial or step-down outpatient management if the infrastructure is in place to ensure careful monitoring and follow-up (weak recommendation, moderate-quality evidence).

  • A7b. Consider oral antibiotic administration if the child is able to tolerate this route of administration reliably (weak recommendation, moderate-quality evidence).

Literature update and analysis.

In the systematic review of pediatric FN RCTs, treatment setting and route of antibiotic administration were examined34 (Table 4). Four studies randomized patients to inpatient versus outpatient therapy43-46; no differences in outcomes were observed. The point estimates favored outpatient management in the mortality analyses, and no infection-related deaths were reported for the 124 randomly assigned low-risk patients treated as outpatients. It is a weak recommendation because institutions must have the infrastructure in place to safely implement outpatient management. Because clinical outcomes were similar among strategies, resources and preferences are important considerations in strategy choice.

Table 4 also lists the comparison between intravenous and oral therapy among patients treated in the same setting (n = eight studies).47-54 There was no significant difference in treatment failure, and no infection-related mortality was reported among the 470 patients randomly assigned to receive oral empirical therapy. It is a weak recommendation because readmission may be higher among outpatients treated with oral versus parenteral therapy, and other outcomes were similar. Thus, resources and preferences are important considerations.

SECTION B: ONGOING MANAGEMENT OF FN EXCLUDING EMPIRICAL THERAPY

Question

When and how should the initial empirical antibiotic therapy be modified during the pediatric FN episode?

Recommendations

  • B1. In patients who are responding to initial empirical antibiotic therapy, discontinue double coverage for gram-negative infection or empirical glycopeptide (if initiated) after 24 to 72 hours if there is no specific microbiologic indication to continue combination therapy (strong recommendation, moderate-quality evidence).

  • B2. Do not modify the initial empirical antibacterial regimen based solely on persistent fever in children who are clinically stable (strong recommendation, low-quality evidence).

  • B3. In children with persistent fever who become clinically unstable, escalate the initial empirical antibacterial regimen to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria (strong recommendation, very low-quality evidence).

Literature update and analysis.

In the 2012 FN CPG, early discontinuation of combination therapy was based on the rationale for initial monotherapy without the addition of an aminoglycoside or empirical glycopeptide. As described previously, the recent systematic review confirmed the efficacy and safety of monotherapy without the addition of an aminoglycoside.34 The evidence remains indirect because the RCTs were in the setting of initial therapy and not ongoing therapy and consequently, this reduces the evidence quality to moderate.

There were no pediatric RCTs that evaluated the role of continuing empirical glycopeptides or the appropriate course of action in patients with persistent fever who remain clinically stable or who deteriorate. Thus, there were no changes to the 2012 recommendations.

Question

When can empirical antibiotics be discontinued in patients with low- and high-risk FN?

Recommendations

  • B4. In all patients, discontinue empirical antibiotics in patients who have negative blood cultures at 48 hours, who have been afebrile for at least 24 hours, and who have evidence of marrow recovery (strong recommendation, low-quality evidence).

  • B5. In patients with low-risk FN, consider discontinuation of empirical antibiotics at 72 hours in patients who have negative blood cultures and who have been afebrile for at least 24 hours, irrespective of marrow recovery status, as long as careful follow-up is ensured (weak recommendation, moderate-quality evidence).

Literature update and analysis.

The 2012 CPG recommendation to discontinue antibiotics in patients with negative blood cultures who have been afebrile for at least 24 hours and who have evidence of count recovery was based on a summary of both randomized and observational trials.55-74 In that analysis, the risk of recurrent fever was low in patients with definitive marrow recovery.

No new RCTs of antibiotic cessation were identified in our recent systematic review,34 and thus, the recommendations have not changed. Two RCTs included in the 2012 CPG compared early cessation with continuation of empirical antibiotics.58,75 Both studies were small and showed no differences in outcomes. However, it is notable that the two patients with bacteremia (viridans group streptococci and Enterobacter aerogenes) were both in the cessation arm. Importantly, a large proportion of patients in one study75 had evidence of marrow recovery at the time of random assignment, whereas this proportion was not stated in the second study.58 Thus, it remains a weak recommendation to discontinue antibiotics in low-risk patients who have been afebrile for at least 24 hours but who have no evidence of count recovery on Day 3, because the specific question of safety of antibiotic discontinuation without marrow recovery has not been directly addressed.

The optimal duration of empirical antibiotics for high-risk patients with sustained bone marrow suppression was not addressed in the systematic review34 and continues to be an important research gap.

SECTION C: EMPIRICAL ANTIFUNGAL TREATMENT

Question

What clinical parameters can classify pediatric patients with persistent FN as high risk or low risk of invasive fungal disease (IFD)?

Recommendation

C1. Patients at high risk of IFD are those with acute myeloid leukemia, high-risk acute lymphoblastic leukemia (ALL), or relapsed acute leukemia, and children undergoing allogeneic HSCT. Children with prolonged neutropenia and children receiving high-dose corticosteroids are also at high risk of IFD. All others should be categorized as IFD low risk (strong recommendation, low quality evidence).

Literature update and analysis.

The updated CPG was modified based on a systematic review of risk factors for IFD specifically in pediatric oncology and HSCT recipients.75a This review included 22 studies76-97 and confirmed most risk factors for IFD previously described in the 2012 CPG. However, additional factors now specified include high-risk ALL and high-dose corticosteroids. The Panel recognized that high-risk ALL is a heterogeneous group and that the risk of IFD may be explained by prolonged neutropenia and corticosteroid administration. However, data to provide further specification around which patient with ALL is at particular risk of IFD and the treatment phases of elevated risk are not available.

Question

What clinical features, laboratory tests, and imaging studies are useful to identify a fungal cause for persistent or recurrent FN despite broad-spectrum antibiotics?

Recommendations

  • C2. In terms of biomarkers to guide empirical antifungal management for prolonged (≥ 96 hours) FN in IFD high-risk patients:

  • C2a. Consider not using serum galactomannan (GM; weak recommendation, moderate-quality evidence).

  • C2b. Do not use β-d-glucan (BG; strong recommendation, low-quality evidence).

  • C2c. Do not use fungal polymerase chain reaction (PCR) testing in blood (strong recommendation, moderate-quality evidence).

  • C3. In terms of imaging for the evaluation of prolonged (≥ 96 hours) FN in IFD high-risk patients:

  • C3a. Perform computed tomography (CT) of the lungs (strong recommendation, low-quality evidence).

  • C3b. Consider imaging of abdomen in patients without localizing signs or symptoms (weak recommendation, low-quality evidence).

  • C3c. Consider not routinely performing CT of sinuses in patients without localizing signs or symptoms (weak recommendation, low-quality evidence).

Literature update and analysis.

In the 2012 CPG, we included recommendations related to surveillance and further investigation of identified foci of infection such as lung nodules. In this CPG update, we realized that these areas were outside of the scope of the FN CPG and thus, those recommendations have been removed.

The 2017 FN CPG altered the recommendation related to GM testing based on a recently conducted systematic review of fungal biomarkers in pediatric cancer and HSCT.98 Eight studies assessed GM as a diagnostic tool in children with symptoms potentially suggestive of IFD, such as prolonged FN.99-106 Among these studies, seven showed positive predictive values (PPV) ≤ 75%, and four studies showed PPV < 50%. Table 5 illustrates a clinical vignette of GM testing in a population with a 10% risk of invasive aspergillosis (IA) during FN and illustrates that using the pooled sensitivity and specificity of 89% and 85% from the systematic review, PPV would be 41% and negative predictive value (NPV) would be 97%. Among 100 patients at high risk of IA evaluated, testing would miss one patient with true infection and would erroneously conclude IA in 14 patients without infection. Of the 23 children with a positive test, only nine would actually have IA; in other words, most patients with a positive test in this clinical setting will not have IA. The basis for the weak recommendation against use of GM during FN was the poor PPV, and the limited usefulness of high NPV because GM does not rule out non-Aspergillus molds.

Table

Table 5. Clinical Implications of Fungal Biomarkers in the Diagnostic Setting

The recommendation related to BG testing remains unchanged. In the systematic review of biomarkers for IFD,98 only one study evaluated BG in an applicable setting,107 and it showed PPV of 49% (95% CI, 32 to 66) and NPV of 96% (95% CI, 89 to 99), precluding clinical usefulness.

The updated CPG includes a new strong recommendation against the use of fungal PCR in blood for evaluation of IFD during prolonged FN based on eight studies99,108-114 that applied PCR in a similar setting.109 Table 5 illustrates a clinical vignette of PCR testing in a population with a 10% risk of IFD during FN and illustrates that using the pooled sensitivity and specificity of 76% and 58% from the systematic review, PPV would be 17% and NPV would be 95%. Among 100 IFD high-risk patients evaluated, testing would miss two patients with true infection and would erroneously conclude IFD in 38 patients without infection. Of the 46 patients with a positive test, only eight would truly have IFD. The basis for the strong recommendation against use of PCR is the poor PPV and NPV, which were not sufficiently high to be clinically useful. The Panel also noted the current lack of standardization for PCR testing, which also makes clinical use challenging.

A limitation of the recommendations related to fungal biomarkers is how we approached them as diagnostic tests and evaluated their usefulness in detecting true disease. Randomized trials comparing utilization with nonutilization of these biomarkers to detect IFD would be a better approach to evaluation, but such trials are unlikely to be feasible. In fact, our current standard to recommend empirical antifungal therapy for IFD high-risk patients with prolonged fever is based on the assumption that prolonged fever is a good predictor of IFD when this factor has never been evaluated as a diagnostic test. Comparative effectiveness studies of fungal biomarker use may be the best way to bridge this knowledge gap.

The data supporting recommendations related to imaging for the evaluation of IFD during prolonged FN are shown in the Data Supplement. A strong recommendation to perform lung CTs remained unchanged in the updated CPG. Of the nine studies evaluating lung CT115-123 for the evaluation of IFD, lungs were usually the most frequent site of infection, and characteristic radiographic signs were often observed. A new weak recommendation for abdominal imaging even in the absence of localizing signs or symptoms was made with this CPG update, based on the systematic review (Data Supplement). Among the four studies included,118,122-124 findings on imaging consistent with IFD were observed in many patients without localizing signs or symptoms. The Panel noted that the ideal imaging modality is not known, but ultrasound is readily available, is not associated with radiation exposure, and usually does not require sedation and thus, is likely preferable over CT or magnetic resonance imaging for abdominal assessment.

In the updated CPG, a revised weak recommendation against routine sinus imaging was made in the absence of localizing signs or symptoms based on the systematic review (Data Supplement). Among the five studies that described sinus findings,118,122,123,125,126 sinus imaging was frequently abnormal in prolonged FN, and abnormalities did not distinguish between those with and without sinus IFD. It is a weak recommendation because studies directly addressing the usefulness of routine sinus CTs were limited.

Question

When should empirical antifungal therapy be initiated, what antifungal agents are appropriate, and when is it appropriate to discontinue empirical therapy?

Recommendations

  • C4. In IFD high-risk patients with prolonged (≥ 96 hours) FN unresponsive to broad-spectrum antibacterial agents, initiate caspofungin or liposomal amphotericin B (L-AmB) for empirical antifungal therapy (strong recommendation, high-quality evidence).

  • C5. In IFD low-risk patients with prolonged (≥ 96 hours) FN, consider withholding empirical antifungal therapy (weak recommendation, low-quality evidence).

Literature update and analysis.

Recommendations regarding the choice of empirical antifungal agents in IFD high-risk patients remain unchanged from the 2012 FN CPG, but they are changed in IFD low-risk patients. Recommendations in IFD high-risk patients were originally based on three RCTs127-129 demonstrating that caspofungin was as effective as L-AmB,127,128 and that L-AmB was less nephrotoxic than amphotericin B deoxycholate.129 Either caspofungin or L-AmB was strongly recommended as empirical antifungal therapy. One recent study prospectively compared administration of empirical antifungal therapy versus withholding empirical antifungal therapy in neutropenic children with persistent fever who were IFD low-risk. No benefit relative to fever resolution or IFD was detected from empirical antifungal therapy.127

No RCTs addressed empirical antifungal therapy cessation or a pre-emptive antifungal therapy approach and thus, original recommendations were unchanged. Both of these areas remain important knowledge gaps in pediatric FN.

We updated the 2012 FN CPG for children with cancer and HSCT recipients. Although most recommendations remained unchanged, some key differences emerged. Changes included the listing of a fourth-generation cephalosporin for empirical therapy, refinement of IFD risk stratification, changes in recommended biomarkers and radiologic investigations for the evaluation of IFD, and a weak recommendation to withhold empirical antifungal therapy in IFD low-risk patients.

Implementation is an important issue, and national and international guidance will be important to effect change. Adaptation will be required at the institutional level to delineate specific rather than generic antibiotic choices and to decide whether to implement or not implement weak recommendations. Decision making for weak recommendations could also be made at the specific provider or patient level. Cost-effectiveness studies may be relevant when deciding whether to implement weak recommendations.

Changes to the updated FN CPG recommendations will likely influence the care of children with cancer and pediatric patients undergoing HSCT. Future work should focus on closing research gaps and identifying ways to facilitate implementation.

© 2017 by American Society of Clinical Oncology

Supported by meeting grants from the Canadian Institutes of Health Research and the Garron Comprehensive Cancer Centre.

Conception and design: Thomas Lehrnbecher, Paula Robinson, Robert Phillips, Brian Fisher, Lillian Sung

Financial support: Lillian Sung

Administrative support: Paula Robinson, Lillian Sung

Collection and assembly of data: Thomas Lehrnbecher, Paula Robinson, Robert Phillips, Brian Fisher, Lillian Sung

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Thomas Lehrnbecher

Consulting or Advisory Role: Gilead Sciences, Merck/Merck Sharp & Dohme, Astellas Pharma

Speakers’ Bureau: Astellas Pharma, Gilead Sciences

Research Funding: Gilead Sciences

Travel, Accommodations, Expenses: Astellas Pharma

Paula Robinson

No relationship to disclose

Brian Fisher

Research Funding: Pfizer (Inst), Merck (Inst), Ansun BioPharma (Inst)

Sarah Alexander

No relationship to disclose

Roland A. Ammann

Travel, Accommodations, Expenses: EUSA Pharma

Melissa Beauchemin

No relationship to disclose

Fabianne Carlesse

Speakers' Bureau: Astellas, United Medical, Pfizer

Andreas H. Groll

Consulting or Advisory Role: Astellas Pharma, Basilea, Gilead Sciences, Merck Sharp & Dohme, Schering-Plough, Zeneus/Cephalon

Speakers' Bureau: Astellas Pharma, Basilea, Gilead Sciences, Merck Sharp & Dohme, Schering-Plough, Zeneus/Cephalon, Pfizer

Research Funding: Gilead Sciences, Merck Sharp & Dohme, Pfizer, Schering-Plough

Gabrielle M. Haeusler

No relationship to disclose

Maria Santolaya

No relationship to disclose

William J. Steinbach

Consulting or Advisory Role: Gilead Sciences, Merck

Research Funding: Astellas Pharma

Elio Castagnola

Consulting or Advisory Role: Basilea, Astellas Pharma, Pharmaceutica, Gilead Sciences, Pfizer

Travel, Accommodations, Expenses: Pfizer

Bonnie L. Davis

No relationship to disclose

L. Lee Dupuis

Consulting or Advisory Role: Jazz Pharmaceuticals

Research Funding: Jazz Pharmaceuticals

Aditya H. Gaur

Research Funding: Gilead Sciences (Inst)

Wim J.E. Tissing

No relationship to disclose

Theo Zaoutis

Consulting or Advisory Role: Napriva

Research Funding: Merck (Inst)

Robert Phillips

No relationship to disclose

Lillian Sung

No relationship to disclose

ACKNOWLEDGMENT

We thank Sandra Cabral and Erin Plenert for administrative support.

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DOI: 10.1200/JCO.2016.71.7017 Journal of Clinical Oncology 35, no. 18 (June 20, 2017) 2082-2094.

Published online May 01, 2017.

PMID: 28459614

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