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Hepatitis B, Rituximab, Screening, and Prophylaxis:Effectiveness and Cost EffectivenessAnnette E. Hay and Ralph M. Meyer, NCIC Clinical Trials Group; Queens University, Kingston, Ontario, Canada
See accompanying article on page 3167
An important role of medical journals is to communicate infor-
mation between stakeholder groups.1,2 These communications may
be between researchers about findings that inform future research;
results of phase I-II trials inJournal of Clinical Oncology (JCO)exem-
plifythispurpose.Alternately,communicationsbetween practitionerscan advise about implementing clinical practices, such as with narra-
tive reviews and case-based manuscripts including JCOsOncology
Grand Rounds, which provide guidance to practitioners.3 Communi-
cations from investigators to practitioners and policy makers include
resultsof randomizedcontrolled trials(RCTs)andsystematicreviews.
Thesecommunicationsinform decisionsaboutmanaging individualpa-
tients and health care delivery policies. For policy determination, eco-
nomicevaluations also have an importantrole. Implicit inconducting an
economicanalysisispriordemonstrationthattheintervention iseffective.
With this knowledge in hand, understanding economic ramifications of
adopting an intervention may be very helpful: a central premise is that
resourcesarescarceanddecisionsaboutalternativesareassociatedwithan
opportunity cost because resourcesused foronepurpose are unavailablefor another use.JCOhas provided guidance to researchers intending to
submita reportof aneconomicanalysis4; high priorityisgiventoanalyses
that affectdecisionsabout adoption.
In the article that accompanies this editorial, Zurawska et al5
provide a cost-effectiveness analysis assessing hepatitis B virus (HBV)
screeningbefore administeringrituximab,cyclophosphamide,doxoru-
bicin, vincristine and prednisone (R-CHOP) chemotherapy to patients
with diffuse large B-cell lymphoma (DLBCL). Their analysis links data
demonstrating that when treated withR-CHOP, patients with DLBCL
who are chronically infected with HBV can experience reactivation of
HBV infection leading to acute hepatitis with consequences including
morbidityassociatedwithinfection,compromiseof chemotherapy deliv-
erythat might resultin morbidityandmortalityassociated with subopti-
mal control of lymphoma, and death from fulminant hepatitis.6,7 This
analysis assumes that effective strategies for screening and prophylaxis
exist. The authors conclude that routine screening of all patients with
DLBCL before chemotherapy is cost effective because, in comparison
with alternatives, it is least costly and associated with superior 1-year
survival. Setting aside the above assumptions and implications of the
authorsconclusions, thisanalysisfollowspublishedrulesfor reportingan
economic evaluation,8 as the study question includes clear alternatives
(screen all, screen high-risk patients, screen none), the perspective of the
analysis is provided (a Canadian provinces Ministry of HealthandLong
Term Care), costing appears to be comprehensive and credibly valued,
andresults were provided using incremental differences and with associ-
ated sensitivity analyses. A minor criticism is that conclusions may be
overstated because the differences in costs and life-years saved between
alternativesaremarginal;stating that a screen-all strategy falls well within
standard benchmarks for cost effectiveness would be a more conserva-tively stated conclusion. Screening all patients with DLBCL would be
expected to be even more cost effective in jurisdictions with HBV preva-
lence rates that exceedthose observed in Canada.
At issue is howthiseconomic analysisinforms decisions to adopt
a strategyto screenallpatients with DLBCL for HBV. Otherinforma-
tion helps to frameZurawska et als5 conclusions.First, the problemis
important:reactivationofHBVinpatientswithcancerreceivingchem-
otherapy is recognized and available data show that this risk is increased
withthemoreprofoundimmunosuppressionassociatedwith lymphoma
and treatment that includes steroids and now rituximab.6,7,9 Second,
authors of a meta-analysis7 that includedtwoRCTsandadditional obser-
vational data concludedthat whilethesedata are associated withimpor-
tant limitations, a reasonable interpretation is that prophylaxis withlamivudine is preferred over a no-treatment approach when patients
withcancertestingpositiveforhepatitis B surfaceantigen(HBsAg)are
treated with chemotherapy. Third, synthesis of these two points has
resultedinpublication of numerousguidelinesrecommending screening
for HBV and antiviral prophylaxis for cancer patients with positive
testing10-15 (Table 1), especially when rituximab is used to treat lym-
phoma. Screening has also been recommended for patients who
are to receive rituximab for treatment of benign conditions.16
Finally, despite these guidelines, practice variation exists with
poor uptake of these recommendations: Zurawska et al cite data
reporting routine screening in their geographic region of only
14% of patients with cancer who are to receive chemotherapy,17
an Australian survey that included oncologists who treat lym-
phoma reported that 47% never screen for HBV before initiat-
ing chemotherapy18 and in a North American teaching hospital
only 36.6% of patients treated with rituximab between 1997 and
2009 had HBV testing although rates increased to 67.4% after
introduction of guidelines.19
A previous survey has suggested that one reason for variable
adoption may be concern about cost effectiveness.18 Zurawska et als5
conclusions might thus promote adoption of screening for patients
with lymphoma, especially if concerns about cost effectiveness were
accentuated by a recent publication in JCOby Day et al,20 which
deemed routine prechemotherapy screening of patients with solid
JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L
V O L UM E 3 0 N U MB E R 2 6 S E P TE M B ER 1 0 2 0 1 2
2012 by American Society of Clinical Oncology 3155Journal of Clinical Oncology, Vol 30, No 26 (September 10), 2012: pp 3155-3157
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tumors cost ineffective. In that analysis, the cost per life-year saved was
$88,224 for patients receiving adjuvant therapy and $1,344,251 for pa-tients receiving palliative chemotherapy (values in Australian dollars).
ReviewofthemethodologiesoftheDayetalandZurawskaetaleconomic
evaluations prompt speculation that botheffectivenessand costeffective-ness of screeningand prophylaxisareamplifiedforpatientswith DLBCL.
In comparison with populations of other patients with cancer receiving
chemotherapy, those with DLBCL mayhave greater background risks ofHBV infection, experience more severe immunosuppression, and are
treated with curative rather than palliative intent and in a manner that is
associated with effect sizes that exceed those anticipated when treatingmost patients with solid tumors. These differences are now even greater
because,incomparisonwith CHOP,R-CHOP isassociatedwithsuperiordisease control andoverall survival,butalso is more immunosuppressive
and appears to be associated with greater risks of HBV reactivation, and
clinical and severe HBV-related hepatitis.21 Thus, preventing HBV reac-tivation is now more important and success should be associated with
opportunities for greater benefit. These suppositions also support an ar-
gument that the 1-year survival end point used by Zurawska et al isconservative, as long-term survival and the morbidity associated
with HBV reactivation are undervalued.
Will Zurawska et als5 analysis alter physician behaviors, strengthenrecommendations from professional societies and health care agencies,
andreducepracticevariation?Whileacommonlyrecommendedpractice
policy is now associated with favorable economic parameters, a largerquestion relates to a core principle of economic evaluations and the as-
sumptions onwhich this analysiswasbased: is there sufficient evidence
demonstrating effectiveness of screening and prophylaxis strategiesforHBV?In 2010, theAmerican Societyof Clinical Oncology (ASCO)
provided a Provisional Clinical Opinion12 (PCO) addressing these
questions (Table 1); the PCO included different conclusions thanthose recommendedby other agencies andthe reasonfor these differ-
ences may help explain why incomplete adoption has occurred. In
contrast with other bodies, such as the U.S. Center for Disease Con-trol,10 the ASCO PCO concluded insufficient evidence exists to deter-
mine net benefits andharms for routine screening in individuals with
cancerand recommends screening only be considered (as opposed touniversallyperformed)forpatientswith lymphoma whoaretoreceive
rituximab; the conclusion that there was inadequate evidenceapplied
to both HBsAg testing as a screening tool and to prophylactic treat-ment for those with a positive test. The conceptual basis of the PCO
process includes recognition that new scientific evidence is complex,
developsrapidly andthat thelabel ofProvisional necessitatesregularreview in order to assure that a goal to answer does this change my
practice? is addressed.22 So, at least with respect to treating DLBCL,
should the ASCO PCO be updated? If updated, Zurawska et alsanalysis indicates that effectiveness of prophylaxis should be empha-
sized; while not minimizing the importance of what constitutes opti-
mum screening, their data suggest that even for populations withrelatively low prevalence rates, screening is likely to be cost effective.
The ASCO PCO statements couldbe considered forthree popu-lations: patients with nonlymphoma cancer, patients with DLBCL
who were previously treated with CHOP and current patients with
DLBCL undergoing active treatment withR-CHOP. Policies forthosewith solid tumors require separate consideration as these patients are
less likely to develop severe hepatitis, and patients receiving palliative
chemotherapy for metastatic disease are more likely to have cancer-related risks that affect morbidity and mortality. The uncertainties
associated with limited evidence referred to in the ASCO PCO most
directly apply to this population. Zurawska et als5 analysis requiresthat up-to-date lymphoma-specific evidence be considered. The only
two RCTs evaluating patients with DLBCL23,24 included treatment
with CHOP, and notR-CHOP, and contributed to the assumptionsused by Zurawska et al. Results of these trials showed reduced rates of
HBV reactivation and HBV-related clinical hepatitis and severe hep-
atitis. The magnitude of reduction of clinically apparent HBV hepatitis(45%versus 5%) was substantial, but the pooledsamplesize was only 84
patients. These trialsprovide insufficient data forconclusions about risks
of clinical hepatitisfollowing cessation of prophylactic therapy andlong-term survival, but were interpreted by developers of most guidelines as
Table 1. Selected Guidance Documents With Recommendations for Hepatitis B Screening
Recommending BodyPatient Groups Included/Recommendation
for Screening Serological Tests Prophylaxis
Centers for Disease Control10 Patients receiving cytotoxic or immunosuppressivetherapy/Screen all
HBsAg, anti-HBc, anti-HBs Prophylactic antiviral therapy for HBsAg-positive patients
American Association for theStudy of LiverDiseases11
Patients receiving cytotoxic or immunosuppressivetherapy/Screen all high-risk patients
HBsAg, anti-HBc Lamivudine, telbivudine, tenofovir orentecavir for all HBV carriers. Continuefor 6 mo post oncologic therapy
American Society of ClinicalOncology12
Patients receiving cytotoxic or immunosuppressivetherapy/Consider screening high-risk groupsand those receiving highly immunosuppressivetherapy
HBsAg, anti-HBc in somepopulations
Consider antiviral therapy with evidence ofchronic HBV infection
European Society for MedicalOncology13
Follicular lymphoma/Screen all Not specified Prophylactic antiviral therapy for HBsAg-positive patients
British Committee forStandardsin Haematology14
Follicular lymphoma/Screen all at baseline andre-screen high-risk patients pre- immunotherapy
Not specified Not specified
National ComprehensiveCancer Network15
Non-Hodgkins lymphoma/Screen all receivingrituximab, from areas with high or unknownHBV prevalence and receiving chemotherapy
HBsAg, anti-HBc. Add e-antigenif risk factors or history ofHBV
Prophylactic antiviral therapy for patientswith a positive test. Monitor viral loadwith PCR monthly. Lamivudine is notthe optimal prophylactic agent
Rituximab Consensus ExpertCommittee16
Rheumatoid arthritis/Screen all receiving rituximab HBsAg, anti-HBc Prophylactic antiviral therapy for HBsAg oranti HBc-positive patients
Abbreviations: anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitisB virus; PCR, polymerase chain reaction.
Editorial
3156 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
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sufficientforadoption of prophylaxis.UseofR-CHOPcreates newcom-plexities. Risks of reactivation in patients with HBsAg positivity are in-
creasedanda newriskgroupisrecognized that includesthosewith testing
that is negative for HBsAg but positive for hepatitis B core antibody(anti-HBc).9,21 Furthermore, R-CHOP is associated with reactivation
risksthat persist aftercompletingprophylactic therapy,25,26 a finding that
coincides with discovery of the YMDD mutation,27 which is associatedwithlamivudineresistance.Thus,guidelineshavemovedbeyondwhether
thesepatientsshouldbescreenedandreceiveprophylaxisandontodebate
about which screening tests to employ, which prophylactic agent to useand theoptimum duration of therapy. These debates assumethat added
risks associated with rituximab-related HBV reactivation create a larger
population in need of prophylaxis and that the efficacy of prophylaxisobserved in two small RCTs evaluating patients treated with CHOP will
notbecompromisedbythemoresevereandprolongedimmunosuppres-
sion associatedwith R-CHOP.It is unlikely that practitioners and policy makers will be in-
formedwithdefinitivedata fromRCTsinthenearfuture. Asindicated
by Zurawska et al,5 a RCT evaluatingscreening will probably never beperformed. Thus, communicationsto practitioners andpolicymakers
about todaysbestpracticesneedto emphasize theimportanceandyetremaininguncertaintiesassociated withthis decision-makingprocess.Theeconomic analysisof Zurawskaet al provides helpful information
addressing one of these uncertainties. Their workcontributesto avail-
able information supporting as a standard of care routine HBVscreening of patients with DLBCL who are to receive R-CHOP and
provision of prophylactic therapy to those with a positive test.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although allauthors completed the disclosuredeclaration, thefollowing author(s)and/or an authorsimmediate family member(s) indicated a financialor otherinterestthatis relevant to the subject matter under consideration in this article.Certain relationships markedwitha Uare those for which no compensation wasreceived; those relationships marked with a C werecompensated. Fora detailed
descriptionof the disclosure categories, or formoreinformation about ASCOsconflict of interestpolicy,please refer to the Author Disclosure Declarationand theDisclosuresof Potential Conflicts of Interestsectionin InformationforContributors.Employment or Leadership Position: None Consultant or AdvisoryRole:NoneStock Ownership:NoneHonoraria:Ralph M. Meyer, EliLilly, CelgeneResearch Funding:Ralph M. Meyer, Amgen, ARIADPharmaceuticals, Astex Therapeutics, AstraZeneca, Boston Biomedical,Bristol-Myers Squibb, Celgene, Geron, GalxoSmithKline, JanssenPharmaceuticals, Eli Lilly, Merck Frosst Canada, Novartis, OncolyticsBiotech, Oncothyreon, Pfizer, Roche, sanofi-aventis, Schering-PloughCanadaExpert Testimony:NoneOther Remuneration:None
AUTHOR CONTRIBUTIONS
Provision of study materials or patients: Annette E. HayManuscript writing:All authorsFinal approval of manuscript: All authors
REFERENCES
1. Haynes RB: Loose Connections between peer-reviewed clinical journals
and clinical practice. Ann Intern Med 113:724-728, 1990
2. Meyer RM, Kouroukis CT: Understanding outcome measures. Evid Based
Oncol 2:172-176, 2001
3. Moran T, Sequist LV: Timing of epidermal growth factor receptor tyrosine
kinase inhibitor therapy in patients with lung cancer with EGFRmutations. J Clin
Oncol [epub ahead of print on July 2, 2012]
4. Levine MN, Ganz PA, Haller DG: Economic evaluation in the J Clin Oncol:
Past, present, and future. J Clin Oncol 25:614-616, 2007
5. Zarawska U, Hicks LK, Woo G, et al: Hepatitis B virus screening before
chemotherapy for lymphoma: A cost-effectiveness analysis. J Clin Oncol 30:
3167-3173, 2012
6. Liang R: How I treat and monitor viral hepatitis B infection in patients
receiving intensive immunosuppressive therapies or undergoing hematopoietic
stem cell transplantation. Blood 113:3147-3153, 2009
7. Loomba R, Rowley A, Wesley R, et al: Systematic review: The effect of
preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann
Intern Med 148:519-528, 2008
8. Department of Clinical Epidemiology and Biostatistics MUHSC: How to
read clinical journals: VII. To understand an economic evaluation (part B). Can
Med Assoc J 130:1542-1549, 1984
9. Yeo W, Chan TC, Leung NWY, et al: Hepatitis B virus reactivation in
lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy
with or without rituximab. J Clin Oncol 27:605-611, 2009
10. Weinbaum CM, Mast EE, Ward JW: Recommendations for identification
and public health management of persons with chronic hepatitis B virus infection.
Hepatology 49:S35-S44, 2009
11. Lok ASF, McMahon BJ: Chronic hepatitis B: Update 2009American Associa-
tion for the Study of Liver Diseases: Practice guideline update. http://www.aasld.org/
practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/
Chronic_Hep_B_Update_2009%208_24_2009.pdf
12. Artz AS, Somerfield MR, Feld JJ, et al: American Society of Clinical
Oncology Provisional Clinical Opinion: Chronic hepatitis B virus infection screen-
ing in patients receiving cytotoxic chemotherapy for treatment of malignant
diseases. J Clin Oncol 28:3199-3202, 2010
13. Dreyling M, Ghielmini M, Marcus R, et al: Newly diagnosed and relapsedfollicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow-up. Ann Oncol 22:vi59-vi63, 2011 (suppl 6)
14. McNamara C, Davies J, Dyer M, et al: Guidelines on the investigation and
management of follicular lymphoma. Br J Haematol 156:446-467, 2012
15. Zelenetz AD, Abramson JS, Advani RH, et al: Non-Hodgkins lymphomas.
J Natl Compr Cancer Netw 9:484-560, 2011
16. Buch MH, Smolen JS, Betteridge N, et al: Updated consensus statement on
the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011
17. Lee R, Vu K, Bell CM, et al: Screening for hepatitis B surface antigen before
chemotherapy: Current practice and opportunities for improvement. Current
Oncology 17:32-38, 2010
18. Day FL, Link E, Thursky K, et al: Current hepatitis B screening practices and
clinical experience of reactivation in patients undergoing chemotherapy for solid
tumors: A nationwide survey of medical oncologists. J Oncol Pract 7:141-147, 2011
19. Mendez-Navarro J, Corey KE, Zheng H, et al: Hepatitis B screening,
prophylaxis and re-activation in the era of rituximab-based chemotherapy. LiverInternational 31:330-339, 2011
20. Day FL, Karnon J, Rischin D: Cost-effectiveness of universal hepatitis B
virus screening in patients beginning chemotherapy for solid tumors. J Clin Oncol
29:3270-3277, 2011
21. Targhetta C, Cabras MG, Mamusa AM, et al: Hepatitis B virus-related liver
disease in isolated anti-hepatitis B-core positive lymphoma patients receiving
chemo- or chemo-immune therapy. Haematologica 93:951-952, 2008
22. Haller DG, Cox JV: Provisional clinical opinion. J Clin Oncol 27:1925, 2009
23. Lau GKK, Yiu HHY, Fong DYT, et al: Early is superior to deferred
preemptive lamivudine therapy for hepatitis B patients undergoing chemo-
therapy. Gastroenterology 125:1742-1749, 2003
24. Hsu C, Hsiung CA, Su IJ, et al: A revisit of prophylactic lamivudine for
chemotherapy-associated hepatitis B reactivation in non-Hodgkins lymphoma: A
randomized trial. Hepatology 47:844-853, 2008
25. Dai MS, Chao TY, Kao WY, et al: Delayed hepatitis B virus reactivation after
cessation of preemptive lamivudine in lymphoma patients treated with rituximabplus CHOP. Ann Hematol 83:769-774, 2004
26. Garcia-Rodriguez MJ, Canales MA, Hernandez-Maraver D, et al: Late
reactivation of resolved hepatitis B virus infection: An increasing complication
post rituximab-based regimens treatment? Am J Hematol 83:673-675, 2008
27. Allen MI, Deslauriers M, Andrews CW, et al: Identification and character-
ization of mutations in hepatitis B virus resistant to lamivudine. Hepatology
27:1670-1677, 1998
DOI: 10.1200/JCO.2012.43.7509; published online ahead of print at
www.jco.org on August 13, 2012
Editorial
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