From: Subject: End Point Assessment in Gliomas: Novel Treatments Limit Usefulness of Classical Macdonald's Criteria -- van den Bent et al. 27 (18): 2905 -- Journal of Clinical Oncology Date: Fri, 3 Jul 2009 11:19:12 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C9FBD0.17801890" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C9FBD0.17801890 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://jco.ascopubs.org/cgi/content/full/27/18/2905 End Point Assessment in Gliomas: Novel Treatments = Limit Usefulness of Classical Macdonald's Criteria -- van den Bent et = al. 27 (18): 2905 -- Journal of Clinical Oncology

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Originally published as JCO Early Release = 10.1200/JCO.2009.22.4998 on=20 May 18 2009

Journal of Clinical Oncology, Vol = 27, No 18=20 (June 20), 2009: pp. 2905-2908
=A9 2009 American Society = of Clinical=20 Oncology.
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COMMENTS AND = CONTROVERSIES

End Point Assessment in Gliomas: Novel Treatments Limit = Usefulness of=20 Classical Macdonald's Criteria

Martin J. = van den=20 Bent

Neuro-Oncology Unit, Daniel den Hoed Cancer = Center,=20 Erasmus University Hospital, Rotterdam, the Netherlands

Michael A. Vogelbaum =

Brain Tumor and Neuro-Oncology Center, = Department of=20 Neurosurgery, Cleveland Clinic, Cleveland, OH

Patrick Y. Wen

Center for Neuro-Oncology, Dana-Farber/Brigham = and=20 Women's Cancer Center; and Division of Neurology, Brigham and = Women's=20 Hospital, Boston, MA

David R. Macdonald =

Department of Oncology, London Regional Cancer = Program;=20 and Division of Medical Oncology, University of Western Ontario, = London,=20 Ontario, Canada

Susan M. Chang

Division of Neuro-Oncology, Department of = Neurological=20 Surgery, University of California San Francisco, San Francisco, CA =


  =20 INTRODUCTION
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3D"INTRODUCTION
LIMITATIONS OF MACDONALD'S...
PFS OR OVERALL SURVIVAL...
NEED FOR STUDY-SPECIFIC END...
AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
REFERENCES
 
R= ecent=20 trials in glioma have revealed significant limitations = in the=20 end points used. This requires a critical and comprehensive=20 review of how brain tumor trials are conducted, = particularly=20 of which end points are defined and how response and=20 progression are defined.


  =20 LIMITATIONS OF MACDONALD'S RESPONSE AND PROGRESSION CRITERIA =
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INTRODUCTION
3D"LIMITATIONS OF=20 MACDONALD'S...
PFS OR OVERALL SURVIVAL...
NEED FOR STUDY-SPECIFIC END...
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AUTHOR CONTRIBUTIONS
REFERENCES
 
I= n=20 1990, Macdonald et al1=20 reported criteria for response assessment in glioma. = These=20 criteria, which rely primarily on computed tomography = (CT)=20 =96based two-dimensional WHO response criteria, marked = the=20 transition from a subjective interpretation of clinical = and=20 radiologic changes toward more objective radiologically = based=20 criteria. Macdonald's criteria use the enhancing tumor = area as=20 the primary measure, while considering the use of steroids = and=20 changes in the neurologic status. Although these criteria = have=20 limitations (particularly the difficulty of measuring the = often=20 irregular shape of gliomas), they have become widely = accepted.=20 However, recent observations have revealed fundamental=20 limitations to Macdonald's criteria.2,3=20 At the core of Macdonald's criteria are changes in = enhancement,=20 and indeed, all too often, the enhancement of = high-grade tumors=20 is perceived as a measure of tumor. However, = enhancement is=20 nonspecific and primarily reflects a disrupted = blood-brain=20 barrier. Enhancement can be influenced by changes in=20 corticosteroid dose and radiologic technique.4,5=20 Enhancement can also be induced by a variety of = nontumoral=20 processes: inflammation, seizure activity, postsurgical = changes, and radiation necrosis.6=96<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/27/18/2905#B9">9=20 As a result, changes in the enhancing area cannot be = equated=20 with changes in tumor size or tumor growth/activity.=20 Macdonald's criteria have proved to be of limited value = in the=20 following clinical situations.

Pseudoprogression and Radiation = Necrosis
Studies of=20 patients with glioblastoma treated with the current = standard of=20 care=97chemoradiation combined with temozolomide=97have = shown=20 consistently that immediately after the end of radiotherapy,=20 20% to 30% of patients suffer from pseudoprogression.10,<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/27/18/2905#B11">11=20 This is defined as an increase of enhancement within = the=20 irradiated field that spontaneously subsides without = new=20 antitumor treatments (Fig = 1).=20 Pseudoprogression appears to be less frequent after=20 fractionated external-beam radiotherapy only.12=20 Moreover, after combined chemoradiation, radiation = necrosis=20 also seems to occur more frequently and earlier than it = does=20 after fractionated external-beam radiotherapy = only.13=20 This limits the validity of progression-free survival = (PFS) as=20 the primary end point in clinical trials and has = significant=20 implications for eligibility in salvage treatment = trials;=20 patients should not be eligible for such trials in the = first=20 months after the end of radiotherapy. Most trials = currently use=20 a 3-month minimum interval, which is admittedly an = arbitrary=20 period.



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  		Fig 1. = Example of=20 pseudoprogression after radiotherapy only. (A) Patient = with=20 biopsy-proven gemistocytic astrocytoma showing mass = effect on=20 magnetic resonance imaging (MRI) < 2 months before = start of=20 radiotherapy underwent 50.4-Gy radiotherapy in = fractions of=20 1.8 Gy. (B) On first follow-up MRI 2 months after end = of=20 radiotherapy, new enhancing lesions were present. (C) = These=20 disappeared 7 months later without any additional = treatment.=20 The patient was asymptomatic throughout this episode = and did=20 not receive steroids. =

 = ;
Enhancement=20 Resulting From Local Treatment
The observation of = postsurgical=20 enhancement confounding assessment of response has = resulted in=20 the exclusion from phase II studies using response as = the=20 primary end point of patients after surgery, unless an=20 immediate postoperative scan (ie, within the first 24 = to 48=20 hours) is obtained.7,14=96= 16=20 However, local treatment=96induced enhancement is not = limited to=20 surgical resection. Transient increases in enhancement = (flare)=20 not reflecting tumor progression have been reported in = multiple=20 studies of local intratumoral treatment.17=96= 20=20 Therefore, PFS may not be an appropriate end point in = such=20 trials. The same holds true for interstitial = brachytherapy and=20 stereotactic radiosurgery, which may induce radiation = necrosis=20 mimicking tumor progression.21=20

Pseudoresponse After Treatment With Agents Affecting=20 Angiogenesis and Blood Vessels
Studies of agents that = modify=20 signal transduction through the vascular endothelial = growth=20 factor (VEGF) signaling pathways (eg, bevacizumab and=20 cediranib) have shown that initiation of therapy often = produces=20 a rapid decrease in enhancement, resulting in high = response=20 rates.22,<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/27/18/2905#B23">23=20 However, these responses result at least partially from = a rapid=20 normalization of abnormally permeable blood vessels or = regional=20 cerebral blood volume, not from antitumor effects. = Moreover, in=20 several patients, increases in the nonenhancing portion = of=20 tumor were observed in T2- or fluid-attenuated = inversion=20 recovery (FLAIR) =96weighted magnetic resonance imaging = (MRI),=20 suggestive of infiltrative tumor progression despite = the=20 continuing radiologic response of the enhancing lesions = (Fig=20 2).24=20 This may explain the disappointing disparity between = the=20 unprecedented high response rates produced by these = agents in=20 recurrent glioblastoma and the modest (if any) survival = benefit=20 reported. To some extent, similar effects have been = observed=20 after treatment with platelet-derived growth factor=20 inhibitors.25=20 Again, the difficulty in assessing progression limits = use of=20 6-month PFS as the primary end point, and in response=20 assessment, changes in T2- or FLAIR-weighted MRI sequences = must=20 also be considered.26=20



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  		Fig 2. = Patient 57=20 years of age with secondary glioblastoma before ([A]=20 T1-weighted magnetic resonance imaging (MRI) with = contrast and=20 [B] fluid-attenuated inversion recovery [FLAIR] = =96weighted MRI)=20 and after 7 months of treatment with bevacizumab and=20 irinotecan, showing reduction in size of initial=20 contrast-enhancing mass but also demonstrating (C) = subtle=20 diffuse enhancement and (D) significantly increased = FLAIR=20 crossing the corpus callosum. This was associated with = increased cognitive impairment. Patient was not = receiving=20 corticosteroids at time of either scan. =

 = ;
Another=20 issue is the occurrence of rebound enhancement and edema = on=20 discontinuation of the VEGF-signaling inhibitor, which = requires=20 special attention if patients are enrolled onto clinical = trials=20 after nonresponse to VEGF-inhibiting agents. In the = example=20 illustrated by Figure=20 3, after a sufficiently long washout interval, a = new=20 baseline scan is needed to avoid the unjustified designation = of=20 failure of subsequent treatment because of rebound = enhancement=20 and edema.



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  		Fig 3. = Example of=20 rebound enhancement after discontinuation of = anti=96vascular=20 endothelial growth factor (VEGF) agent. (A) Axial = T1-weighted=20 magnetic resonance imaging with contrast of patient = with=20 recurrent right temporal glioblastoma who initially = responded=20 to aflibercept (VEGF Trap; Regeneron, Tarrytown, NY); = (B) at=20 recurrence when aflibercept was discontinued; and (C) = 4 weeks=20 after, showing significant increase in contrast = enhancement.=20 (D) Patient began receiving bevacizumab with = significant=20 reduction in enhancement 4 weeks later, suggesting = that=20 worsening was in part result of aflibercept = discontinuation=20 and not just of tumor progression. =

 = ;
Nonenhancing=20 Tumors: Low-Grade Glioma
Macdonald's criteria were = designed=20 primarily to evaluate high-grade gliomas and focus on = changes=20 in enhancing tumor volume. However, low-grade gliomas = usually=20 do not show contrast enhancement in CT or MRI. = Untreated, these=20 tumors often have low growth rates, on the order of 3 = to 5 mm=20 per year.27=20 Because it would take a considerable period of time to = reach=20 the Macdonald-specified 25% increase in area, this = obscures the=20 detection of progression. Moreover, low response rates = have=20 been observed in several trials despite significant = clinical=20 benefit (particularly seizure reduction) and prolonged = disease=20 control.28=96= 30=20 One problem seems to be that residual abnormalities, = which may=20 persist after successful treatment, cannot be = distinguished=20 from active tumor in T2- or FLAIR-weighted MRI. =

Application of Macdonald's Criteria After Complete = Resection of=20 Enhancing Disease
Macdonald's criteria define disease=20 progression as an increase in enhancing tumor area of = 25% or the=20 appearance of new enhancing lesions. Surgical = techniques have=20 evolved such that so-called gross total resection (eg,=20 resection of all of the enhancing disease) is performed = on a=20 more regular basis.31=20 If there is no enhancement present at postoperative = imaging=20 study, any enhancement on subsequent scans=97no matter = how small=20 or nonspecific=97by definition implies tumor = progression.=20 Currently, there are no generally accepted criteria to=20 determine progression after gross total resection. =

In theory, both alternative imaging tools and alternative = trial=20 designs and end points could be used to overcome these = imaging=20 issues. Indeed, more sophisticated MRI techniques and = metabolic=20 positron emission tomography with radioactively labeled = amino=20 acid tracers may provide answers to some of these issues, = but=20 these techniques are not widely available, nor have they = been=20 validated for use in trials of glioma.32,<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/27/18/2905#B33">33=20 Their value remains to be established in future = studies.=20


  =20 PFS OR OVERALL SURVIVAL AS THE PRIMARY END POINT=20
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W= hether=20 PFS can be an appropriate primary end point in phase = III=20 trials=97or whether overall survival (OS) should be the = primary=20 end point in these trials as a matter of principle=97is = an=20 ongoing discussion in oncology. The evaluation of the effect = of=20 a particular treatment on OS may be influenced by subsequent=20 salvage treatments. Until recently, the lack of effective=20 treatments in glioma made this a hypothetic = consideration in=20 glioma trials. However, the bevacizumab studies in = recurrent=20 glioblastoma have suggested that salvage treatments may = indeed=20 affect OS.23=20 In contrast, some recent trials of newly diagnosed = glioma=20 have shown improved PFS after initially intensified = treatment=20 without an impact on OS.34=96= 36=20 None of these trials have clarified whether this = increase in=20 PFS signified clinical benefit for the patients. = Prolonging PFS=20 may be beneficial to a patient if the toxicity of = initial=20 treatment is low, good function is maintained as long = as the=20 tumor is controlled, and progression is associated with = a=20 significant deterioration in function or quality of = life.=20 Unfortunately, until recently, most studies of = treatment for=20 newly diagnosed gliomas did not gather adequate = functional or=20 quality-of-life data to assess these issues. Moreover,=20 validated and accepted tools to assess neurologic=20 deterioration=96free survival are currently not = available.=20


  =20 NEED FOR STUDY-SPECIFIC END POINTS =
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C= learly,=20 different and study-specific end points are required = depending=20 on the type of trial, investigational treatment, and = clinical=20 setting (newly diagnosed or recurrent high-grade or = low-grade=20 glioma). If classical cytotoxic drugs that do not = interfere=20 with enhancement are tested in recurrent glioblastoma, = then a=20 classical approach with 6-month PFS as the primary end = point=20 can be used. In newly diagnosed glioblastoma, analyses = have=20 suggested that 12-month OS may be considered as a surrogate = end=20 point, although this end point would be subject to the = effects=20 of salvage treatments.37,<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/27/18/2905#B38">38=20 PFS is not adequate in trials of local treatments, = trials of=20 newly diagnosed glioma managed with chemoradiation = combined=20 with temozolomide, or trials with antiangiogenic = agents. In=20 these cases, the diagnosis of progression as assessed = by=20 conventional MRI is too uncertain. Crossover is an issue = if the=20 investigational agent is active in recurrent disease or = is=20 likely to be used in the control arm at time of progression. = If=20 so, no OS benefit may be observed, despite clear activity = of=20 the investigational agent. In these circumstances, trial = design=20 should emphasize other parameters of clinical benefit = for=20 patients.

To address these issues and develop specific guidelines = for=20 end points in various types of neuro-oncology trials, an=20 international working party has been formed to develop=20 recommendations for each of these situations. It is = expected=20 that through this effort, widely accepted criteria will = again=20 become available for use in clinical trials in the = coming=20 years.


  =20 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST=20
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LIMITATIONS OF MACDONALD'S...
PFS OR OVERALL SURVIVAL...
NEED FOR STUDY-SPECIFIC END...
3D"AUTHORS' DISCLOSURES = OF...
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<= I>Although=20 all authors completed the disclosure declaration, the = following=20 author(s) indicated a financial or other interest that = is=20 relevant to the subject matter under consideration in = this=20 article. Certain relationships marked with a "U" are those = for=20 which no compensation was received; those relationships = marked=20 with a "C" were compensated. For a detailed description = of the=20 disclosure categories, or for more information about = ASCO's=20 conflict of interest policy, please refer to the Author=20 Disclosure Declaration and the Disclosures of Potential=20 Conflicts of Interest section in Information for=20 Contributors.

Employment or Leadership Position: None Consultant or = Advisory Role: Martin J. van den Bent, = Schering-Plough (C),=20 Roche (C), Bristol-Myers Squibb (C), Ark Therapeutics = (C),=20 Siena Biotech (C), Antisense Pharma (C); Michael A. = Vogelbaum,=20 Genentech (C) Stock Ownership: None = Honoraria:=20 Martin J. van den Bent, Merck KGaA, Ark Therapeutics; = Michael=20 A. Vogelbaum, Schering-Plough, MGI Pharma; David R. = Macdonald,=20 Schering-Plough Research Funding: Martin J. van = den=20 Bent, Novartis Expert Testimony: None Other=20 Remuneration: David R. Macdonald, Schering-Plough =


  =20 AUTHOR CONTRIBUTIONS
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LIMITATIONS OF MACDONALD'S...
PFS OR OVERALL SURVIVAL...
NEED FOR STUDY-SPECIFIC END...
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3D"AUTHOR = CONTRIBUTIONS
REFERENCES
 
<= B>Conception=20 and design: Martin J. van den Bent, Michael A. Vogelbaum, = Patrick Y. Wen, David R. Macdonald, Susan M. Chang =

Manuscript writing: Martin J. van den Bent, Michael A.=20 Vogelbaum, Patrick Y. Wen, David R. Macdonald, Susan M. = Chang

Final approval of manuscript: Martin J. van den Bent,=20 Michael A. Vogelbaum, Patrick Y. Wen, David R. = Macdonald, Susan=20 M. Chang


  =20 Acknowledgment
 
We = thank=20 Jacolien Bromberg, MD, for providing critical comments. = S.M.C.=20 is supported in part by NIH Grant No. PO1 CA118816.


  =20 REFERENCES
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INTRODUCTION
LIMITATIONS OF MACDONALD'S...
PFS OR OVERALL SURVIVAL...
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Opera = requires=0A= the Sun Java Runtime Environment .=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_0000_01C9FBD0.17801890 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://jco.ascopubs.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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Copyright =A9 2009=20 by the American Society of Clinical Oncology, Online ISSN: = 1527-7755.=20 Print ISSN: 0732-183X
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