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3D" 3D" Vol. 303 No. 10, March 10, = 2010 3D" 3D"
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CLINICIAN'S CORNER
A 31-Year-Old Woman With a Transformed = Low-grade=20 Glioma

Peter=20 C. Warnke, MD, Discussant

JAMA. 2010;303(10):967-976.

ABSTRACT
3D" 3D"

Low-grade=20 gliomas in adults have an incidence of 0.8 to 1.2 = per=20 100 000, and their causes are unknown. Despite = their=20 histological classification as low-grade, they cannot = be=20 cured by any current treatment mode, and no class = I=20 evidence exists to guide initial treatment of = these=20 tumors. Median survival ranges between 7.5 years = and 10=20 years, with a 5-year survival probability between = 55% and=20 86%. The prognosis depends on age, World Health=20 Organization (WHO) tumor grade, Karnofsky performance=20 score, cytological type (oligodendroglioma vs=20 astrocytoma), and, potentially, the extent of = resection.=20 Oligodendrogliomas with loss of heterozygosity on = chromosomes 1p and 19q have a distinctly more = favorable=20 prognosis and therapeutic response rate. = Low-grade tumors=20 progress to high-grade gliomas with aggressive = biological=20 behavior at increasing frequency with advancing age. = Ms P=20 is a young woman with a previously treated = oligodendroglioma,=20 WHO grade II, with loss of heterozygosity on = chromosomes=20 1p and 19q, which at a third resection had = transformed=20 into an oligodendroglioma of WHO grade III. She = wants to=20 know her current and future therapeutic = options.=20



INTRODUCTION
3D" 3D"
 Jump to=20 Section
 =95 Top=
 =95 Introduction
 =95 Ms=20 q: her view
 =95 At=20 the crossroads: = questions...
 =95 Recomm= endations=20 for ms q
 =95 Author= =20 information
 =95 Refere= nces
3D"
3D"

DR DELBANCO: Ms Q = is a=20 31-year-old health care professional who is = married and=20 has children. She is currently not working and = has=20 commercial health insurance.

Without history of seizure disorder, Ms Q experienced a=20 generalized tonic-clonic seizure about 30 months = prior to=20 this conference. Thereafter, Ms Q's physical = examination=20 results were normal, but computed tomography (CT) = and=20 magnetic resonance imaging (MRI) scans showed a = right=20 temporal mass with surrounding mild edema (= Figure=20 1A), and the lesion was thought to likely represent = a=20 primary brain tumor. Ms Q and her physicians concluded = that=20 resection would be her best option.


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Figure 1. Imaging of Ms = Q's Tumor at=20 Diagnosis and at Recurrence

A, Fluid-attenuated inversion recovery = (FLAIR)=20 magnetic resonance imaging (MRI) of Ms Q's = tumor=20 at diagnosis. The white signal-intense = areas in=20 the right temporal lobe correlate with the = tumor.=20 Note the lack of a clear demarcated = border. B,=20 Left panel, FLAIR MRI of Ms Q's tumor at = first=20 recurrence. The tumor has regrown in the = dorsal=20 wall of the previous resection cavity, = seen as a=20 small dark zone (yellow arrowhead) in = front of the=20 FLAIR signal. Note the more circumscribed=20 appearance, suggesting a more delineated = tumor=20 growth. Right panel, arterial = spin-labeling (ASL)=20 MRI reflecting blood flow at first = recurrence of=20 Ms Q's tumor. The dark areas in the region = of the=20 tumor (blue arrowhead) reflect reduced = blood flow=20 indicative of a low-grade tumor. C, = Arterial=20 spin-labeling MRI at second recurrence of = Ms Q's=20 tumor. The tumor still appears dark (blue=20 arrowhead), signifying reduced blood flow = compared=20 with the surrounding cortex and white = matter,=20 compatible with a low-grade glioma. =


Prior to resection, a Wada test (intracarotid sodium=20 amobarbital procedure) demonstrated left = hemisphere=20 dominance for language. Ms Q underwent subtotal = resection=20 for a World Health Organization (WHO) grade II/IV = oligodendroglioma because the tumor was hardly=20 distinguishable from the surrounding infiltrated brain = tissue and had no sharp border on MRI. Using the = staining=20 index for the anti-Ki67 monoclonal antibody = MIB-1, the=20 tumor was shown to have a proliferative fraction = of 1% to=20 2%. Chromosome 1p/19q deletions identified in the = tumor=20 indicated a favorable prognosis.

Twelve months later, a follow-up MRI showed recurrence of = the mass (= Figure=20 1B [left panel]). Ms Q underwent a second, more=20 extensive resection to remove a macroscopic tumor, and = the=20 tissue revealed the same pathologic results as = before.=20 Early in 2008, 21 months after her second = operation, an=20 MRI showed a third recurrence of the mass, and = subsequent=20 resection revealed WHO grade III = oligodendroglioma. MIB-1=20 staining showed that the tumor had a = proliferative=20 fraction of 50%. Although Ms Q had a somewhat = prolonged=20 postoperative recovery, it was complete and she = is=20 currently feeling well while taking oral temozolomide=20 chemotherapy.

Ms Q has never smoked and she does not use alcohol or = drugs.=20 There is no history of brain tumor in her family. She = has=20 a history of Hashimoto thyroiditis, which = currently=20 requires no therapy, and underwent uneventful=20 cholecystectomy for cholecystitis in the past. A = recent=20 physical examination performed in the brain tumor = clinic=20 was unremarkable, revealing no neurological=20 abnormalities. There were no unusual laboratory = findings.=20 Her current medications include levetiracetam, = 500 mg=20 twice daily, and temozolomide, monthly, per = protocol,=20 with a goal of 18 months of therapy.


MS Q: HER VIEW
3D" 3D"
 Jump to=20 Section
 =95 Top=
 =95 Introdu= ction
 =95 Ms q: her=20 view
 =95 At=20 the crossroads: = questions...
 =95 Recomm= endations=20 for ms q
 =95 Author= =20 information
 =95 Refere= nces
3D"
3D"

After the=20 first surgery, the whole tumor wasn't removed. They=20 thought at first that it was, but it wasn=92t. There = was=20 a small part of the tumor that was left that they = watched=20 for a little bit over a year. And then in June = 2007, I=20 had to have a second surgery because it started = to grow=20 back.

I had a PET [positron emission tomography] scan, and they = thought the tumor was gone. But it was not. I do = wish=20 that the doctors could tell me why they can't see = the=20 cells. I know they are so small, but while you're = in the=20 surgery, why can't the doctors look and see which = cells=20 are bad and should be removed? So then in January = 2008, I=20 had to again face the fact that I was probably = going to=20 have to have another surgery.

After the third surgery, the pathology of the tumor has=20 changed, and it's a grade III anaplastic=20 oligodendroglioma. The 2 options I have now are = radiation=20 and chemotherapy or a combination of the 2. = Watchful=20 waiting is not an option right now because it is = a=20 cancerous tumor. I=92m very anxious to have another = MRI to=20 see if the tumor is completely gone at this point. = There=20 have been more than enough times that it wasn't really = gone.

After the surgeries, I felt that I wasn't like myself. = For=20 one thing, when I got up, it felt like my head = was a lot=20 larger than it really was, that it was a lot more = swollen. I knew I was talking normally, but I = would ask=20 whoever I was talking to, "Do I sound like = myself? Do I=20 sound like I=92m making sense?" I felt like I = wasn't making=20 sense. And I wasn't able to do things in order. = For=20 instance, I=92d turn on the water faucet, but = then I would=20 realize that I needed to turn on the light. I=92d = turn on=20 the light, but then turn off the light again when = I went=20 to turn off the water faucet. It's those things = that you=20 take for granted that you=92d just be able to do, = something=20 as easy as doing that in order, that you're not able = to=20 do in order. I actually had to think about what I was = doing.=20 So I didn't feel like myself. I felt like somebody = else,=20 or like I=92d taken a lot of steps backward. =

As a clinician, in my care of patients before my illness, = I=20 tried to be empathetic, and I tried to spend time. And = I=20 thought I was doing a really good job at that. = But then=20 after I had the seizure and after the first time = going=20 back to work, I realized that I could be = empathetic to a=20 greater extent. Now, instead of trying to get = people to=20 shorten their stories, I=92m trying to really = listen to=20 what they have to say. I think the attitude that = I=92ve=20 seen with surgeons is they want to solve the = problem, and=20 they think, "Now we=92ve done this. We=92ve = solved this=20 problem. We=92ve done this miracle. Now, you can = move on."=20 And maybe they don't want to feel like they're = not able=20 to heal you, or feel like they're actually not = able to=20 deal with your problem.

Having a brain tumor has affected my life in every area. = It=20 makes you look at things completely differently = because=20 you don't know how much time you have. I worry = about my=20 family more than myself all the time. Any time I = have=20 something new that I have to deal with, I worry = about=20 who's going to take care of my kids, and how I am = going=20 to be able to take care of my kids, because = they're my=20 responsibility.


AT THE CROSSROADS: QUESTIONS FOR DR WARNKE=20
3D" 3D"
 Jump to=20 Section
 =95 Top=
 =95 Introdu= ction
 =95 Ms=20 q: her view
 =95 At the = crossroads:=20 questions...
 =95 Recomm= endations=20 for ms q
 =95 Author= =20 information
 =95 Refere= nces
3D"
3D"

What are the=20 epidemiology and natural history in adults of glial = cell=20 tumors of the brain? What are their clinical = presentation=20 and differential diagnosis and how should clinicians=20 assess the various signs and symptoms patients = first=20 demonstrate? What are the indications for biopsy = vs=20 excision and what are the current treatment = modes? What=20 morbidity may accompany perioperative care and = ongoing=20 treatment? What does the future hold with respect = to=20 treatment of these illnesses? What do you recommend for = Ms=20 Q?

DR WARNKE: Ms Q=20 presented for evaluation after a first seizure.=20 Radiological workup showed a mass in the right = temporal=20 lobe (= Figure=20 1A). She was then evaluated by a neurologist, who = suggested=20 she undergo a lumbar puncture because the differential = diagnosis also included temporal encephalitis. = The spinal=20 fluid analysis results were normal, and further=20 neuroradiological workup with MRI scanning with=20 fluid-attenuated inversion recovery (FLAIR) = T2-weighted=20 and diffusion tensor sequences indicated a low-grade=20 glioma. To lateralize her language = function before=20 her first scheduled surgery, Ms Q had a Wada test, = consisting of=20 intracarotid injection of sodium amobarbital to evaluate = language=20 and memory function in the injected hemisphere. The patient = is awake=20 during the injection and undergoes continuous testing. In = view of=20 the fact that the patient was right-handed, and the lesion = was on=20 the right side, I would not consider this part of a standard = diagnostic workup because the likelihood of ipsilateral = language=20 localization in a right-handed person is less than 10%, and = this can=20 be clarified noninvasively with a functional MRI.1-2=20 She then underwent navigation-guided resection.

Ms Q experienced a first recurrence in 2007, and the = tumor=20 was again resected using navigation-guided = microsurgical=20 resection and the same anatomical approach. Her = recent=20 third surgery was with a widened craniotomy, = again with=20 navigation. Even before the second recurrence, = the tumor=20 showed a pattern of hypoperfusion on MRI = (arterial spin=20 labeling) (= Figure=20 1, B [right panel] and C), which is not = indicative of=20 malignant transformation. Furthermore, on PET = with=20 18fluourodeoxyglucose measuring glucose use, = the=20 tumor was always hypometabolic and showed no signs of=20 malignant transformation. The only indication = that the=20 phenotype had become more malignant was an = elevated=20 choline/creatinine ratio on the last MR = spectroscopy=20 before the third resection (= Figure=20 2). The choline/creatinine ratio can serve as = an=20 objective marker for removal of the malignant = areas, and=20 the ratio was again normalized after the third = resection=20 as measured in the tissue adjacent to the = resection=20 cavity. At that point, using imaging criteria = alone, the=20 surgeon believed that total resection was = achieved. This=20 evolution of a low-grade oligodendroglioma to a = malignant=20 transformation in 3 years in a patient younger than = 40=20 years is unusual. The fact that Ms Q had 3 surgeries = before=20 implementation of adjuvant treatment also seems = unusual.=20 The first surgery was believed to be radical, but = she=20 experienced a recurrence within 12 months and, = given her=20 young age, a second resection was thought to be = necessary=20 to delay adjuvant treatment further, in the hope = that the=20 second resection could be more radical. When she = had a=20 third recurrence, doubts arose as to the tumor's=20 histology; therefore, a new tissue specimen was=20 necessary, combined with another resection. The most=20 likely explanation for this course is that some = malignant=20 cells were present at the first surgery but not = sampled=20 or revealed in radiological studies. All = treatment=20 decisions were made by the tumor board and not an = individual neurosurgeon.


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Figure 2. Magnetic = Resonance=20 Spectroscopy at Second Recurrence of Ms = Q's Tumor

The 3 peaks from left to right = represent=20 choline, creatinine, and = N-acetylaspartate.=20 In normal brain, N-acetylaspartate = is the=20 prevalent peak. In tumors of higher grade, = the=20 choline peak becomes the largest and the = ratio of=20 choline to creatinine is indicative of the = grade.=20 Ratios of 2 or higher are associated with = more=20 malignant phenotypes in gliomas. Here, the = ratio=20 is 2.87. The tumor otherwise had features=20 consistent with a low-grade recurrence; = the=20 magnetic resonance spectroscopy was the = only=20 indicator of a malignant regrowth. =


Epidemiology and Natural History of = Low-grade Gliomas=20 in Adults

Low-grade gliomas originate from the glial tissue within = the=20 brain and have either predominantly astrocytic or=20 oligodendroglial differentiation.3=20 Gliomas are categorized using a 4-tier grading = system=20 implemented by WHO.4=20 The different grades refer to the degree of = malignant=20 behavior and the prognosis (= Table=20 1). Adult low-grade gliomas are grade II = whereas=20 malignant gliomas are grade III or IV. Grade I = tumors are=20 benign, often indolent lesions of childhood-like=20 pilocytic astrocytomas and gangliogliomas. = Whereas=20 malignant gliomas show rapid clinical and radiographic=20 progression and a short survival (in the range of 1-3=20 years), low-grade gliomas (WHO grade II) have a = prolonged=20 course over many years. They affect young adults = and are=20 characterized by slow growth, a high degree of = cellular=20 differentiation, and, in the majority of cases, = diffuse=20 infiltration of the surrounding brain = tissue.3=20 Adult low-grade gliomas comprise 25% of all adult = diffuse=20 astrocytomas. The incidence of low-grade gliomas is = 6 per=20 1 million adjusted standard population, estimated from=20 countries with a standard cancer registry.5-6=20 Among low-grade gliomas, the histological = entities are=20 astrocytoma, WHO grade II (15%-25%); = oligodendroglioma,=20 WHO grade II (5%-18%); oligoastrocytoma, WHO = grade II=20 (10%-19%); and, with a significantly lower frequency = and=20 predominantly growing inside the ventricles, = ependymoma,=20 WHO grade II (3%-9%).7=20 Rare entities include neurocytomas (0.2%-0.5%) = and=20 subependymomas.


View this=20 table:
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Table 1. Adult Low-grade=20 Gliomas4 =


The natural history of WHO grade II astrocytomas,=20 oligodendrogliomas, and oligoastrocytomas is = usually=20 characterized by a plateau phase after diagnosis, = when no=20 volume increase is found, and then 3 to 5 years = of very=20 slow, if any, progression both clinically and=20 radiographically.8-9=20 Untreated tumors progress over years in an = age-dependent=20 manner.10=20 In patients older than 40 years, tumors show a = higher=20 rate of malignant transformation to WHO grade III = or=20 grade IV tumors (33% within 5 years, 54% after 10 = years,=20 and 67% after 15 years) and concomitantly change their=20 clinical as well as radiographic behavior, with=20 progressive symptoms, sometimes starting as = refractory=20 seizures.11=20 These data are derived from a study with 239 = patients=20 treated between 1972 and 1992, with a median = follow-up of=20 10.3 years. Radiographically, tumors start to = show areas=20 of contrast enhancement, signifying the = anaplastic=20 focus.12=20 In functional imaging like PET and regional = cerebral=20 blood flow measurements, tumors show areas of = hypermetabolism,=20 increased blood volume, and increased cerebral blood=20 flow.13-16=20

Low-grade gliomas are tumors of young adulthood, with a = peak=20 incidence at about age 35 years, close to the age when = Ms=20 Q's tumor occurred. There is no influence of sex = or race;=20 no causes or risk factors are known except for=20 neurofibromatosis.17=20 Although malignant gliomas show a male = predominance, this=20 has not been established for low-grade gliomas=20 specifically. For unknown reasons, prognosis = worsens with=20 age in all brain tumors.18-19=20

Ms Q's tumor is atypical: it progressed rapidly in less = than=20 3 years and, despite her young age, transformed into a = more malignant tumor during this time. However, = her tumor=20 is an oligodendroglioma, which carries a better = prognosis=20 than a pure astrocytoma and has 10-year survival = rates of=20 up to 50%.20-22=20 Within the oligodendrogliomas, she has a = particular=20 molecular fingerprint that is characterized by = loss of=20 heterozygosity on chromosomes 1p and 19q. In contrast=20 with oligodendrogliomas without associated deletions, = Ms=20 Q's tumor has a significantly better prognosis,=20 exhibiting higher sensitivity to radiotherapy and = chemotherapy, particularly to temozolomide and to = the=20 procarbazine, CCNU (lomustine), and vincristine = (PCV)=20 regimen with combined complete and partial = response rates=20 between 62% and 92% using MacDonald criteria of = volume=20 assessment based on CT or MRI.23-26=20

Clinical Presentation

No pathognomonic sign or symptom provides a = clinical=20 diagnosis or even leads physicians to suspect a low-grade = glioma,=20 but 68% to 92% of patients come to attention with a = first-time=20 seizure as adults. More than 60% of patients have no=20 neurological deficit.27=20 Ms Q had the classical presentation of a first-time = adult=20 seizure. Her seizure semiology indicated a lesion in = the=20 temporal lobe (ie, a secondary generalized grand = mal=20 seizure). She had a short period of confusion = with=20 stereotypic movements that evolved into a grand = mal=20 seizure. Among young adults presenting with = complex=20 seizures, up to 30% harbor low-grade gliomas.28=20

The differential diagnoses of patients = presenting with=20 first-time seizures include idiopathic epilepsy and other=20 nonneoplastic epileptogenic lesions, such as arteriovenous=20 malformations and cavernomas. Depending on the location of = the=20 tumor, a variety of focal neurological deficits may be = observed,=20 ranging from minute changes in oculomotor function due to = small=20 tectal gliomas to significant motor deficits due to tumors = invading=20 the internal capsule or the motor cortex.29-31=20 Only a small proportion of patients show signs of = increased intracranial pressure. In addition, = cerebral=20 vasculitis, multiple sclerosis, and infectious lesions = in=20 the central nervous system are in the differential=20 diagnosis.

Any of the aforementioned clinical presentations require = an=20 MRI scan to refine the differential diagnosis and the=20 extent of the lesion, and today an MRI scan is = almost=20 always indicated. Although a CT scan may rule out = larger=20 lesions or those with a higher tumor cell = density, based=20 on clinical experience CT scans are less = sensitive than=20 MRI scans. In particular, MRI scans are more = effective=20 than CT scans for identifying diffusely growing = tumors=20 and small tumors in epileptogenic areas (ie, the=20 hippocampus or the structures of the mesial temporal = lobe).=20 While electroencephalograms are used to localize the=20 seizure or to analyze interictal phenomena, they = are not=20 an acceptable substitute for MRI.

Magnetic resonance imaging may include T1-weighted and=20 T2-weighted imaging, as well as gradient echo, = FLAIR=20 imaging, and MR spectroscopy. Low-grade gliomas = present=20 as nonenhancing lesions with T2 hyperintensity = and, in=20 the case of oligodendrogliomas, often calcifications. = The=20 sensitivity of morphological MRI imaging in detecting a = low-grade glioma is 80% to 85%, while specificity is = only=20 in the range of 60% to 64% compared with the gold = standard of histology.32-35=20 Magnetic resonance spectroscopy increases sensitivity = by=20 differentiating nonenhancing low-grade gliomas from=20 nonenhancing high-grade gliomas, which, in = several=20 series, comprise up to 40% of nonenhancing MRI = lesions in=20 patients aged 45 or older. In a case series of=20 oligodendroglial tumors, MR spectroscopy was able = to=20 differentiate between high-grade and low-grade=20 oligodendrogliomas without regard to their = enhancement=20 pattern.36=20 Ms Q's tumor was diagnosed by MRI, whereas the CT = scan=20 showed a hypodensity but not the other features = of a=20 low-grade glioma, corroborating the superiority = of MRI in=20 the diagnosis of low-grade gliomas.

Positron emission tomography with fluorodeoxyglucose F18=20 imaging has successfully identified anaplastic = foci=20 within a low-grade glioma, as verified by = stereotactic=20 biopsy with coregistration.37=20 Amino acid PET using either tyrosine or methionine and=20 exploiting the active transport mechanism for = amino acids=20 at the blood-brain barrier has been successful in = diagnosing low-grade gliomas and in = differentiating them=20 from high-grade gliomas.38-39=20 Amino acid PET is also useful to delineate the = extent of=20 biological tumor activity, which is usually=20 underestimated by the MRI scan. In this regard, = PET=20 serves 2 purposes: by integration into stereotactic=20 imaging, it can guide biopsies toward the biologically = most active and prognostically most relevant = parts of the=20 tumor, and by delineating the real extent of the = tumor,=20 it could also guide radiotherapy planning more=20 efficiently, thereby avoiding underdosing of the = tumor=20 periphery.40-41=20

Indications for Biopsy vs Excision and = Current=20 Treatment Modes

Among neurosurgeons and neuro-oncologists, disagreement=20 about the best management of low-grade gliomas = abounds.=20 Collectively, there is much to learn. To = establish a=20 histological diagnosis, the decision between = stereotactic=20 biopsy and primary resection is not based on = high-grade=20 evidence but relies on personal experience and = beliefs=20 about the natural history of low-grade gliomas.42-43=20 Tumors that are resectable only with unacceptable = morbidity=20 and mortality (ie, tumors in the basal ganglia, brain=20 stem, or highly eloquent areas of the cortex) are = an=20 indication for a primary stereotactic biopsy. At = the=20 opposite end of the spectrum, large resectable = lesions=20 causing midline shift and mass effect should be=20 candidates for primary resection, with the aim of=20 debulking. Epileptogenic tumors that have caused=20 refractory epilepsy can be an indication for = primary=20 resection if epilepsy cannot be controlled = medically. In=20 this circumstance, resection is primarily for = functional=20 reasons rather than for oncological = indications.=20

In the rest of cases, whether tumors should be biopsied,=20 resected, or partially resected is a difficult=20 decision.44-46=20 While microsurgery, with a combination of = functional MRI=20 and electrocorticography, has pushed the = boundaries of=20 resectability=97particularly for tumors in the = vicinity of=20 the primary motor cortex or the primary speech = area=97it is=20 unclear whether this retards progression and = improves=20 overall survival.47=20 Clearly, it has made neurosurgery in these = regions both=20 technically feasible and safer.48-49=20 However, a robust evidence base to support treatment=20 options in individual patients is lacking. A = systematic=20 review by Keles et al50=20 found that options for treatment are not supported = by=20 sufficient evidence to make firm recommendations. While=20 numerous articles from single institutions = suggest a=20 potential correlation between extent of resection = and=20 survival, none of these studies presents class I=20 evidence; ie, data generated by prospective = randomized=20 controlled trials with sufficient follow-up and = statistical=20 power to examine the scientific hypothesis. In Ms Q's=20 case, her tumor did not exert any mass effect at = the time=20 of first presentation, and the indication for a = resection=20 was relative. A stereotactic biopsy would have = been an=20 alternative. After the first rapid recurrence = indicating=20 a faster-growing lesion, a resection or = chemotherapy were=20 the alternatives. Resection was chosen to defer=20 chemotherapy and its adverse effects given her = young age.=20 At the second recurrence, a wide resection was = warranted,=20 given the suspicion that a shift to a malignant = phenotype=20 had occurred.

Although the search term low-grade glioma has 3193 = citations in PubMed, no Cochrane review of = evidence-based=20 treatment options has been performed. For Ms Q = and other=20 adults with low-grade gliomas, no systematic = analysis of=20 treatment options has been conducted, and the = options=20 range from watchful waiting to radiotherapy, = surgery,=20 interstitial radiosurgery, and, in predominantly=20 oligodendroglial tumors, chemotherapy. A Medical = Research=20 Council trial comparing "wait and see" vs early=20 radiotherapy was never completed because of = problems with=20 accrual.51=20 A German low-grade glioma observational study led = to some=20 recommendations, including debulking for lesions = with=20 mass effect, radiotherapy for diffuse lesions after = documented=20 progression, and interstitial radiosurgery for=20 circumscribed tumors.51=20

The different treatment results based on best evidence=20 available are summarized in = Table=20 2. No head-to-head comparison studies of = treatment=20 options have been conducted.


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Table 2. Treatment Results = Based on=20 Best Available Evidence =


External Beam Radiotherapy. Fractionated external = beam=20 radiotherapy has been evaluated in prospective = randomized=20 controlled trials generating class I evidence. = However,=20 these trials examined either delayed vs early=20 postoperative radiotherapy (European Organization = for=20 Research and Treatment of Cancer [EORTC]) or = low-dose (45=20 Gy) vs high-dose (59.4 Gy) radiotherapy.54-56=20 No class I evidence exists as to the efficacy of=20 radiotherapy per se. Thus, the actual effect of=20 radiotherapy on overall survival has not been = measured in=20 a randomized controlled trial, since all patients = received radiotherapy at some point in time and = no=20 radiation-naive control group exists. A new trial = (EORTC=20 22033-26033) is currently under way to compare the=20 efficacy of radiotherapy vs temozolomide = chemotherapy=20 after stratification for genetic 1p loss. This = ongoing=20 phase 3 study will hopefully shed some light on = the=20 efficacy of radiotherapy vs chemotherapy.

The aforementioned studies show that early postoperative=20 radiotherapy, compared with initiating = radiotherapy at=20 the time of recurrence, prolongs = progression-free, but=20 not overall, survival. In contrast with the same = dosing=20 studies in high-grade gliomas, studies comparing=20 different doses of fractionated radiotherapy show = no=20 advantage vs higher doses of radiotherapy. Class II and = class=20 III evidence in several studies indicate that=20 postoperative radiotherapy, regardless of the = timing of=20 its initiation, has some effect on overall = survival.=20 Finally, retrospective studies indicate that = radiotherapy=20 improves concomitant epilepsy.62-63=20

The efficacy of radiotherapy depends to a significant = degree=20 on targeting endothelial tissue, which in the brain is = unique compared with the extracranial = vasculature.64-65=20 Comparing individuals receiving low-dose vs = high-dose=20 radiotherapy,66=20 scores addressing quality of life are = significantly lower=20 in the high-dose group.

Surgical Resection. Surgical resection of = low-grade=20 gliomas is currently not supported by any class I = evidence; the evidence available stems from class = II and=20 III studies. The surgical literature can be = subdivided=20 into the prevolumetric and the volumetric era. In = the=20 prevolumetric era, gross measures regarding the = extent of=20 resection were used for biopsies, subtotal resection, = and=20 gross total resection. In contrast, MRI volumetry, both = before and after resection, actually quantifies the = extent=20 of resection. The prevolumetric era produced = inconsistent=20 data, supporting both "the more, the better" and = "less is=20 more." Several studies indicate that patients = with=20 resection, compared with those with biopsy, have=20 significantly longer overall survival.67=20 Others show no effect of resection on survival.46,=20 68=20 These studies are retrospective, and most lack=20 multivariate analysis of independent prognostic=20 variables, such as age, Karnofsky score (the = National=20 Cancer Institute's standard score for tumor = patients),=20 WHO subtype, and presence or absence of contrast=20 enhancement on MRI. In an extensive systematic review=20 published in 2001, Keles et al came to a = disappointing=20 conclusion: "Currently, for patients with = low-grade glial=20 tumors located in the cerebral hemisphere, the = only=20 management standard based on high-quality = evidence is=20 tissue diagnosis."50=20

More recently, quantitative MRI volumetry from defined = MRI=20 sequences has provided some evidence that = aggressive=20 resection results in improved survival.42,=20 52-53,69=20 Unfortunately, these studies are again limited by = several=20 factors. First, as retrospective, = single-institution=20 studies, they are at high risk of patient = selection bias.=20 Second, if a small percentage of the tumor is = left=20 behind, as in subtotal resection, the survival = advantage=20 is lost. Data presented so far show no continuous=20 correlation between the extent of resection and = survival;=20 only maximal or gross total resections affect = survival.=20 Given that these tumors are invasive by = definition, a=20 true, complete "resection" is impossible, raising = doubts=20 as to the "threshold" effect of resection. Thus, = if small=20 areas of tumor are left behind that just escape = MRI=20 detection, as may have been the case for Ms Q, residual = tumor should be continuously correlated with survival, = rather than there being a threshold at which = point the=20 correlation no longer exists. Third, = nonprospective,=20 population-based studies of much larger patient = cohorts=20 question the effect or extent of resection on = survival in=20 patients with low-grade gliomas and raise again = the point=20 of selection bias in single-institution = series.46=20

In summary, although surgery is the treatment of choice = for=20 space-occupying lesions that cause a neurological = deficit,=20 exert mass effect (measured as midline shift), or = cause=20 refractory epilepsy, no class I evidence supports = a=20 general recommendation that a patient like Ms Q = undergo=20 surgery.

Interstitial Stereotactic Radiosurgery. For = circumscribed,=20 small gliomas with a maximum diameter of 3 to 3.5 = cm,=20 several European groups have used stereotactic,=20 interstitial radiosurgery in large patient = cohorts with=20 extensive long-term follow-up.11,=20 65,=20 70-72=20 This technique involves the permanent or temporary=20 implantation of radioactive small seeds into the tumor = center, thus using low-dose-rate continuous = radiation to=20 the tumor, with a very high dose in the center = and a=20 steep dose drop-off to the periphery. Because of = its=20 highly localized character, this treatment = strategy can=20 apply only to demarcated, nondiffuse tumors that = tend to=20 proliferate very slowly. Since the likelihood of = damaging=20 a tumor cell in its vulnerable replication cycle = is=20 exponentially higher, such continuous hyperfractionated=20 radiation should have a much higher "hit rate." = In=20 addition, DNA repair mechanisms are less = effective,=20 resulting in a higher tumor cell kill rate. = Several=20 groups have studied the radiobiology of interstitial=20 radiosurgery, and the 5- and 10-year median survival = rates=20 in both adult and pediatric low-grade gliomas = rival those=20 of surgery and radiotherapy.11,=20 62,=20 71,=20 73-74=20 Again, like open surgery, interstitial = stereotactic=20 radiosurgery is reported by single institutions, = thereby=20 increasing the likelihood of selection bias. =

Chemotherapy. Chemotherapy, used extensively in = pediatric=20 low-grade gliomas, has also been used in adult = low-grade=20 gliomas for patients who were either inoperable = or=20 refused radiotherapy. In purely astrocytic = gliomas,=20 reports on response rates are anecdotal. For=20 oligodendroglioma, there is evidence for = chemosensitivity=20 to alkylating agents, such as temozolomide or the PCV=20 regimen.24,=20 57,=20 75-76=20 In this subgroup of tumors, chemosensitivity appears = to=20 correlate with the molecular fingerprint, (ie, the loss = of=20 heterozygosity on chromosomes 1p and 19q), and Ms Q = has=20 such a fingerprint. The data derive from = nonprospective,=20 nonrandomized, uncontrolled studies using = objective=20 response criteria from MRI and molecular = stratification.=20 Current consensus is that chemotherapy should be = used=20 before radiotherapy in younger patients.76-78=20 The good news for Ms Q is that the effect of = chemotherapy=20 can go beyond an improved MRI result. It translates = into=20 significantly prolonged overall and = progression-free=20 survival in patients whose imaging results = improve with=20 chemotherapy.

Perioperative Care and Morbidity Due to=20 Treatment

For patients undergoing either biopsy resection or=20 stereotactic interstitial radiosurgery for = low-grade=20 glioma, perioperative care varies. Stereotactic = biopsy=20 requires local anesthesia, with intraoperative = imaging=20 and postoperative CT scans to rule out = hemorrhage.=20 Following these procedures, patients generally = spend only=20 1 night in the hospital. For craniotomies performed = while=20 the patient is awake, the patient is generally given = anesthesia=20 during the craniotomy and surgical opening. For = complex=20 resections, patients undergo several hours of = general=20 anesthesia and must therefore be stable from a = cardiac=20 and pulmonary standpoint. After surgery, such = patients=20 require monitoring of cerebral function and = usually stay=20 overnight in an intensive care unit. For patients = undergoing stereotactic interstitial radiosurgery,=20 perioperative care is nearly identical to that of a=20 stereotactic biopsy. During radiosurgery, = radiation=20 monitoring is performed during implantation of = the=20 radioactive source, as well as after wound = closure, to=20 document and certify that the amount of radiation = emitted=20 by the patient reaches legally acceptable levels before = the patient can be discharged.

Morbidity from the treatment options differs widely. With = the use of sophisticated electrophysiology and = navigation=20 systems using functional MRI, which allows the = surgeon to=20 visualize brain function on a morphological MRI = image, as=20 well as the incorporation of intraoperative MRI = and CT,=20 surgical morbidity has fallen to 4% to 6% in = modern=20 series, and mortality is usually less than = 1%.52,=20 79-80=20 Stereotactic biopsies carry a morbidity of 2% and = a=20 mortality of less than 0.5% if carried out with = MRI=20 guidance and image fusion.81=20 Finally, as might be expected, surgical morbidity = also=20 depends heavily on the location of the tumor. Ms = Q's=20 reports of changed self-awareness and time perception=20 correlate well with the site of her lesion in the = right=20 lateral temporal lobe and are almost classic. Her = perception of the neurosurgical mind-set being = such that=20 "a problem has been solved" although the problem = cannot=20 be solved surgically is a wonderful description = of the=20 neurosurgical deformation professionelle = and=20 describes the need for neurosurgeons dealing with = tumors=20 to address their patients' concerns and goals as part = of=20 the treatment approach and follow-up.

Adverse effects from radiotherapy are classified as = acute,=20 early delayed, and late delayed. Morbidity is = related to=20 total dose, fraction size, and volume of = irradiated=20 brain. The most important morbidity is that of=20 symptomatic radionecrosis, wherein brain tissue = undergoes=20 necrosis that can be progressive and is accompanied = by=20 perifocal edema. Such patients require long-term = corticosteroid=20 therapy and, at times, resection of the necrotic mass. = The=20 2-year actuarial incidence is 2.5% after 50.4 Gy = and 5%=20 after application of 64.8 Gy.55=20 Late radiation effects center on leukoencephalopathy = and=20 concomitant cognitive decline.82-83=20 Interstitial radiosurgery is associated with a = permanent=20 morbidity of less than 3%, which is dose- and = dose=20 rate=96dependent.84=20

Chemotherapy-associated morbidity is drug-dependent,=20 classified according to National Cancer Institute = criteria, and ranges between 3% and 25%. = Permanent=20 morbidity from the most commonly used drugs (ie,=20 temozolomide or PCV) is in the range of 4% to = 8%.85-86=20 For women of childbearing age, fertility is = significantly=20 influenced by these drugs and needs to be taken into=20 consideration because reported infertility rates = after=20 PCV chemotherapy are about 50%.87=20

The Future of Low-grade Glioma=20 Management

Although low-grade gliomas appear histologically benign,=20 their behavior is malignant because no curative = treatment=20 exists. I believe that further improvement in = outcomes=20 from surgery, radiotherapy, or classic cytotoxic=20 chemotherapy is unlikely. The = relative=20 resistance to standard oncological treatment is founded in = the=20 unique biology and physiology of low-grade gliomas. In the=20 beginning, these tumors grow slowly and with low = proliferative=20 indexes. Histologically, there are no anaplastic features; = these=20 gliomas have no border and infiltrate the surrounding brain = at a=20 very early stage. They grow within highly functional tissue = and have=20 an intact blood-brain barrier. Before they transform into = malignant=20 phenotypes, their blood flow and blood volume is low. Thus, = they are=20 fundamentally different from most other tumors in the = body. If=20 the interspersed normal brain is to be spared, = new=20 treatments that target the specific tumor and its = biology=20 are needed. Ideally, such an agent both would target=20 tumor cells in the infiltrated brain specifically by=20 binding to a receptor selectively expressed on = tumor=20 cells and would not be toxic to normal brain. It = would=20 either cross the blood-brain barrier easily or be = delivered directly to the extracellular space of = the=20 tumor.

Such an agent could either cause cell death or induce=20 redifferentiation of tumor cells and halt the = malignant=20 transformation.88=20 Used so far in malignant gliomas, one approach is = to use=20 convection-enhanced delivery of conjugated = immunotoxins=20 that bind to either the transferrin receptor or = the=20 interleukin 12 receptor, both expressed only by = tumor=20 cells in the brain.89-90=20 Trials in malignant gliomas have not been = promising=20 because of several factors, including tumor = physiology,=20 with enlarged extracellular spaces and pressure = gradients=20 within the tumor. These do not pertain to low-grade=20 gliomas, making them an interesting target for = convection.=20 Another intriguing approach is to use stem cells, = which=20 have enormous tropism for tumor cells scattered = within=20 the brain.91=20 Finally, in some gliomas, truly interstitial = radiosurgery=20 could be performed by attaching radionuclides = with a=20 short-range energy to molecules targeting tumor = cells via=20 receptor binding.92=20 Ideally, alpha emitters would be attached, as = they=20 irradiate on almost a single-cell level. In = summary, as=20 technology advances, I anticipate that glioma = treatment=20 will result in more than palliation and will be = performed=20 more and more frequently as "molecular neurosurgery." =


RECOMMENDATIONS FOR MS Q
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 Jump to=20 Section
 =95 Top=
 =95 Introdu= ction
 =95 Ms=20 q: her view
 =95 At=20 the crossroads: = questions...
 =95 Recommendations for ms=20 q
 =95 Author= =20 information
 =95 Refere= nces
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Ms Q has=20 undergone gross total resection of a malignant=20 oligodendroglioma after 2 previous resections for = a=20 low-grade glioma in the same location. Without = adjuvant=20 treatment, her progression-free interval will = likely be=20 short. Adjuvant options are chemotherapy and = radiotherapy=20 either alone or in combination. Although radiotherapy = for=20 malignant oligodendrogliomas has been the standard for = decades=20 and is efficacious in virtually all malignant gliomas, = it=20 is associated with a risk of significant = irreversible=20 adverse effects, such as radionecrosis and=20 leukoencephalopathy.

At this point, Ms Q's tumor has undergone malignant=20 transformation. However, because her tumor cells = have=20 shown loss of heterozygosity on chromosomes 1p = and 19q,=20 her prognosis remains favorable and her = likelihood of=20 response to chemotherapy is between 62% and 92% = since she=20 has a recurrent but chemotherapy-naive tumor.93=20 In addition, she exhibited hypometabolism on PET with = F18,=20 and had a negative thallium 201 scan result. Both = are=20 independent prognostic variables associated with = response=20 to chemotherapy; hypermetabolic tumors have a = median=20 progression-free survival of 22 months vs a = median not=20 reached in the hypometabolic group with a median=20 follow-up of 25 months.93-94=20

In view of Ms Q's age and her favorable prognosis, I=20 recommend deferring radiotherapy and its possible = associated adverse effects as long as possible, = since an=20 effective, less toxic treatment is available that = will=20 likely result in long-term control. I would = reserve=20 radiotherapy for a possible point when the tumor = becomes=20 chemoresistant or the bone marrow reserve capacity is=20 exhausted. Unfortunately, little can be done for her=20 temporal lobe=96related symptoms.


AUTHOR INFORMATION
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 =95 Top=
 =95 Introdu= ction
 =95 Ms=20 q: her view
 =95 At=20 the crossroads: = questions...
 =95 Recomm= endations=20 for ms q
 =95 Author=20 information
 =95 Refere= nces
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Corresponding Author: Peter C. Warnke, = MD,=20 Division of Neurological Surgery, Beth Israel = Deaconess=20 Medical Center, 110 Francis St, Ste 3B, Boston, = MA 02215=20 (pwarnke{at}partners.org ).

Financial Disclosures: Dr Warnke reports that he = has=20 received grants through the Royal College of = Surgeons,=20 British Medical Journal, Direct = Therapeutics, and=20 ABC Foundation and that he serves as an associate = editor=20 for the Journal of Neurology, Neurosurgery, = and=20 Psychiatry.

Additional Contributions: We thank the patient for = sharing=20 her story and providing permission to publish = it.=20

This conference took place at the Surgical Grand = Rounds at=20 Beth Israel Deaconess Medical Center, Boston,=20 Massachusetts, on May 21, 2008.

Clinical Crossroads at Beth Israel Deaconess Medical=20 Center is produced and edited by Risa B. = Burns, MD,=20 series editor; Tom Delbanco, MD, Howard Libman, = MD,=20 Eileen E. Reynolds, MD, Amy N. Ship, MD, and = Anjala V.=20 Tess, MD.

Author=20 Affiliations: Dr Warnke is Visiting Professor of = Surgery,=20 Harvard Medical School, and Neurosurgeon in Chief, Division = of=20 Neurological Surgery, Beth Israel Deaconess Medical Center, = Boston,=20 Massachusetts.


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 Jump to=20 Section
 =95 Top=
 =95 Introdu= ction
 =95 Ms=20 q: her view
 =95 At=20 the crossroads: = questions...
 =95 Recomm= endations=20 for ms q
 =95 Author= =20 information
 =95 References
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Clinical Crossroads Section Editor: Margaret = A.=20 Winker, MD, Deputy Editor.



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}=0A= if (typeof(this.onsitedoms.test)=3D=3D"function"){=0A= return this.onsitedoms.test(host);=0A= }=0A= else if (this.onsitedoms.length>0){=0A= var doms=3Dthis.dcsSplit(this.onsitedoms);=0A= var len=3Ddoms.length;=0A= for (var i=3D0;i0)&&(pr.indexOf("http")=3D=3D0)&&!this.dcsIsOnsite(hn)){=0A= if(this.WT.cg_s!=3Dundefined){=0A= delete this.WT.cg_s;=0A= }=0A= if(this.WT.cg_n!=3Dundefined){=0A= delete this.WT.cg_n;=0A= }=0A= var = qry=3De.search?e.search.substring(e.search.indexOf("?")+1,e.search.length= ):"";=0A= var = pth=3De.pathname?((e.pathname.indexOf("/")!=3D0)?"/"+e.pathname:e.pathnam= e):"/";=0A= = this.dcsMultiTrack("DCS.dcssip",hn,"DCS.dcsuri",pth,"DCS.dcsqry",this.tri= moffsiteparams?"":qry,"DCS.dcsref",window.location,"WT.ti","Offsite:"+hn+= pth+"?"+qry,"WT.dl","24","WT.nv",this.dcsNavigation(evt));=0A= = this.DCS.dcssip=3Dthis.DCS.dcsuri=3Dthis.DCS.dcsqry=3Dthis.DCS.dcsref=3Dt= his.WT.ti=3Dthis.WT.dl=3Dthis.WT.nv=3D"";=0A= }=0A= }=0A= }=0A= }=0A= =0A= 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(window.RegExp){=0A= var tire=3Dnew = RegExp("^"+window.location.protocol+"//"+window.location.hostname+"\\s-\\= s");=0A= WT.ti=3Ddocument.title.replace(tire,"");=0A= }=0A= else{=0A= WT.ti=3Ddocument.title;=0A= }=0A= }=0A= WT.js=3D"Yes";=0A= WT.jv=3D(function(){=0A= var agt=3Dnavigator.userAgent.toLowerCase();=0A= var major=3DparseInt(navigator.appVersion);=0A= var mac=3D(agt.indexOf("mac")!=3D-1);=0A= var ff=3D(agt.indexOf("firefox")!=3D-1);=0A= var ff0=3D(agt.indexOf("firefox/0.")!=3D-1);=0A= var ff10=3D(agt.indexOf("firefox/1.0")!=3D-1);=0A= var ff15=3D(agt.indexOf("firefox/1.5")!=3D-1);=0A= var ff20=3D(agt.indexOf("firefox/2.0")!=3D-1);=0A= var ff3up=3D(ff&&!ff0&&!ff10&!ff15&!ff20);=0A= var = nn=3D(!ff&&(agt.indexOf("mozilla")!=3D-1)&&(agt.indexOf("compatible")=3D=3D= -1));=0A= var nn4=3D(nn&&(major=3D=3D4));=0A= var nn6up=3D(nn&&(major>=3D5));=0A= var ie=3D((agt.indexOf("msie")!=3D-1)&&(agt.indexOf("opera")=3D=3D-1));=0A= var ie4=3D(ie&&(major=3D=3D4)&&(agt.indexOf("msie 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(document.all){=0A= = WT.bs=3Ddocument.body?document.body.offsetWidth+"x"+document.body.offsetH= eight:"unknown";=0A= }=0A= else{=0A= WT.bs=3Dwindow.innerWidth+"x"+window.innerHeight;=0A= }=0A= WT.fv=3D(function(){=0A= var i,flash;=0A= if (window.ActiveXObject){=0A= for(i=3D10;i>0;i--){=0A= try{=0A= flash=3Dnew ActiveXObject("ShockwaveFlash.ShockwaveFlash."+i);=0A= return i+".0";=0A= }=0A= catch(e){=0A= }=0A= }=0A= }=0A= else if (navigator.plugins&&navigator.plugins.length){=0A= for (i=3D0;i0;i--){=0A= for (j=3D9;j>=3D0;j--){=0A= v=3Di+"."+j;=0A= if (Silverlight.isInstalled(v)){=0A= slv=3Dv;=0A= break;=0A= }=0A= }=0A= if (slv=3D=3Dv){=0A= break;=0A= }=0A= }=0A= }=0A= }=0A= return slv;=0A= })();=0A= if (this.i18n){=0A= if (typeof(document.defaultCharset)=3D=3D"string"){=0A= WT.le=3Ddocument.defaultCharset;=0A= } =0A= else if (typeof(document.characterSet)=3D=3D"string"){=0A= WT.le=3Ddocument.characterSet;=0A= }=0A= else{=0A= WT.le=3D"unknown";=0A= }=0A= }=0A= WT.tv=3D"8.6.2";=0A= // WT.sp=3D"@@SPLITVALUE@@";=0A= WT.dl=3D"0";=0A= WT.ssl=3D(window.location.protocol.indexOf('https:')=3D=3D0)?"1":"0";=0A= DCS.dcsdat=3DdCurrent.getTime();=0A= DCS.dcssip=3Dwindow.location.hostname;=0A= DCS.dcsuri=3Dwindow.location.pathname;=0A= WT.es=3DDCS.dcssip+DCS.dcsuri;=0A= if (window.location.search){=0A= DCS.dcsqry=3Dwindow.location.search;=0A= }=0A= if (DCS.dcsqry){=0A= var dcsqry=3DDCS.dcsqry.toLowerCase();=0A= var = params=3Dthis.paidsearchparams.length?this.paidsearchparams.toLowerCase()= .split(","):[];=0A= for (var i=3D0;i');=0A= }=0A= }=0A= WebTrends.prototype.dcsMeta=3Dfunction(){=0A= var elems;=0A= if (document.all){=0A= elems=3Ddocument.all.tags("meta");=0A= }=0A= else if (document.documentElement){=0A= elems=3Ddocument.getElementsByTagName("meta");=0A= }=0A= if (typeof(elems)!=3D"undefined"){=0A= var length=3Delems.length;=0A= for (var i=3D0;i0){=0A= if (name.toUpperCase().indexOf("WT.")=3D=3D0){=0A= this.WT[name.substring(3)]=3Dcontent;=0A= }=0A= else if (name.toUpperCase().indexOf("DCSEXT.")=3D=3D0){=0A= this.DCSext[name.substring(7)]=3Dcontent;=0A= }=0A= else if (name.toUpperCase().indexOf("DCS.")=3D=3D0){=0A= this.DCS[name.substring(4)]=3Dcontent;=0A= }=0A= }=0A= }=0A= }=0A= }=0A= WebTrends.prototype.dcsTag=3Dfunction(){=0A= if (document.cookie.indexOf("WTLOPTOUT=3D")!=3D-1){=0A= return;=0A= }=0A= var WT=3Dthis.WT;=0A= var DCS=3Dthis.DCS;=0A= var DCSext=3Dthis.DCSext;=0A= var i18n=3Dthis.i18n;=0A= var = P=3D"http"+(window.location.protocol.indexOf('https:')=3D=3D0?'s':'')+":/= /"+this.domain+(this.dcsid=3D=3D""?'':'/'+this.dcsid)+"/dcs.gif?";=0A= if (i18n){=0A= WT.dep=3D"";=0A= }=0A= for (var N in DCS){=0A= if (DCS[N]&&(typeof DCS[N]!=3D"function")){=0A= P+=3Dthis.dcsA(N,DCS[N]);=0A= }=0A= }=0A= var keys=3D["co_f","vtid","vtvs","vt_f_tlv"];=0A= for (var i=3D0;i0)){=0A= P+=3Dthis.dcsA("WT.dep",WT.dep);=0A= }=0A= if (P.length>2048&&navigator.userAgent.indexOf('MSIE')>=3D0){=0A= P=3DP.substring(0,2040)+"&WT.tu=3D1";=0A= }=0A= this.dcsCreateImage(P);=0A= this.WT.ad=3D"";=0A= }=0A= WebTrends.prototype.dcsDebug=3Dfunction(){=0A= var t=3Dthis;=0A= var i=3Dt.images[0].src;=0A= var q=3Di.indexOf("?");=0A= var r=3Di.substring(0,q).split("/");=0A= var m=3D"Protocol
"+r[0]+"
";=0A= m+=3D"Domain
"+r[2]+"
";=0A= m+=3D"Path
/"+r[3]+"/"+r[4]+"
";=0A= m+=3D"Query = Params"+i.substring(q+1).replace(/\&/g,"
")+"";=0A= = m+=3D"
Cookies
"+document.cookie.replace(/\;/g,"
")= +"";=0A= if (t.w&&!t.w.closed){=0A= t.w.close();=0A= }=0A= = t.w=3Dwindow.open("","dcsDebug","width=3D500,height=3D650,scrollbars=3Dye= s,resizable=3Dyes");=0A= t.w.document.write(m);=0A= t.w.focus();=0A= }=0A= WebTrends.prototype.dcsCollect=3Dfunction(){=0A= if (this.enabled){=0A= this.dcsVar();=0A= this.dcsMeta();=0A= this.dcsAdv();=0A= this.dcsTag();=0A= }=0A= }=0A= =0A= function dcsMultiTrack(){=0A= if (typeof(_tag)!=3D"undefined"){=0A= return(_tag.dcsMultiTrack());=0A= }=0A= }=0A= =0A= function dcsDebug(){=0A= if (typeof(_tag)!=3D"undefined"){=0A= return(_tag.dcsDebug());=0A= }=0A= }=0A= =0A= Function.prototype.wtbind =3D function(obj){=0A= var method=3Dthis;=0A= var temp=3Dfunction(){=0A= return method.apply(obj,arguments);=0A= };=0A= return temp;=0A= }=0A= ------=_NextPart_000_0000_01CAD327.83AD5300--