Baumert, B. G.

Stupp, R.

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Annals of Oncology 14: 1695–1696, 2003Editorial DOI: 10.1093/annonc/mdg501© 2003 European Society for Medical OncologyPromises and controversies in the management of low-grade gliomaLow-grade gliomas (LGGs) are a heterogeneous group of relativelyslow-growing primary tumors of astrocytic and/or oligodendroglialorigin. Peak incidence occurs in the second and third decade oflife. Many patients will present with easily controlled seizures andwill remain stable for many years, whereas others may progressrapidly, with increasing neurological symptoms, to a higher-gradetumor. Although morphologically indistinguishable at diagnosis,the time interval to progression varies considerably from a fewmonths to several years. To date treatment options were limited tosurgery when feasible, and radiotherapy and palliative chemo-therapy at recurrence. Oligodendroglioma with specific molecularchanges (allelic loss on chromosomes 1p and 19q) have beenrecognized over the last decade to be a distinct subgroup with abetter prognosis and a particular sensitivity to chemotherapy [1].New chemotherapy agents against malignant glioma are currentlyin development, and temozolomide, a novel alkylating agent, hasbeen approved for the treatment of recurrent malignant (high-grade) glioma [2].In this issue, two prospective phase II trials report radiologicaland clinical response to single agent temozolomide chemotherapyin patients with LGG, albeit based on quite different patient popu-lations. A British study included patients with stable or progressivedisease and who have not received any prior chemo- or radiotherapy[3]. In the study from Italy patients were required to have progres-sive disease, over two-thirds of their patients had received priorradiotherapy and one-third had also received previous chemo-therapy [4]. No repeat histological confirmation was performed,but on repeat surgery anaplastic features were present in eight of16 operated patients. Contrast enhancement on MRI, another signof possible malignant transformation, was present in 60% ofpatients. Interestingly, although the objective response rates arequite different between the two trials (10% in the British trial com-pared with 47% in the Italian trial), when minor responses are alsoconsidered, the tumor regression rates are 57% and 56%, respect-ively. There is inherent difficulty with response assessment in thebrain, where tumor cannot always be distinguished from associatededema and normal tissue. In some patients the radiologicalresponse was only demonstrated after several months of therapy.Sophisticated imaging techniques like positron emission tomo-graphy (PET) using amino acid traces or functional imaging (e.g.MR spectroscopy) may be of help in the future.Progression-free survival in the British study was 94% and 76%at 1 and 2 years, respectively, while, despite the higher responserate, in the Italian trial more than half of the patients had pro-gressed within 1 year, reflecting the different patient populations.In LGG initial and long-term symptom control and quality of lifeare end points as important as tumor shrinking on imaging. Bothstudies document a clinical benefit with improvement in seizurecontrol in about half of the patients.The British study had to be closed prematurely short of only afew additional patients. The authors indicate ‘availability of theinvestigational agent’ as the reason. Conducting clinical researchis becoming increasingly difficult. The desire of patients to betreated with a new agent paired with a strong pressure by the phar-maceutical industry to prescribe new and expensive drugs hamperaccrual into trials. New techniques or therapeutic options will thusnever be fully explored nor properly evaluated. Additional obstaclescome from the health authorities and regulatory bodies warrantingspecific additional insurance coverage and industrial funding formost protocols, while similar treatments outside clinical trials canbe freely prescribed.Where do these reports lead us? Should patients with LGG nowbe considered for primary chemotherapy? At initial diagnosismany patients do not require any specific therapy, but rathercareful psychological guidance. Surgery should be attempted forprecise diagnosis and in cases where a complete resection can beachieved [5, 6]. Based on two randomized trials, the EuropeanOrganization for Research and Treatment of Cancer (EORTC)provides us with a useful prognostic score for identifying patientswith the worst prognosis who are most likely to benefit fromtherapy [7]. Age ≥40 years, astrocytic tumor type, tumor size>6 cm, tumor crossing the midline and neurological deficit atdiagnosis were identified as independent prognostic factors, andthe presence of three or more of these factors was associated withan unfavorable prognosis.For patients with unfavorable prognostic factors radiotherapycurrently remains the established treatment option. Two random-ized trials have examined the dose of radiotherapy and thereappears to be no survival benefit for total doses >45–50 Gy [8, 9].Of concern with frequently ill-defined and diffusely infitratingtumors are the required large radiation volumes, which may leadto debilitating late sequelae in patients who will survive for manyyears [10, 11]. Highly conformal radiation techniques (e.g.intensity-modulated radiotherapy) combined with co-registeredMR and PET imaging may limit the amount of normal brain tissueirradiated [12–14].The timing of radiation therapy was the object of a randomizedtrial comparing immediate radiotherapy with delayed radiotherapyat progression [15]. Although time to progression was longer inthe immediate therapy group, progressing patients whose radio-therapy had been delayed could be successfully salvaged, and sur-vival was identical in both arms. Two-thirds of the progressingpatients subsequently received radiation accounting for only 38%1696of the patients in the observation group. Thus, radiotherapy couldbe withheld in almost two-thirds of patients for >5 years.Whether primary chemotherapy with the currently availabledrugs allows the delay of radiation and its sequelae remains to bedemonstrated. Secondary malignancies are to be expected withlong-term alkylating agent chemotherapy. A randomized trialcomparing standard radiotherapy to chemotherapy will be con-ducted by the EORTC and the National Cancer Institute ofCanada. In contrast to the present reports, temozolomide will beadministered as a low-dose continuous schedule. Chronic drugexposure may be critical for response in a slow-growing indolenttumor. In this trial patients will only be treated at documented pro-gression or in the presence of unfavorable prognostic factors.Patients will be prospectively stratified for histological and formolecular markers (1p loss). This allows the identification of sub-groups of patients who are more likely to benefit from one or fromthe other treatment modality.Management of LGG remains a challenging task. More precisedefinition of tumor entities, including also specific molecularmarkers, is necessary to identify patients in need of a more aggres-sive treatment strategy. Evaluation of the known prognostic fac-tors by an experienced multidisciplinary team is the basis for anytreatment recommendation or for watchful waiting. The role ofchemotherapy and new biological agents currently in develop-ment needs to be established in well-designed clinical trials.Long-term toxicity is of concern in a disease where patients maylive for many years.R. Stupp1, B. G. Baumert21Multidisciplinary Oncology Center, University Hospital,Lausanne, Switzerland; 2Department of Radiation-Oncology,University Hospital, Maastricht, The Netherlands(E-mail: Roger.Stupp@chuv.hospvd.ch or b.baumert@rtil.nl )References1. Cairncross JG, Ueki K, Zlatescu MC et al. Specific genetic predictors ofchemotherapeutic response and survival in patients with anaplasticoligodendrogliomas. J Natl Cancer Inst 1998; 90: 1473–1479.2. Stupp R, Gander M, Leyvraz S, Newlands E. Current and future develop-ments in the use of temozolomide in the treatment of brain tumors. LancetOncol 2001; 2: 552–560.3. Brada M, Viviers L, Abson C et al. Phase II study of primary temozolomidechemotherapy in patients with WHO grade II gliomas. Ann Oncol 2003;14: 1715–1721.4. Pace A, Vidiri A, Galiè E et al. Temozolomide chemotherapy for progressivelow-grade glioma: clinical benefits and radiological response. Ann Oncol2003; 14: 1722–1726.5. Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of extent ofresection on recurrence in patients with low grade cerebral hemispheregliomas. Cancer 1994; 74: 1784–1791.6. Keles GE, Lamborn KR, Berger MS. Low-grade hemispheric gliomas inadults: a critical review of extent of resection as a factor influencingoutcome. J Neurosurg 2001; 95: 735–745.7. Pignatti F, van den Bent M, Curran D et al. Prognostic factors for survivalin adult patients with cerebral low-grade glioma. J Clin Oncol 2002; 20:2076–2084.8. Karim AB, Maat B, Hatlevoll R et al. A randomized trial on dose–response in radiation therapy of low-grade cerebral glioma: EuropeanOrganization for Research and Treatment of Cancer (EORTC) Study22844. Int J Radiat Oncol Biol Phys 1996; 36: 549–556.9. Shaw E, Arusell R, Scheithauer B et al. Prospective randomized trial oflow- versus high-dose radiation therapy in adults with supratentoriallow-grade glioma: initial report of a North Central Cancer TreatmentGroup/Radiation Therapy Oncology Group/Eastern Cooperative OncologyGroup study. J Clin Oncol 2002; 20: 2267–2276.10. Klein M, Heimans JJ, Aaronson NK et al. Effect of radiotherapy and othertreatment-related factors on mid-term to long-term cognitive sequelae inlow-grade gliomas: a comparative study. Lancet 2002; 360: 1361–1368.11. Surma-aho O, Niemela M, Vilkki J et al. Adverse long-term effects ofbrain radiotherapy in adult low-grade glioma patients. Neurology 2001;56: 1285–1290.12. Nuutinen J, Sonninen P, Lehikoinen P et al. Radiotherapy treatment plan-ning and long-term follow-up with [11C]methionine PET in patients withlow-grade astrocytoma. Int J Radiat Oncol Biol Phys 2000; 48: 43–52.13. McKnight TR, von dem Bussche MH, Vigneron DB et al. Histopathologicalvalidation of a three-dimensional magnetic resonance spectroscopy indexas a predictor of tumor presence. J Neurosurg 2002; 97: 794–802.14. Pirzkall A, Nelson SJ, McKnight TR et al. Metabolic imaging of low-grade gliomas with three-dimensional magnetic resonance spectroscopy.Int J Radiat Oncol Biol Phys 2002; 53: 1254–1264.15. Karim AB, Afra D, Cornu P et al. Randomized trial on the efficacy of radio-therapy for cerebral low-grade glioma in the adult: European Organiza-tion for Research and Treatment of Cancer Study 22845 with the MedicalResearch Council study BRO4: an interim analysis. Int J Radiat OncolBiol Phys 2002; 52: 316–324.

Promises and controversies in the management of low-grade glioma

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