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Journal of Clinical Oncology, Vol 24, No 8 (March 10), 2006: pp. 1225-1227 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.6069
CNS Malignancies: At Last, Real ProgressUniversity of Michigan Medical Center, Ann Arbor, MI
The Mayo Clinic, Rochester, MN
The University of Texas M.D. Anderson Cancer Center, Houston, TX This Journal of Clinical Oncology Special Series issue focuses on issues surrounding the treatment of malignancies occurring within the CNS. We felt this was a timely subject because of recent key advances in translational biology and of multimodality therapy, which have tended to be of major interest to JCO readers. Many of the advances in therapy described herein have depended on a revolution in the technology of brain imaging, so it seemed reasonable to begin this issue with a review of brain imaging (Cao et al1). Magnetic resonance imaging (MRI) is now the gold standard for defining brain tumor anatomy. In addition to tumor location, MR spectroscopy can reveal the chemical composition of a tumor that correlates with grade and, after radiation, can also distinguish active tumor from necrosis. MR diffusion imaging shows promise in predicting response to radiation therapy during the course of treatment before anatomic changes can be detected. MRI permits the measurement of cerebral blood flow and volume and can give a quantitative assessment of the blood-tumor and blood-brain barriers. Although not discussed in this issue, positron emission tomography (PET) scanning also has an important potential role in brain imaging, particularly methionine PET which has a better signal:noise ratio than fluorodeoxyglucose (FDG) -PET (for a recent review, see Newberg and Alavi2). The majority of this issue to devoted to primary CNS malignancies. Lang and Gilbert3 critically analyze the dilemmas that continue to face us in the treatment of low-grade gliomas. Because of these tumors' infiltrative nature and their long natural history, the traditional surgical approach has been to perform a biopsy or, at most, a modest partial resection. However, the development of improved surgical techniques now permits more aggressive resections; whether this benefits patients remains to be determined. Radiation therapy has conclusively been demonstrated to prolong disease-free survival, but not overall survival. However, because there are few data comparing the quality of life of patients who are treated early compared with that of patients who are initially observed, both early treatment and careful observation are still considered standard. Chemotherapy (traditionally procarbazine, lomustine, and vincristine [PCV], and, more recently, temozolomide [TMZ]) has now been shown to produce responses in both newly diagnosed and relapsed low-grade gliomas, and the potential to integrate chemotherapy into initial treatment is an area of great interest. Jaeckle et al4 describe recent findings surrounding anaplastic oligodendroglioma. Our understanding of anaplastic oligodendroglioma has increased substantially with the recent completion of two randomized trials by the Radiation Therapy Oncology Group (RTOG 9402)5 and the European Organisation for Research and Treatment of Cancer (EORTC 26951),6 which randomly assigned patients with anaplastic oligodendroglioma to radiation alone or radiation followed or preceded by PCV chemotherapy, with the primary end point of overall survival. Both studies yielded negative results, with a suggestion that chemotherapy modestly improves disease-free survival at the cost of substantial toxicity. However, the striking conclusion from both studies is that patients who have 1p and 19q deletions have a far better prognosis than those with the same histology who do not have evident deletions. Given the recent positive randomized trial of concurrent TMZ and radiation for glioblastoma (reviewed in Reardon et al,7 which is discussed in the next paragraph), it is logical that concurrent chemoradiotherapy will be attempted for anaplastic oligodendroglioma as well. Advances in the most malignant form of brain tumor, glioblastoma multiforme, are the focus of the article by Reardon et al.7 They review the recent randomized trial showing that the combination of TMZ and radiation significantly prolongs survival compared with the standard of radiation alone. Given the many trials using sequential radiation and chemotherapy that have yielded negative results, it is tempting to speculate that a key factor in the success of this study was the low-dose TMZ that was administered daily with radiation rather than the adjuvant TMZ, but the relative roles of concurrent versus sequential TMZ are not yet known. Additional analyses suggest that the patients who benefit the most from TMZ are those whose tumors contain methylated O6-alkylguanine-DNA alkyltransferase (AGT). AGT is responsible for repairing the DNA damage inflicted by TMZ, and methylation of the AGT promoter, which decreases AGT expression, appears to make tumors more sensitive to TMZ. The authors feel that additional validation is required before concluding that AGT testing should become a routine part of treatment decisions. They also review other promising new advances, particularly the potential role of molecularly targeted therapies. Many tumors demonstrate overexpression of EGFR, and some clinical results suggest that this is an exploitable target. Donaldson, Laningham, and Fisher8 complete our review of glial tumors by describing approaches to brainstem gliomas. Patients with nondiffuse brainstem gliomas can be treated surgically, or can receive focal radiation as sole or adjuvant therapy. In some cases, patients can be observed after a subtotal resection or shunt placement; this strategy has particular appeal in children, for whom the long-term toxicity of treatment tends to be significant. Diffuse brainstem gliomas present unique difficulties in treatment among the primary CNS tumors because they are unresectable, the damage they produce by local extension is unusually devastating, and they have proven to be extraordinarily resistant to therapy. As most patients with high grade glioma will, unfortunately, recur, this issue includes a review by Butowski, Sneed, and Chang9 on how to approach this difficult situation. It is important, but often challenging, to distinguish recurrence from radiation changes (which will resolve without intervention) or from radiation necrosis (which may require treatment with corticosteroids or resection). MR spectroscopy has assumed a key role in making this distinction, and appears to be superior to FDG-PET, which is hampered by the finding that macrophages associated with necrosis can have high uptake and fill in the "hole" that is supposed to associated with necrosis. Re-resection, re-irradiation, and new drug therapies are all under investigation. In addition to primary glial cancers, the CNS is a site for primary lymphomas (Batchelor and Loeffler10). Although this malignancy tends to be sensitive to radiation, radiation produces significant neurotoxicity in patients older than 60 years who have also received chemotherapy. Thus, new chemotherapy regimens are actively being explored, with radiation reserved for use at the time of relapse. Current research has been aimed at intensifying chemotherapy, including the use of high-dose chemotherapy followed by autologous stem-cell rescue, although it is not yet clear that these most recent intensifications have improved outcome over less intensive chemotherapy approaches. The formation of the International Primary CNS Lymphoma Collaborative Group should facilitate the search for improved therapies. Brain metastases are far more common than primary CNS tumors, and we have devoted two reviews to this area. The first, by Vogelbaum and Suh,11 discusses resectable brain metastases and describes recent improvements in surgical and radiation techniques. Level I evidence demonstrates that, for patients with one metastasis, the combination of resection or radiosurgery with whole-brain radiation can prolong survival compared with whole-brain radiotherapy alone. Substantial benefits can also be derived from surgery or radiosurgery for selected patients with two or three lesions. The second, by Khuntia et al,12 addresses the role of whole-brain radiation, both for patients with multiple lesions and in the adjuvant setting. In the case of multiple lesions, they describe promising efforts to develop new drugs to increase the effectiveness of radiation therapy. With regard to adjuvant treatment, they provide a thoughtful discussion of the risks of neurotoxicity versus the benefits of a significant decrease in relapse. Both articles note that the benefits of treatment will depend heavily on the status of systemic disease. The toxicity of treatment of intracranial malignancies has been alluded to a number of times in the articles mentioned in the preceding paragraphs, and is the focus of the review by Meyers and Brown.13 They describe the inadequacies of the standard mini–mental-status exam, and the need for both a detailed initial assessment and longitudinal data to understand fully the neurocognitive effects of treatment, because toxicity can take years to develop. This article and the one by Khuntia et al12 provide an up-to-date review of both the methodology for measurement and the effects of treatment. Finally, this issue contains a comprehensive review of the risk and management of venous thromboembolism in patients with intracranial neoplasms (Gerber, Grossman, and Streiff14). Of all patients with cancer, those with brain tumors are among the most at risk for venous thromboembolism. In addition, the decision whether to administer anticoagulants to these patients is often made difficult because of recent surgery and increased risk of bleeding. This review synthesizes recent data and makes practical recommendations for management. In summary, although the treatment of intracranial malignancies continues to present challenges, there have been important advances both in our understanding of the biology of these illnesses and in treatment. We hope this issue represents a useful summary of the state of the art, and will stimulate additional research to improve the outcomes for this group of diseases. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
REFERENCES
1. Cao Y, Sundgren PC, Tsien CI, et al: Physiologic and metabolic magnetic resonance imaging in gliomas. J Clin Oncol 24:1228-1235, 2006 2. Newberg AB, Alavi A: The role of PET imaging in the management of patients with central nervous system disorders. Radiol Clin North Am 43:49-65, 2005[CrossRef][Medline] 3. Lang FF, Gilbert MR: Diffusely infiltrative low-grade gliomas in adults. J Clin Oncol 24:1236-1245, 2006 4. Jaeckle KA, Ballman KV, Rao RD, et al: Current strategies in treatment of oligodendroglioma: Evolution of molecular signatures of response. J Clin Oncol 24:1246-1252, 2006 5. Cairncross G, Berkey B, Shaw E, et al: An intergroup trial by the Radiation Therapy Oncology Group, North Central Cancer Treatment Group, Southwest Oncology Group, National Cancer Institute Clinical Trials Group, and Eastern Cooperative Oncology Group. J Clin Oncol (in press) 6. van den Bent MJ, Carpentier AF, Brandes AA, et al: Adjuvant PCV improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: A randomized European Organisation for Research and Treatment of Cancer trial. J Clin Oncol (in press) 7. Reardon DA, Rich JN, Friedman HS, et al: Recent advances in the treatment of malignant astrocytoma. J Clin Oncol 24:1253-1265, 2006 8. Donaldson SS, Laningham F, Fisher PG: Advances toward an understanding of brainstem gliomas. J Clin Oncol 24:1266-1272, 2006 9. Butowski NA, Sneed PK, Chang SM: Diagnosis and treatment of recurrent high-grade astrocytoma. J Clin Oncol 24:1273-1280, 2006 10. Batchelor T, Loeffler JS: Primary CNS lymphoma. J Clin Oncol 24:1281-1288, 2006 11. Vogelbaum MA, Suh JH: Resectable brain metastases. J Clin Oncol 24:1289-1294, 2006 12. Khuntia D, Brown P, Jing L, et al: Whole-brain radiation in the management of brain metastasis. J Clin Oncol 24:1295-1304, 2006 13. Meyers CA, Brown PD: Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol 24:1305-1309, 2006 14. Gerber DE, Grossman SA, Streiff MB: Management of venous thromboembolism in patients with primary and metastatic brain tumors. J Clin Oncol 24:1310-1318, 2006
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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