A multidisciplinary approach to gliomas
Experts explore role of temozolomide in postsurgery chemotherapy
Until recently, brain tumors have been viewed with pessimism. In the past, there was almost nothing that could be done with brain tumors. But there are now changes in the management of patients with brain tumor, according to Dr. Mayvelyn Gose, professor at the University of the Philippines College of Medicine.
Gose was one of the speakers in a forum on Changing Paradigms: An Update on the Multidisciplinary Management of Malignant Gliomas organized by Schering Plough Philippines in July.
Gose said the good news is that brain-tumor trends have been fairly stable, the increase mainly accounted for by population growth. Asians also tend to have lower rates.
Survival trends, however, are relatively poor although some gains have been achieved in the past few decades. In Finland, for instance, the five-year survival rate for all gliomas has risen from 21 percent in the 1950s to 36 percent in the 1980s.
Some host factors could increase the risk for certain glial tumors. For instance, menopausal women are at increased risk for gliomas and acoustic neuromas, since female hormones are linked to their development. Meanwhile, being born to an older mother with a history of fetal death could raise the risk of a child's having astrocytoma. A strong association between congenital malformations and the risk of central-nervous-system tumors has also been found.
There are also environmental factors, like exposure to diagnostic and therapeutic radiation and certain infections (Eppstein-Barr virus has been associated with cerebral lymphoma). Viruses may also play a role in CNS carcinogenesis by gene rearrangement and amplification of normal oncogenes. Occupation (jobs that expose one to radiation or certain chemicals), diet (consumption of N-nitroso compounds), tobacco (firsthand or secondhand), and intake of certain drugs have been associated with certain CNS tumors.
Histologic diagnosis and grade, age, duration of symptoms, its score on the Karnofsky Presentation Scale (KPS), location, and completeness of resection determine prognosis. Histologically, necrosis is associated with aggressiveness and a shorter postoperative survival. "The length of survival is inversely proportional to the number of features, i.e. mitosis, nuclear atypia, necrosis, and endothelial-cell proliferation," said Gose.
Glial tumors occurring in patients younger than 10 years and older than 45 are generally more aggressive, with a shorter postoperative survival rate. After 10 and before 65, longer survival is associated with younger age at presentation. A recent or acute onset with fast progression of neurologic symptoms is also associated with shorter survival rates. Site of growth may also affect prognosis, since cerebellar astrocytomas in children are generally associated with prolonged survival. The presence of gene alterations has been linked to progression from anaplastic to the higher-grade glioblastoma multiforme (GBM).
Integral but not enough
In the management of brain tumors, neurosurgery is integral and necessary, "but we know that surgery is not enough," said Dr. Manuel Mariano, a fellow of the Academy of Filipino Neurosurgeons. "It may be the answer to a lot of benign tumors, but not for malignant gliomas."
The average rate of survival of patients with malignant gliomas who only underwent surgery is 20 weeks, but this increases to 36 weeks when followed with postsurgical radiotherapy. And when surgery, radio-, and chemotherapy are combined, survival could go as high as 40 to 50 weeks.
Studies demonstrate that complete surgical resection results in longer survival, reduces the tumor burden, and allows for adjuvant chemotherapy. Total tumor removal, or at least removing the bulk of the tumor, removes heterogeneously resistant cells. There is improved oxygenation and a greater vulnerability to radiotherapy. When tumor-cell density is reduced, there is a lower potential for further mutation.
The introduction of image-guided surgery has led to better outcomes. Frameless stereotaxy uses intraoperative ultrasound fused with magnetic resonance imaging (MRI) and computed tomography (CT). Endoscopes can also be used to target deep-seated lesions. These modern advances provide minimal and optical access to craniotomies, avoid critical brain structures, and give optimal control to surgeons.
Postoperative radiotherapy and cognitive decline
The role of postoperative radiation in the management of malignant gliomas is straightforward, but its use in low-grade gliomas may spark controversy because of side effects, said Dr. Michael Mejia, a radiation oncologist from the Makati Medical Center.
Low-grade gliomas have been associated with a protracted median survival of five to 15 years. Thus, cognitive deficits as sequelae of treatment can have a sustained negative effect on quality of life.
Cranial radiotherapy can result in cognitive decline (De Angelis et al., 1989) because of demyelination. But these are often reversible. The more dreaded complications are the late encephalopathies (progressive cognitive decline, gait abnormalities, and urinary incontinence), which may appear as early as six months or as late as 10 years after radiotherapy and which may eventually progress to dementia.
It has been found that 30 percent of patients treated with cranial radiation for brain tumors showed signs of late encephalopathy (Crossen, 1994), which may even be understated, said Mejia.
In postoperative radiotherapy, there could be diverging rates (36 to 100 percent) in five-year survival since most of the available data are from retrospective studies instead of randomized, controlled trials. Still, the retrospective data showed that at some point radiotherapy confers a survival advantage in subtotally resected low-grade gliomas. In EORTC 22845, the progression-free-survival (PFS) curve increased for those receiving postoperative RT.
While the benefit of early radiotherapy may be questionable for those with good prognostic factors, delaying radiotherapy itself is not without its own risks. There is a need to treat more patients, since there is an increased risk of developing neurocognitive deficits later on in the disease.
Temozolomide (Temodal) in treating glioma patients
Dr. Gina Panuncialman, chief of the hematology and oncology section at the University of Santo Tomas Hospital, said several biologic issues may limit the effectiveness of chemotherapy for malignant brain tumors. While most chemotherapeutic agents act on dividing cells, not all brain tumors are actively dividing, such as the anaplastic and low-grade gliomas. Also, only small molecules can penetrate the blood-brain barrier (BBB), so the larger molecules of chemotherapeutic agents find some difficulty getting through. Protein binding, pH, and lipid solubility further contribute to the BBB's relative impenetrability. Also important factors are drug toxicity and neurotoxicity.
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But the novel agent temozo-lomide (Temodal) could make a difference. Its cytotoxic effects are via methylation of DNA at the sixth oxygen and seventh nitrogen atom of guanine, resulting in mismatch repair and ultimately in DNA breaks. It causes p53-indepedent apoptosis, but a resistance mechanism exists involving the nuclear enzyme alkyltransferase.
Pharmacokinetically, temozolomide has good oral bioavailability. It can penetrate the central nervous system and cerebrospinal fluid, reaching 30 to 40 percent plasma concentration, and whose clearance is largely unaffected by other drugs used in tumor patients. It has a dose-linear pharmacokinetics following oral administration, is unaffected by pH, widely distributed, with low intra- and intersubject variability.
Yung et al. (2000) found in a randomized trial that after six months, progression-free survival (PFS) improved from eight percent for procarbazine-treated patients to 21 percent for those given temozolomide. The median PFS improved-from eight months to 12 months-in temozolomide patients, although this was statistically insignificant.
While there were no complete responses (something that had been expected), the results were consistent with that of a stable disease plus partial response. There was still significant difference noted in the number of partial responders with stable disease in the temozolomide group than the procarbazine group.
Meanwhile, Osaba et al. (2000) showed that health-related quality of life (QOL) in patients treated with temozolomide was much better than in those treated with procarbazine. They experienced significantly greater time before neurologic failure with longer progression-free interval.
A phase-II trial showed encouraging results for combination radiotherapy and temozolomide against newly diagnosed GBM, with a two-year survival rate of 31 percent comparable with historical control, at a dose without added toxicity. Some side effects noted were lymphopenia, opportunistic infections, and thrombocytopenia.
A phase-III trial by Stupp et al. (2005) randomized patients with newly diagnosed and histologically confirmed glioblastoma into receiving radiotherapy alone or radiotherapy plus daily continuous temozolomide. Most of the patients underwent debulking surgery (83 to 84 percent), 16 to 17 percent had biopsy alone. However, only about 40 percent had complete resection.
By the first year, a wide divergence was seen in the end points. By the second year, the PFS rate in the radiation-plus-temozo-lomide group was 11 percent, but only two percent in the radiation-alone group. Said Panun-cialman: "Those who had concurrent temozolomide and radiation therapy had better [overall] survival at any point in the curve. The two-year survival of Temodal patients was at 26 percent compared to 10 percent from radiotherapy alone."
Thus, the Stupp trial established a new standard of care for first-line therapy of GBM patients. It demonstrated a statistically significant and clinically meaningful survival advantage for temozolomide use in GBM, with confirmation of safety and tolerability. However, predictive markers still need to be determined, to identify which patients will most benefit from the combination treatment. M
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