Older patients with central nervous system (CNS) disease present a unique set of problems for the health care provider. Often their presentation can be atypical, potentially confounding or delaying the correct diagnosis. For example, older patients often present with cognitive dysfunction suggesting dementia, or personality changes suggesting depression rather than more typical symptoms such as headache. This population also has various comorbidities, which often complicate the potential for neurosurgery. Additionally, this group of patients may have a tendency to tolerate radiation, chemotherapy, or supportive agents (such as steroids or antiepileptics) poorly. Also, CNS tumors in general carry with them a significant risk of morbidity and mortality, independent of the patient’s age, which may only further complicate the decision making process in the older adult patient. In this chapter, various intracranial neoplastic disease processes and their management in the older adult are considered.

Low-Grade Gliomas

Low-grade gliomas (i.e., astrocytomas and oligodendrogliomas) are relatively uncommon in patients older than 65 years. Therapy usually involves maximally feasible resection. Radiation therapy (RT) may be reserved for symptomatic patients, or patients with recurrent disease. In a randomized European trial, RT did not improve overall survival, but did improve progression free survival. Another indication for RT relates to a patient for whom minimal disease progression might result in significant neurological deterioration. It should be noted that low-grade oligodendrogliomas with chromosomal deletions in the 1p and 19q loci are very sensitive to both radiation and chemotherapy. This enhanced sensitivity to therapy is also true for anaplastic oligodendroglioma (discussed below).

Anaplastic Gliomas

Grade 3 astrocytomas, as well as anaplastic oligodendroglioma, are also less common in older patients with a peak incidence in adults during the third decade of life. The mainstay of therapy is surgery and RT. The definitive role for chemotherapy is yet to be defined in these diseases. By extrapolation from the success of temozolomide chemotherapy (TMZ) in the treatment of newly diagnosed grade 4 astrocytoma (i.e., glioblastoma multiforme [GBM, discussed below]), some oncologists feel there is a role for TMZ chemotherapy in treating these patients at the time of diagnosis. There are, however, no level one data to support this therapeutic approach currently.

Glioblastoma Multiforme

Background

Geriatric patients have an increasing incidence of GBM. This diagnosis in a geriatric patient population is typically associated with shorter survivals (than comparable patients who are younger) and may not be treated as aggressively (Table 99-2). Reasons for this may include the “biology” of primary GBM in these patients, comorbidities, and the inability to tolerate toxic therapies. Elderly patients with GBM appear to be less responsive to chemotherapy, and age appears to have a negative correlation with the tumor’s response to treatment and time to disease progression, but a positive correlation with toxicity for patients older than 60 years (Table 99-1). Several studies have demonstrated that overall survival declines with increasing age and decreasing performance status, as measured by Karnofsky performance status (KPS).

Many studies have been performed in elderly patients in an attempt to determine the optimal management; the majority of these studies have used a “less is better” approach to treatment. This literature is summarized under two main points: what constitutes “elderly” is not well defined, and may be as low as 60 years of age, and studies have used different parameters for “good” versus “poor” performance status, (e.g., KPS). Both of these factors impact outcome. Another confounder to interpreting outcome data in GBM is extent of surgery. Gross total resection surgery appears to have a modest benefit on survival, particularly in patients with good performance status. This is a surgery that removes all tumor visible to the naked eye. Relative to this, many older patients simply undergo a biopsy or partial resection, resulting in an incomplete surgical removal of tumor.

Radiation Therapy

Most radiation studies in the geriatric patient population have focused on abbreviated courses of RT. Survivals obtained are similar or slightly less than the standard 6-week course, but require less time for treatment. The benefits of RT decrease with increasing age and are affected to some degree by extent of surgical resection. Villa et al. (1998) treated patients (median age 70) with 54 to 66 gray (Gy) of external beam radiation with a median survival of 18.1 weeks for all patients and 45 weeks for those who started RT. The median survival of patients younger than 70 years was 55 weeks, compared to 34 weeks for patients older than 70 years. Pierga et al. (1999) treated 30 patients (median age 73 and KPS 60–70) with 45 Gy for more than 5 weeks after maximal resection and found a median survival of 36 weeks. Philips et al. (2003) found that non-significant survival advantage for patients treated with 60 Gy (median survival of 41 weeks) versus 35 Gy (35 weeks). McAleese et al. (2003) compared patients treated with 30 Gy to a case matched control group of patients treated with 60 Gy and found an increase in survival of 2.5 to 4.5 months longer; the authors questioned whether the lesser survival was outweighed by an improved quality of life. Chang et al. (2003) treated 59 patients (median age 65) with 50 Gy in 4 weeks and found a median survival of 28 weeks, which was comparable to the Radiation Therapy Oncology Group (RTOG) database. Roa et al. (2004) randomized patients >60 (median was 72 years) to 60 Gy in 6 weeks or 40 Gy in 3 weeks. Median survival was similar at 20 weeks and 21 weeks with fewer patients in the lower dose group requiring an increase in steroids.

Chemotherapy

The first glimpse of a therapeutic breakthrough in the treatment of GBM occurred in 2002 when Stupp and coworkers reported results of the use of daily TMZ (75 mg orally per square meter body surface area) during radiation (approximately 6–7 weeks), followed by 6 months of adjuvant therapy at 150 to 200 po mg/m2 on days 1 through 5 of a 28-day cycle. The median survival in this phase II study was 16 months. The rationale for this approach included the possibility of radiosensitization. The concept of daily dosing was an attempt to overcome TMZ drug resistance. The background for this related to observations demonstrating that the repeated administration of TMZ depletes the DNA-repair enzyme 06-methylquanine-DNA methyltransferase (MGMT). MGMT is a resistance mechanism for TMZ. Thus, it is termed a “suicide enzyme.” After MGMT removes a methyl group from DNA (deposited by TMZ), it is no longer active. The use of adjuvant TMZ starting 1 month postradiotherapy was predicated on the inherent antitumor activity of the drug. As the study by Stupp et al. demonstrated a promising 2-year survival rate of 31%, the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) launched a phase III trial comparing this phase II regimen to radiotherapy alone. Recently, data presented from Stupp et al. in a randomized phase 3 study (2005) demonstrated that the combination of RT and TMZ followed by 6 months of TMZ was better than RT alone in terms of overall survival and disease control. This has become the new standard of care for GBM. Patients treated with chemotherapy and radiation had a progression free survival of 6.9 months compared to 5 months, a median survival of 14.6 months compared to 12.1 months, and a 2-year survival of 27% compared to 10%; all values were statistically significant. Importantly, in that study, patients older than 70 years were not eligible so the benefit in this group remains undefined. It is notable that the American Radiation Therapy Oncology Group (RTOG) in cooperation with the EORTC and the NCIC has launched a new phase 3 trial (RTOG 0525): one arm is the aforementioned Stupp regimen; the other is a dose dense TMZ treatment (75 mg/m2 for 21 days on a 28-day schedule) postradiation (in an attempt to overcome resistance). This study will have no age limitation, and therefore should provide important new data.

Despite the data available, the best approach for the elderly patient is not known with a variable approach depending on the biases of individual practitioners. For patients with a good performance status and no significant comorbidities, maximal resection followed by RT (60 Gy) + TMZ followed by TMZ for 6 months should probably be the approach to use. It has become a convention in the United States to treat patients with TMZ for 1 year post-RT, but there is no level one data to support this practice.

A geriatric patient population with newly diagnosed GBM is the ideal one for further study. One possible aim is the evaluation of the potential benefits of adjuvant TMZ. In a nongeriatric patient population, the benefit of concurrent and adjuvant chemotherapy as an overall treatment has been demonstrated, but the benefits of adjuvant chemotherapy (i.e., TMZ post-RT) as a portion of that approach has not been assessed. In a phase II (n = 55) study done in Germany with a somewhat older patient population, TMZ was given with RT at a dose of only 50 mg/m2 rather than the 75 mg/m2 as in the Stupp study; no TMZ was given post-RT. The overall survival in this study approximated the Stupp trial. As many patients fail to complete the adjuvant treatment, it is possible that the concurrent therapy (TMZ/RT) is most important. In older patients, the decision to offer a trial comparing these options is justified by the greater uncertainty about the benefits of the overall treatment program with TMZ, as well as, the greater risk of toxicity of these regimens in older patients, and the poorer overall survival. The issue of survival is relevant as adjuvant therapy may occupy a period of time greater than the predicted median survival for the population.

A few studies have looked at the role of TMZ chemotherapy in the elderly post-RT only, or as sole treatment without RT. A small series of 23 GBM patients (mean age 68, all with good performance status) treated with surgery, TMZ and RT, with a median survival time of 15.38 months. Notable in this series was the development of leukoencephalopathy in 2 patients older than 70 years old. TMZ alone has been retrospectively compared to survival for RT alone, with no statistical difference between the two groups. Consistently, performance status was a predicator of survival. In prospective studies of TMG alone, neurologic improvement has been reported in 50% of patients with an overall survival of 6.4 months, and a median progression free survival of 5 months.

In spite of the advances described above, the overall prognosis for patients with GBM (in general, and particularly for the elderly) remains poor. Interestingly, the marked genetic heterogeneity of GBM may provide another opportunity for directed therapy. Recent elucidation of signaling pathways and evaluation of targeted agents has been an exciting approach in the treatment of cancer patients in general. For GBM, there are several promising targets. For example, GBM tends to overexpress epidermal growth factor receptor (EGFR). Additionally, research suggests that the status of the PTEN gene involved in the activity of the Akt signal transduction pathway (which is involved in resistance to apoptosis and acceleration of cell proliferation) may have implications for prognosis as well as response to EGFR tyrosine-kinase inhibitors for GBM. In a retrospective study, Mellinghoff et al. found that activated EGFR, (i.e., EGFR vIII) in combination with wild-type PTEN was associated with a very high response rate to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib. Similarly, another group reported that EGFR amplification and low levels of protein kinase B/Akt phosphorylation was associated with response.