Clinical Investigation
Patterns and Timing of Recurrence After Temozolomide-Based Chemoradiation for Glioblastoma

https://doi.org/10.1016/j.ijrobp.2009.09.018Get rights and content

Purpose

To determine recurrence patterns of glioblastoma treated with temozolomide-based chemoradiation.

Methods

Pretreatment and serial posttreatment magnetic resonance imaging scans of 54 patients were retrospectively evaluated. Central recurrence (i.e., local progression) and the development of new (i.e., interval appearance of discrete enhancing lesion) in-field, marginal, and distant recurrences were assessed, with the pattern of recurrence of individual lesions defined relative to the 95% isodose line (D95). Distant recurrences were defined as lesions completely outside D95, marginal recurrences crossed D95, and in-field recurrences were completely inside D95.

Results

At a median follow-up of 17 months, 39 of 54 (72%) patients developed recurrent glioblastoma. Among these 39 patients, central recurrence occurred in 80% (at a median of 7 months from diagnosis); new in-field recurrence developed in 33% (at a median of 14 months); marginal recurrences developed in 15% (at a median of 18 months); and distant recurrences developed in 20% (at a median of 11 months). The actuarial rates of central, new in-field, marginal, distant, and any new recurrences at 1-year were 46%, 15%, 3%, 14%, and 25% respectively, whereas at 2 years, the rates were 68%, 60%, 32%, 28%, and 66%, reflecting an increasing probability of new lesions developing at later time points. Ten patients developed subependymal recurrences, of whom 7 developed multiple subependymal lesions.

Conclusions

Whereas central recurrence of glioblastoma treated with radiation and temozolomide predominates and persists over time, new in-field, marginal, and distant recurrences commonly develop, particularly at later time points in patients with longer survival.

Introduction

Glioblastoma is a high-grade primary brain malignancy with a dismal prognosis. The median survival is on the order of 6 to 18 months, with nearly all patients eventually succumbing to their disease. The standard treatment for newly diagnosed glioblastoma includes a multimodality approach with surgery, radiation therapy (1), and chemotherapy (2). A recent European and Canadian randomized study demonstrated a survival benefit with the addition of concurrent and adjuvant temozolomide (3).

Although autopsy (4) and stereotactic biopsy (5) studies demonstrate widespread microscopic infiltration within the brain, local recurrence predominates with this disease, most often within 2 cm of the original tumor volume after whole brain radiation 6, 7, 8 or more conformal radiation (9, 10, 11, 12, 13, 14, 15, 16, 17). Conformal radiation to the enhancing tumor and peritumoral edema has become standard. Generally, doses of ∼60 Gy are prescribed 1, 18. Dose escalation to 90 Gy 19, 20 or the addition of stereotactic radiosurgery (SRS) boost (21) may reduce failures within the high-dose volumes, although recurrence then tend to occur just outside the high-dose region. Several studies have analyzed recurrences after implant boost 22, 23, 24, 25, though the data on how implants affect patterns of recurrence is conflicting, with at least one study demonstrating a preponderance of out-of-field recurrences (24).

We retrospectively reviewed the patterns of recurrence of patients treated with radiation therapy concurrently with temozolomide chemotherapy. Temozolomide acts a radiation sensitizer, potentially augmenting the local control of glioblastoma. It is not known whether patients are then more susceptible to developing recurrences outside of the radiation field as a result of this improved tumor control and longer survival. Conversely, temozolomide, by virtue of its systemic activity, may help to prevent the development of new lesions remote from the primary tumor. We hypothesized that the longer survival and better tumor control of glioblastoma in patients treated with temozolomide-based chemoradiation may affect the patterns of recurrence, and sought to better characterize the patterns of recurrence in these patients.

Section snippets

Methods and Materials

Since 2005, patients treated for glioblastoma at the University of Rochester have been routinely treated, as standard therapy, with temozolomide concurrent with radiation. The medical records of patients with glioblastoma diagnosed between March 2005 and March 2008 were reviewed. The study was approved by the University of Rochester Research Subjects Review Board.

Patients underwent biopsy or resection before receiving radiation, with all patients having pathologic confirmation of glioblastoma.

Results

A total of 116 patients with glioblastoma were seen at the University of Rochester from March 2005 to March 2008. Of these, 54 were eligible for this study. Reasons for exclusion of the other 62 were as follows (with 11 having >1 reason): 26 received twice-daily radiation therapy per a University of Rochester protocol, 2 declined any adjuvant therapy, 8 received palliative radiation fractionation, 14 were not offered concurrent temozolomide, 13 had multifocal disease, 11 died before completing

Discussion

The present study is one of the first 17, 31, 32 to examine recurrence patterns after temozolomide-based chemotherapy. We hypothesized that temozolomide, by virtue of its radiation sensitization, may augment the effective radiation dose and therefore may affect patterns of recurrence. The systemic activity of temozolomide may also affect recurrence patterns. However, in a recent European Organization for Research and Treatment of Cancer study in which first recurrences were mapped using

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