Stereotactic radiosurgery (SRS)

The treatment of recurrent glioblastoma multiforme (GBM) is still one of the most challenging issues in neurooncology. In the past, most methods to control tumor growth have been ineffective, and almost all gliomas recur at some point. The inability to achieve local tumor control is associated with progressive neurological deficits, causing eventual death in most patients with recurrent GBM. Initial therapy commonly includes surgery and a full course of radiotherapy and/or chemotherapy, limiting treatment options at the time of recurrence.

Surgery is possible in a subgroup of patients; however, it is limited by the risk of substantial morbidity due to the infiltrative nature of the disease.1, 2 Therefore, the role of surgery in patients with recurrent GBM is controversial. Systemic chemotherapy can be applied using regimens such as carmustine, temozolomide, or PCV (prednisone, carmustine, vincristine), but commonly offers only minimal long-term benefit.3-5 Reirradiation can be applied for the treatment of recurrent tumors, but is limited by the high doses of radiotherapy applied after primary diagnosis and the tumor volume at the time of recurrence.

Localized irradiation in the form of brachytherapy has been reported as an effective treatment in patients with recurrent glioma.6 However, due to the highly invasive procedures this technique is often associated with high morbidity, and therefore limited to a small subgroup of patients.

Stereotactic external beam radiotherapy is a noninvasive means of delivering localized irradiation. It can be applied in single fractions as stereotactic radiosurgery (SRS) or as fractionated stereotactic radiotherapy (FSRT). FSRT has been shown to be effective and well tolerated in patients with recurrent low-grade as well as high-grade gliomas.7, 8 However, treatment time amounts to about 4 weeks, whereas SRS can be applied in a single fraction, limiting treatment and hospitalization times.

Recently, SRS has been applied effectively in the treatment of malignant primary brain tumors as well as in brain metastases, acoustic neuromas, and selected patients with meningioma.9-12 In SRS, a relatively high dose of radiation is applied in a single fraction, prescribed precisely to a defined target volume while sparing adjacent healthy brain tissue and risk organs.9, 13-15 This can be achieved by a steep dose fall-off outside the targeted volume.16, 17 Commonly, it is limited to smaller lesions to prevent radiation-induced injury. The role of SRS in the treatment of malignant glioma has been studied extensively over the years. Early trials have shown encouraging results.18, 19

Prior results from our institution show that SRS is safe and effective in first-line radiotherapy as well as in the management of recurrent malignant gliomas.14, 15 The present series updates our experience in the treatment of patients with recurrent malignant glioma at a single institution with SRS as salvage therapy at the time of recurrence.

MATERIALS AND METHODS

From January 1993 to August 2001, 32 patients were treated with SRS for 36 lesions of recurrent GBM. Nineteen patients were male and 13 were female. The median age at primary diagnosis of the tumor was 56 years (range, 33–76 yrs). At the time of initial diagnosis, a total neurosurgical resection was performed in 7, a subtotal resection in 21, and a biopsy in 4 patients. Histology evaluations revealed WHO glioblastoma multiforme (WHO Grade IV) in all 32 patients. In all patients radiotherapy was performed as the first-line therapy with a median target dose of 54 Gy (range, 40–64 Gy) in a median weekly fractionation of 5 × 2 Gy. Radiosurgery was delivered for recurrence of GBM. No concurrent chemotherapy was applied.

Thirteen patients received chemotherapy between the first and the second radiotherapy. Chemotherapy regimens included PCV, temozolomide, carmustine, carboplatin, thalidomide, and nimustine (ACNU). The median time interval from primary diagnosis to SRS for tumor progression was 10 months (range, 1–77 mo). At the time of recurrence, the median age was 56 years (range, 33–76 yrs) and the Karnofsky performance score was ≥ 80 in 28 patients. Twenty-seven patients presented with neurological symptoms, including headache, seizures, nausea, vomiting, and motor and sensory deficits. The patients' characteristics are shown in Table 1.

High-precision radiosurgery was performed using a linear accelerator (Linac, Siemens Mevatron, Siemens, Erlangen, Germany) with 6-MeV or 15-MeV photons. Patients were immobilized using an individual mask fixation system made individually for each patient using Scotch-Cast material. For treatment planning, contrast-enhanced computer tomography (CT) and magnetic resonance imaging (MRI) scans were performed with the mask attached to a stereotactic frame allowing a geometric accuracy of 1–2 mm.20, 21 Details of the geometric and anatomic verification can be found in Schad et al.22 The target volume was defined using a commercial three-dimensional treatment planning system (STP, Stryker-Leibinger, Freiburg, Germany) or VIRTUOS software (DKFZ, Heidelberg, Germany). After image fusion of CT and MRI data, the target was defined as the contrast-enhancing lesion in T₁-weighted MR images, adding a 2–5 mm safety margin. Plan calculation was performed on the CT data cube as described previously.23 The median planning tumor volume (PTV) was 10 ml (range, 1.2–59.2 ml).

The median dose applied was 15 Gy (range, 10–20 Gy) prescribed to the 80% isodose line that encompassed the target volume. The dose prescription was based on size and localization of the lesion (Fig. 1). All patients received 20 mg dexamethasone 1 hour before and 6 hours after radiosurgery, together with H2-antihistamines for stomach ulcer prophylaxis. No concomitant chemotherapy was administered.

After SRS, patients were seen for a follow-up visit after 6 weeks and thereafter in 3 month intervals. Each follow-up appointment included a thorough clinical examination, including a neurological assessment and a contrast-enhanced MRI. Additional examinations including PET and MR-spectroscopy were scheduled as needed to help distinguish radiation necrosis from tumor progression. The median follow-up time was 10 months (range, 1–25 mos).

Endpoints of the analysis were overall and progression-free survival. Overall survival was calculated from the time of primary diagnosis and survival after SRS was calculated from the time of SRS. Progression-free survival was calculated from the time of SRS until tumor progression or death, whichever occurred first, using the Kaplan–Meier method.24, 25

RESULTS

Treatment was well tolerated by all patients. No acute toxicities > CTC Grade II occurred. Alopecia was restricted to small areas and was fully reversible in most patients. No severe long-term toxicities including radionecrosis was observed. The median follow-up time was 10 months (range, 1–25 mos). All patients died of tumor progression during follow-up.

The median overall survival calculated from primary diagnosis of the tumor was 22 months. The survival rate at 1 year was 88%, and was 41% and 19% at 2 and 3 years, respectively. Figure 2 illustrates the overall survival curve from primary diagnosis. No prognostic factors for overall survival could be calculated, including Karnofsky performance score ≥ 80 versus Karnofsky < 80 (P = 0.13), extent of surgical resection (P = 0.51), age (≤ 50 vs. > 50; P = 0.39), or RPA classification (P = 0.8). The median time between primary diagnosis and reirradiation for tumor recurrence was 10 months (range, 1–77 mos).

After SRS, median overall survival was 10 months (Fig. 3). At 6 and 12 months after SRS, survival rates were 72% and 38%, respectively. Median progression-free survival after SRS was 5 months. Progression-free survival at 6 months after SRS was 33%.

Figure 2 depicts the survival curve after reirradiation. No prognosticators for overall survival and progression-free survival after SRS, including size of the PTV (< 10 mL vs. ≥ 10 mL; P = 0.71), Karnofsky performance score (≥ 80 vs. < 80; P = 0.26), time between initial diagnosis and recurrence (< 10 mos vs. =10 mos; P = 0.2), age (≤ 50 vs. > 50; P = 0.82), as well as RPA classification (P = 0.62) could be identified.

DISCUSSION

Malignant gliomas still represent one of the most aggressive and devastating tumors in neurooncology. In spite of extensive research, the treatment outcome is still not satisfying.

At primary diagnosis, treatment commonly consists of neurosurgical resection, as radical as possible without resulting in marked morbidity, followed by postoperative radiotherapy. With this combination overall survival rates of 9–12 months could be obtained.26, 27 Recently, novel chemotherapy regimens have been added to this treatment combination. Radiochemotherapy with temozolomide has achieved a significant increase in overall survival times up to 14.6 and 19 months.28, 29 Concomitant administration of ACNU/VM26 to radiotherapy could extend overall survival to 16.5 months.30 However, almost all GBM recur, with local failure being the most common pattern of recurrence.31 Therefore, local control is the most critical issue to help improve overall survival for patients with GBM.

In most patients, treatment options at the time of recurrence are limited. Chemotherapy is the most frequently applied treatment for recurrent gliomas, leading to median survival times of about 5 months.4, 5, 32, 33 Recently, newer agents such as temozolomide have been developed and implemented successfully with good results. After treatment with temozolomide, 6 months progression-free survival rates of 46–60% can be found in the literature.34, 35

Surgical resections may be possible in some patients.1, 2 However, total resection of the tumor is limited by substantial postsurgical morbidity due to the infiltrative growth pattern of gliomas.

Radiotherapy as a treatment for recurrent gliomas is controversial. Commonly, high doses of irradiation have been applied postoperatively after primary diagnosis, and reirradiation is associated with a higher risk of radiation necrosis, with toxicity outweighing its benefits.36 However, a number of studies have shown that stereotactically guided fractionated reirradiation can be applied safely with good treatment results in this patient population.7, 8 With FSRT, effective radiotherapy doses can be applied to a defined target volume while exploiting the radiobiological effects of fractionation. This is likely to reduce the risk of long-term radiation-induced toxicity, especially with regard to large target areas for reirradiation or organs at risk in close vicinity, such as the brain stem or optic chiasm. Survival times after reirradiation of 23 and 8 months, respectively, could be achieved by stereotactically guided reirradiation of recurrent low-grade gliomas and glioblastomas.7, 8

Interstitial brachytherapy has been applied effectively in recurrent gliomas.6, 37, 38 For patients with malignant astrocytoma and glioblastoma multiforme treated with high-activity iodine-125 interstitial implants, median survival times of 81 and 54 weeks, respectively, were reported.6 Other groups reported survival times after brachytherapy that were comparable to SRS. The main advantage of SRS over brachytherapy is the noninvasive approach, enabling the local application of radiation without surgical intervention. Patients will likely benefit from the noninvasive application.

A large study published by Shrieve et al.38 demonstrated that the overall survival time of 86 patients treated with SRS for recurrent glioma was 10.2 months, which is comparable to the 11.5 months in 32 patients with recurrent glioma treated with brachytherapy. Overall survival at 2 and 3 years was 45% and 19%, respectively. In accordance with data from our present study, the mean PTV for SRS was 10 ml, supporting our concern that SRS for large tumor volumes bears an increased risk of radiation-induced side effects. A large study conducted by the Radiation Therapy Oncology Group (RTOG) evaluated single-dose radiosurgery in recurrent previously irradiated brain tumors.39 In that study, escalating doses up to 24 Gy were evaluated as being overall tolerable with regard to radiation-induced side effects. However, unacceptable toxicity was more likely to appear in larger tumor volumes. The median overall survival obtained in that study was 11.4 months for patients with recurrent gliomas. Patients with lower RPA classes showed increased overall survival times compared to patients with higher RPA classes. However, in our present analysis the RPA classification did not significantly influence overall survival as well as survival after SRS.

In many other studies, SRS has been shown to be an excellent treatment option for smaller lesions of recurrent gliomas. Preliminary data from our institution had demonstrated that SRS is highly effective in the management of recurrent gliomas.14 However, a rigid mask fixation system manufactured individually for each patient is required to allow for precise positioning. This fixation system is strenuous for the patients and requires an overall tolerable performance status. Therefore, the present patient collective might be highly selected, with confounding factors influencing outcome.

In a large study comparing SRS and FSRT for recurrent glioma, overall survival times of 11 months after SRS and 12 months after FSRT were obtained.40 In the present study, we analyzed 32 patients with recurrent glioma treated with SRS. The median overall survival since primary diagnosis was 22 months, with an actuarial overall survival rate of 88% at 1 year, and 41% and 19% for 2 and 3 years, respectively. Calculated from SRS, the median survival was 10 months. These results are well within the times reported in the literature.6, 38, 41

CONCLUSION

The present data suggest that SRS is a safe and effective treatment modality in a subgroup of patients with smaller recurrent malignant gliomas. The observed acute and long-term toxicities including radionecroses are low. As SRS is applied in a single fraction, it is limited to smaller lesions to minimize the risk of radiation-induced toxicity. However, due to the application in a single fraction, hospitalization times can be kept short and systemic therapy might be applied earlier in the time course.

Although SRS cannot be considered a curative treatment approach for patients with glioblastoma multiforme, satisfactory treatment results can be obtained and progression of neurological symptoms can be postponed. Further evaluation, especially the concomitant application of chemotherapeutic substances, might further improve progression-free and overall survival times. However, for every patient a very individual decision based on clinical performance, tumor characteristics, and previous treatments has to be made as to which radiotherapeutic treatment alternative for reirradiation might offer the best benefit while minimizing the risk of toxicities.