Historical Context of Radiation Therapy and Dose

Historically, standard treatment for glioblastoma (GBM) was surgical resection alone. The first randomized trial to show a survival benefit with adjuvant radiation therapy (RT) was the Brain Tumor Study Group trial published in 1978, which showed a median survival of 37.5 weeks for RT alone, 25 weeks for adjuvant carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)] chemotherapy alone, and 17 weeks for supportive care without adjuvant treatment; combination of RT plus (+) BCNU yielded a survival of 40.5 weeks. In this study, whole-brain radiation therapy (WBRT) was delivered with parallel opposed fields to a dose of 50 to 60 Gy. The same group also conducted a dose-response analysis from less than 45 to 60 Gy and found improvement in median survival for doses of 50 to 60 Gy. A combined Eastern Cooperative Oncology Group (ECOG)/Radiation Therapy Oncology Group (RTOG) study in 1983 compared standard 60 Gy WBRT with 3 other arms: 60 Gy WBRT + 10 Gy partial-brain RT boost, 60 Gy WBRT + BCNU, and 60 Gy WBRT + lomustine and dacarbazine. This study showed no survival benefit with the 10 Gy boost and 60 Gy became the standard treatment dose with external beam RT (EBRT) for GBM.

Interstitial brachytherapy is a form of internal radiation that involves intraoperative placement of small radioactive sources into a tumor or resection cavity. Brachytherapy allows the delivery of high doses of radiation with significant dose fall-off at a short (brachy) distance to minimize damage to surrounding tissues. Early attempts at dose escalation were investigated using interstitial brachytherapy with iodine 125 (I-125) in 2 prospective randomized trials. The first randomized trial from Princess Margaret Hospital compared EBRT to 50 Gy in 2 Gy fractions versus (vs) EBRT 50 Gy + I-125 brachytherapy implant delivering an additional 60 Gy to the tumor or resection cavity. This study showed no survival benefit with the brachytherapy implant, yielding a median survival of 13.2 months in the standard arm vs 13.8 months in the brachytherapy arm ( P = .49). The Brain Tumor Cooperative Group went on to conduct the largest prospective randomized study with brachytherapy for malignant gliomas with 270 patients enrolled. Patients were assigned to either EBRT (60.2 Gy in 35 fractions) + BCNU or EBRT + BCNU + I-125 implant (60 Gy). Median survival was 68.1 weeks with I-125 compared with 58.8 weeks without I-125 ( P = .101). The lack of a statistically significant survival benefit despite large boost doses of brachytherapy, along with the logistical complexity, time factor, and operator dependence of the procedure, tempered the impetus for further investigation with brachytherapy. Enthusiasm for brachytherapy has further waned with advances in EBRT for dose escalation, including stereotactic radiosurgery as described later in this chapter as well as heavy particle RT such as proton therapy and carbon ion therapy.

With the advent of three-dimensional (3D) conformal RT (3DCRT), the dose could be further escalated to the tumor volume with EBRT. A study from the University of Michigan examined dose escalation up to 80 Gy without dose-limiting toxicity. Despite higher doses, 89% of patients developed an in-field recurrence. RTOG 8302 was a prospective phase I/II trial comparing dose escalation with hyperfractionation or accelerated hyperfractionation with BCNU. Hyperfractionation dosing included 64.8 Gy, 72 Gy, 76.8 Gy, and 81.6 Gy delivered twice daily in 1.2 Gy fractions, whereas accelerated hyperfractionation included 48 Gy and 54.4 Gy in 1.6 Gy twice-daily treatments. A preliminary report from this trial showed best survival in the 72 Gy hyperfractionation arm. Subsequently, a phase III study (RTOG 9006) examined 72 Gy hyperfractionation vs 60 Gy conventional fractionation; however, there was no survival benefit to hyperfractionation. Therefore, 60 Gy in 2 Gy daily fractions remains the standard of care with EBRT.

Current Standard of Care

The current standard of care for management of GBM is maximal surgical resection followed by concurrent chemoradiation therapy (chemoRT) with daily temozolomide (TMZ) to a radiation dose of 60 Gy, followed by further adjuvant TMZ. This regimen is based on level I evidence from the landmark European Organisation for Research and Treatment of Cancer (EORTC)–National Cancer Institute of Canada (NCIC) study published in 2005 by Stupp and colleagues, which showed a survival benefit to chemoRT with TMZ vs adjuvant RT alone. Before this study, adjuvant RT + BCNU was considered standard of care, but no randomized phase III trial had shown a statistically significant survival benefit with RT + BCNU compared with adjuvant RT alone for GBM. RT in the EORTC-NCIC study was delivered with 3DCRT to a dose of 60 Gy in 2 Gy fractions 5 days per week with a 2-cm to 3-cm margin around the gross tumor volume. For the chemoRT arm, TMZ was administered 7 days per week at a dose of 75 mg/m ² from the first day until the last day of RT. After a 4-week break, adjuvant TMZ dosed at 150 to 200 mg/m ² for 5 days was administered every 28 days for 6 cycles. Because TMZ can lead to lymphocytopenia, patients were administered prophylaxis against Pneumocystis carinii pneumonia with either pentamidine or trimethoprim-sulfamethoxazole. Median survival was 14.6 months with RT + TMZ and 12.1 months with RT alone, which translates to a 37% relative reduction in risk of death ( P <.001). Survival at 2 years was 26.5% for RT + TMZ and 10.4% with RT alone. Tumor progression was defined as an increase in tumor size by 25%, the appearance of a new lesion, or an increased need for corticosteroids. Median progression-free survival (PFS) was 6.9 months for RT + TMZ vs 5 months for RT alone ( P <.001). Only 8% of patients discontinued adjuvant TMZ because of toxic effects, and grade 3 or 4 toxicity was seen in 7% of patients in the RT + TMZ arm.

An update of the EORTC-NCIC trial reported that the long-term survival advantage with TMZ persists at 5 years follow-up. Overall survival (OS) comparing RT + TMZ vs RT alone was 16% vs 4.4% at 3 years, 12.1% vs 3% at 4 years, and 9.8% vs 1.9% at 5 years, respectively (hazard ratio, 0.56; 95% confidence interval [CI], 0.47–0.66; P <.0001). Patients who had gross total resection survived longer than those with subtotal resection. The worst outcome was in patients with unresectable tumors who had undergone biopsy only. Promotor methylation of O6-methylguanine-DNA methyltransferase (MGMT) was the strongest prognostic factor and predictor for survival with TMZ, as discussed in further detail later in this chapter.

Immobilization

To minimize daily setup errors and intrafractional patient movement, creating a reproducible immobilization device is paramount to delivering an accurate RT plan. Patients should be simulated supine on a head cup or pad, with a thermoplastic mask that conforms to the patient’s face for immobilization ( Fig. 8.1 ). This position confers a daily setup error of 3 mm, which is the current standard for clinical target volume (CTV) to planning target volume (PTV) expansion when creating RT volumes. Newer technologies include an open-faced mask that uses an optical surface tracking system via camera pods to capture facial features for tracking to ensure correct patient setup. The benefit of this newer system is that it circumvents daily x-ray radiation exposure for patient alignment and potentially mitigates patient discomfort and claustrophobia compared with a standard thermoplastic mask. This technology also allows radiation oncologists to track intrafractional movement with the ability to halt RT via real-time feedback if the patient moves past a threshold (eg, 3 mm) during treatment. Once the patient is immobilized, a computed tomography (CT) simulation scan is performed using 1-mm to 3-mm slice thickness from vertex to below the skull base for treatment planning.

Aquaplast mask immobilization for fractionated radiation therapy. The thermoplastic mask material conforms to the patient’s face and skull, with pegs or screws that fasten to a board that is indexed on the table of the computed tomography (CT) simulator and treatment machine. The patient is immobilized daily in the same position to ensure treatment accuracy.

Target Volumes

A postoperative MRI scan including T1-weighted postcontrast (T1C+) MRI and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI should be fused with the CT simulation scan to generate target volumes for radiation treatment planning. A postoperative MRI within 72 hours after surgery allows for the best assessment of the extent of residual tumor before blood and postoperative edema cloud the clinical picture. MRI performed <2 weeks before RT is ideal because further edema may cause midline shift. There is also the potential for tumor regrowth from the time of surgery to RT. Although functional imaging modalities such as magnetic resonance spectroscopy (MRS) and dynamic contrast-enhanced MRI may potentially add information regarding target volume contouring and treatment planning, these modalities have not been validated and are still considered investigational. There are some differences in target volume delineation between the EORTC and the RTOG, as detailed in ( Table 8.1 ). The main difference is that the RTOG treats the FLAIR signal hyperintensity with a margin to account for peritumoral spread from edema followed by a cone-down boost to the T1C+ MRI enhancement, whereas the EORTC treats only the T1C+ MRI volume without a boost. Regardless, both the RTOG and EORTC advocate a 2-cm volumetric 3D expansion around the gross tumor volume (GTV) visualized on T1C+ MRI to create the CTV, with a reduction in margins to respect anatomic barriers, including the skull, ventricles, falx cerebri, tentorium cerebelli, optic chiasm/nerve, and brainstem. The CTV margins are based on historical studies showing that approximately 80% of recurrences are within a 2-cm margin of the enhancement seen on T1C+ MRI scans. An additional 3-mm to 5-mm margin is added to the CTV to account for daily setup error to create the PTV. An example of target volume contouring based on RTOG guidelines is shown in Fig. 8.2 . RTOG 0525 and CENTRIC clinical trials allowed for contouring based on either guideline and showed no difference in PFS or OS when comparing the 2 guidelines for target volumes. Retrospective studies comparing the EORTC and RTOG contouring guidelines also showed no difference in tumor recurrence. In the United States, most radiation oncologists follow the RTOG guidelines, although the EORTC margins may lead to reduced toxicity with no proven disadvantage in local control or survival.

Target volume delineation for a patient with GBM following subtotal resection. ( A ) Axial postoperative FLAIR MRI is fused with the CT simulation scan to contour the initial GTV ( red ), which is treated to 46 Gy (GTV 46). Areas of FLAIR changes are included in the GTV. ( B ) A 2-cm volumetric expansion around the GTV is used to create the CTV 46 ( blue ) to account for microscopic disease. Margins are reduced to respect anatomic barriers of tumor infiltration. In this example, the CTV does not extend to the left hemisphere, because the falx cerebri is a barrier to contralateral tumor spread. ( C ) The PTV is a 3-mm volumetric margin around the CTV to account for daily setup error. Note that the PTV 46 ( orange shaded ) extends to the contralateral hemisphere because it is not modified by barriers of tumor spread. ( D ) Postoperative T1 postcontrast MRI is fused with CT simulation scan to create the GTV boost volume ( red ), which is treated to 60 Gy (GTV 60). Area of enhancement is included in the GTV. This patient is the same as in A – C , but shown at a more inferior (caudal) extent of the tumor. ( E ) A 2-cm expansion around the GTV 60 is used to create the CTV 60 ( blue ), with reduced margins to respect anatomic boundaries. CTV margin is shaved off areas that extend into or are in close proximity to critical OARs. In this example, note how the CTV is shaved off the superior aspect of the right cerebellar hemisphere, because the tentorium cerebelli is a barrier to anatomic spread. As well, the CTV is shaved off the brainstem because the perimesencephalic cistern is an anatomic barrier to tumor spread. ( F ) PTV 60 ( orange shaded ) expansion for the 60 Gy boost volume shown on the CT simulation scan. The GTV 60 ( red ) and CTV 60 ( blue ) are also outlined. The brainstem is contoured ( light green ). Normally, the PTV should not be modified. However, in this situation, the PTV is shaved off the brainstem, which must be kept at less than 60 Gy point maximum dose. For institutions that incorporate a planning risk volume (PRV), there is an even greater separation between the brainstem and the juxtaposed PTV. Note that the PTV is not shaved off the right cerebellar hemisphere because it is not an OAR. In addition, note that the 3-mm CTV → PTV expansion does not appear uniform on this single CT axial slice; the reason for this is that the 3-mm expansion is a volumetric 3D expansion, as opposed to a 3-mm two-dimensional expansion on each axial slice. Hence, the CTV volumes on the superior and inferior axial CT slices contribute to the PTV volume seen on this axial CT slice.

Organs at Risk

Organs at risk (OARs) to be contoured along with tolerance doses and toxicity are summarized in Table 8.2 . Doses to OARs should be evaluated by a dose-volume histogram (DVH). Sometimes the dosimetric goals of the OARs may not be achievable because of the location and size of the PTV. In these scenarios, the radiation oncologist must make a clinical decision regarding the risks of reducing PTV coverage against the benefits of avoiding potential radiation damage to OARs. The most critical organs to avoid exceeding the tolerance dose are the brainstem, optic chiasm, and optic nerves, because of the potentially severe consequences of radiation-induced injury to these structures. Some radiation oncologists incorporate a planning risk volume (PRV) around the OARs, which is congruous to the CTV → PTV expansion, to also account for variability in daily setup for the OARs during fractionated RT.

Treatment Planning and Delivery

In the past, 3DCRT was used for partial-brain treatment planning for GBM. However, with modern treatment techniques such as intensity-modulated RT (IMRT) and volumetric intensity-modulated arc therapy (VMAT), which are now available at most radiation centers, a more conformal treatment plan can be created to deliver the prescribed treatment dose while minimizing dose to OARs. Ideally, the treatment planning goals should be the following: 95% of the PTV should receive 100% of the prescription dose (D95 = 100%) and 100% of the CTV and GTV should receive 100% of the prescription dose. Maximum plan dose (hot spots) should be ≤115% of the prescription dose. Daily image-guided RT with cone-beam CT should be aligned to the skull to maintain treatment accuracy. A treatment plan with isodose lines and DVH for a patient with GBM is shown in Fig. 8.3 .

Treatment plan and DVH. VMAT treatment plan with isodose lines and DVH for the patient shown in Fig. 8.2 . ( A ) PTV 46 ( orange shaded ) with isodose lines shown. Isodose lines: light blue, 46 Gy; red, 54 Gy; yellow, 60 Gy. ( B ) PTV 60 ( orange shaded ). Sometimes the PTV needs to be undercovered to protect a critical OAR, such as the brainstem in this case. ( C ) PTV 60 with isodose lines on multiple CT simulation scan views. Clockwise from upper left image: axial, 3D reconstruction, sagittal, and coronal views. ( D ) DVH. X-axis: dose in centigray (cGy). Y-axis: percent volume. The DVH is used to evaluate dose delivered to the GTV, CTV, PTV, and OARs. The GTV and CTV should receive 100% of the prescription dose. At least 95% of the PTV should receive 100% of the prescription dose. As shown in this example, with crosshairs placed on 6000 cGy (60 Gy), more than 95% of the PTV 60 is covered by 100% of the prescription dose (60 Gy).

Prognosis

MGMT repairs DNA damage induced by alkylating agents. The MGMT gene can be silenced by methylation of its promoter, thereby preventing DNA damage repair and increasing the effectiveness of TMZ. MGMT promoter methylation is prognostic (meaning that it affects survival regardless of treatment) and also predictive for improved survival with TMZ in patients with GBM. In the updated results of the EORTC-NCIC trial, MGMT methylation was the strongest prognostic factor for survival. Methylation status of the MGMT gene promoter was determined retrospectively by methylation-specific polymerase chain reaction analysis. The 2-year OS for patients treated with RT + TMZ was 48.9% for MGMT-methylated and 14.8% for unmethylated tumors. MGMT methylation is present in approximately 45% of patients with GBM.

Loss of heterozygosity on chromosome arms 1p and 19q are frequently found in oligodendrogliomas. Codeletion of 1p/19q has been associated with improved PCV (procarbazine, lomustine, and vincristine) chemosensitivity in grade III gliomas with a trend for improved PFS and OS. However, codeletion of 1p/19q is rare in GBM, presenting in approximately 5% of cases. An oligodendroglioma-like component (GBM-O) was seen in 15% of 339 patients with GBM, but was not found to have prognostic significance.

Recursive partitioning analysis (RPA) classification for malignant gliomas was developed to categorize patients based on factors that could affect survival and prognosis. The EORTC and RTOG have both developed RPA classifications, as detailed in Table 8.3 . Of note, the RTOG classification also includes anaplastic astrocytomas, whereas the EORTC RPA only includes GBM. There are also some differences in performance status and neurologic functioning assessment. Survival data by RPA class from the phase II and phase III EORTC trials along with the RTOG database are compared in Table 8.4 . The EORTC RPA classification retains prognostic significance in patients receiving RT + TMZ and patients treated with RT alone for GBM. RPA is predictive of survival with TMZ in class III ( P = .006) and class IV ( P = .0001) patients, with a trend for survival prediction in class V patients ( P = .054). In summary, RPA classification is an important tool for assessing survival outcomes and should be used as a guide to discuss prognosis for patients with GBM.

Management of Elderly Patients

In patients more than 70 years old with good performance status and in otherwise good overall health, standard of care remains maximal surgical resection followed by concurrent chemoRT and adjuvant TMZ. In the landmark EORTC-NCIC study, median OS was similar (10.9 vs 11.8 months) when comparing RT + TMZ vs RT alone for patients 60 to 70 years old. However, there was a statistically significant advantage in OS with TMZ when comparing OS at 2 years (21.8% vs 5.7%) and 5 years (6.6% vs 0%). Note that older patients who are not in good health or with poor Karnofsky performance status (KPS) may not be able to tolerate RT + TMZ, and the risks of toxicity in these patients should be weighed against the potential for improved survival. For these patients, alternative treatments include hypofractionated RT with concurrent chemotherapy, RT alone, or chemotherapy alone. This section will focus specifically on radiation therapy and modifications in dosing and fractionation for elderly patients who may not be able to tolerate the standard regimen.

A phase II trial of 71 patients with age ≥70 years and KPS ≥ to 60 was designed to evaluate the efficacy and safety of concurrent and adjuvant TMZ with short-course RT (40 Gy in 2.66 Gy fractions). Median and 1-year OS were 12.4 months and 58%, respectively. Median and 1-year PFS were 6 months and 20%, respectively. All patients completed RT. TMZ was discontinued because of toxicity in 6 patients (8%). Health-related quality of life was maintained until the time of disease progression in most patients. Subsequently, the same group retrospectively reviewed patients with age ≥65 years and KPS ≥60 who received concurrent and adjuvant TMZ with standard RT (60 Gy) vs short-course RT (40 Gy). CTV was defined as a 2-cm expansion around the T1C+ MRI enhancement while respecting anatomic boundaries, with a 3-mm to 4-mm margin for PTV. Standard RT was administered in 1.8 Gy to 2 Gy fractions to a dose of 59.4 to 60 Gy without a cone-down boost, and short course was treated at 2.66 Gy for 15 fractions to a dose of 40 Gy. Median OS and PFS were similar: 12 months and 5.6 months for standard RT vs 12.5 months and 6.7 months for short-course RT, respectively. MGMT methylation was the most favorable prognostic factor ( P = .0001). Standard RT was associated with higher rates of grade 2 and 3 neurotoxicity ( P = .01), worsening KPS after treatment ( P = .01), and higher doses of corticosteroids ( P = .02). The investigators concluded that short-course RT is an effective alternative in older patients that yields similar survival and reduced toxicity compared with conventional RT for GBM. Standard RT vs short-course RT with TMZ is currently being investigated prospectively in a phase III trial ( NCT00482677 ).

RT alone is an effective alternative in older patients with poor performance status and may be preferable to TMZ alone, especially for MGMT-unmethylated tumors. A retrospective study comparing hypofractionated RT with or without concurrent and adjuvant TMZ for age >70 years was conducted and showed no survival benefit with the addition of TMZ. Median OS was actually higher in the RT-alone patients (9.3 vs 6.9 months), although it was not statistically significant ( P = .351). On subgroup analysis of the RT-alone group, patients salvaged with TMZ for disease progression had increased OS of 13.3 months compared with 5.7 months with no further treatment ( P = .012). This study suggests that concurrent TMZ does not confer survival benefit in patients >70 years of age and that a sequential approach of hypofractionated RT alone followed by TMZ for salvage may be a more effective strategy.

A prospective trial of 81 elderly patients randomly assigned to receive RT alone vs supportive care alone after undergoing surgery showed median survival of 29.1 weeks and 16.9 weeks, respectively. Biopsy alone was performed in half (42 of 81) of the patients. Median PFS was 14.9 weeks with RT vs 5.4 weeks with supportive care. Fractionated RT was delivered at 1.8 Gy per fraction to a total dose of 50.4 Gy. CTV was defined as a 2-cm margin around the enhancement seen on T1C+ MRI. There was no impairment of quality of life or cognitive function with RT.

A prospective randomized comparison of hypofractionated RT vs standard RT alone in 100 patients ≥60 years old showed no difference in OS (5.6 vs 5.1 months; P = .57). However, more patients receiving standard RT required a post-treatment increase in dexamethasone dose (49%) vs hypofractionated RT patients (23%), ( P = .02). Recognizing the reduced treatment time and lower dexamethasone requirement with hypofractionated RT in the setting of equivalent OS, the investigators advocate hypofractionated RT in older patients with GBM who are not good candidates for combined treatment with TMZ. In a subsequent prospective randomized trial by the same group, an even more hypofractionated course of RT (25 Gy in 5 fractions) was compared with 40 Gy in 15 fractions. The study included elderly (≥65 years old) and frail patients (age ≥50 years and KPS 50–70). The 25 Gy short-course arm was non-inferior to the 40 Gy arm with median OS of 7.9 vs 6.4 months ( P = .988). There was no difference in quality of life between the two arms. As such, this study supports an even shorter hypofractionated course for elderly patients with poor KPS.

There are 2 major randomized prospective trials that examined the efficacy of RT alone compared with TMZ alone for older patients: the Methusalem (NOA-8) trial and the Nordic Clinical Brain Tumor Study Group trial. The NOA-8 trial compared TMZ alone vs standard fractionation RT alone to 60 Gy with a 2-cm margin around the GTV with no boost. There was no difference in OS between the two groups (8.6 months for TMZ vs 9.6 months for RT). Event-free survival was longer in patients with MGMT methylation who received TMZ than in those who underwent RT alone (8.4 months [95% CI, 5.5–11.7] vs 4.6 months [95% CI, 4.2–5.0]), whereas the opposite was true for patients with unmethylated MGMT (3.3 months [95% CI, 3.0–3.5] with TMZ vs 4.6 months with RT [95% CI, 3.7–6.3]). This study suggests that MGMT methylation status may help with clinical decision making in patients undergoing single-modality therapy for GBM when deciding between chemotherapy vs RT alone. Notably, MGMT methylation was associated with longer survival regardless of treatment, and TMZ was associated with more grade 3 or 4 hematologic toxicity compared with RT alone.

The Nordic trial randomly assigned patients with median age 70 years to 3 arms: TMZ alone, standard RT (60 Gy), and hypofractionated RT (34 Gy in 10 fractions). This study found that although TMZ resulted in significantly improved median OS compared with standard RT (8.3 vs 6 months; P = .01), TMZ showed no survival advantage compared with hypofractionated RT (7.5 months; P = .24). MGMT methylation was associated with improved survival for patients receiving TMZ (9.7 vs 6.8 months; P = .02), but MGMT methylation status did not affect survival in patients receiving RT in either arm. The results of these two trials are conflicting, and further study using a more common hypofractionated regimen (40 Gy in 15 fractions) compared with standard TMZ dosing is warranted to further investigate the efficacy of single-modality treatment in elderly patients.

Patients with GBM older than 65 years have worse prognosis compared with younger patients. RPA classification of more than 700 patients with GBM ≥70 years of age demonstrated 4 prognostic groups ( Table 8.5 ). MGMT methylation is present in approximately 58% of patients with GBM over 70 years of age, and the prognostic and predictive values have been reported in elderly patients. Acknowledging that single-modality therapy is better tolerated than chemoRT, MGMT methylation status may guide selection between TMZ vs RT alone for older patients.

Stereotactic Radiosurgery

Stereotactic radiosurgery (SRS) is an RT technique that is available at many radiation oncology facilities and allows physicians to administer large doses of RT in one or a few treatments with high conformity and steep dose fall-off outside the target to spare normal tissues. Treatment platforms include Gamma Knife radiosurgery (GKRS) and linear accelerator (LINAC)–based radiosurgery. GKRS consists of 192 or 201 cobalt-60 sources with a helmet over a fixed frame with 4 screws attached to the patient’s skull for immobilization. The latest Leksell GKRS unit (Icon) now allows for a thermoplastic mask–based system without screws. LINAC-based radiosurgery uses a standard RT linear accelerator that generates photon beams to deliver conformal SRS. LINAC SRS can involve a rigid head frame or a mask that conforms to the patient’s skull and face. Several newer immobilization technologies have emerged for LINAC SRS, including infrared sensors that can be attached either to the surface of the mask or a bite block, as well as frameless immobilization that uses a series of cameras to detect facial structures to verify patient positioning before and during treatment.

RTOG 9305 is the only level I study to assess the efficacy of SRS for GBM. Patients were randomly assigned to chemoRT with BCNU to 60 Gy vs SRS boost (15–24 Gy) followed by chemoRT with BCNU to 60 Gy. Patients who had gross total resection (GTR) were not eligible for the trial. This trial turned out to be a negative study because there was no difference in median survival between the two groups (13.6 months with no SRS vs 13.5 months with SRS) and no difference in 2-year or 3-year survival rates. Quality of life and cognitive decline were comparable. RTOG 0023 was a phase II trial of 76 patients treated with fractionated RT to 50 Gy with weekly fractionated stereotactic radiotherapy boost (5 or 7 Gy for 4 treatments) to a total cumulative dose of 70 to 78 Gy. BCNU chemotherapy was given adjuvantly after RT. Median survival was 12.5 months and no survival benefit was seen compared with the historical RTOG database. One patient developed radionecrosis and 11 patients experienced grade 3 neurologic toxicity. There was a trend for improved survival in patients who had GTR and underwent stereotactic boost compared with historical RTOG controls.

There have been several single-institution and retrospective SRS studies (some of which include TMZ) that showed promising survival rates after treatment. These studies are summarized in Table 8.6 . Although the 2 major RTOG trials for SRS in GBM failed to show benefit, examination of SRS boost with TMZ in a prospective trial may be warranted. Other areas of potential investigation include a rethinking of the tumor volume treated with SRS for GBM. Leading-edge SRS treats a volume of predictive likelihood of relapse along with the T1C+ MRI enhancement, which can be aided with multiparametric MRI and other imaging modalities such as PET. It would also be interesting to evaluate the benefit of SRS boost specifically for unresectable (biopsy alone) cases. Dose escalation with SRS boost for patients with unresectable GBM may provide improved tumor control compared with fractionated RT, analogous to how lung SBRT (stereotactic body radiation therapy) has now become the standard of care for early-stage unresectable lung tumors.

Table 8.6

SRS for treatment of newly diagnosed GBM

Author	N	SRS Modality	Radiation Dose (Range)	Surgical Resection Extent	Survival Rate	Median OS (mo)	Toxicity
Souhami et al, 2004	89	GKRS or LINAC	15–24 Gy SRS + 60 Gy RT + BCNU	GTR not eligible	2-y OS, 21%; 3-y OS, 9%	13.5	Neurologic grade 1, 3 patients; grade 2, 6 patients; grade 3, 3 patients
Cardinale et al, 2006	76	LINAC	50 Gy RT + (5–7 Gy × 4 FSRS) + BCNU	Biopsy (24%), STR (35%), GTR (41%)	22 mo OS, 17%	12.5	1 patient (1%) developed radionecrosis; 11 patients (14%) with grade 3 neurologic toxicity
Sarkaria et al, 1995	115	LINAC	54–60 Gy RT + 12 Gy (6–20) SRS	Biopsy (44%), STR (53%), GTR (3%)	2-y OS, 45%; 2-y OS for KPS ≥70, 51%; 2-y OS for KPS <70, 0%	NR	19 out of 115 (16%) patients experienced complications from radiosurgery: 17 patients with radiation necrosis, 1 patient with hemiparesis, 1 patient with double vision and hydrocephalus requiring ventricular shunt. 47% of patients required prolonged steroid use
Gannett et al, 1995	30	LINAC	44–62 Gy RT + 10 Gy (0.5–18) SRS	Biopsy (10%), STR (60%), GTR (30%)	1-y DSS, 57%; 2-y DSS, 25%	13.9	No significant acute or late toxicity; no documented occurrence of symptomatic radiation necrosis. All patients were managed with oral steroids for prophylaxis
Masciopinto et al, 1995	31	LINAC	50–66 Gy RT + 10–20 Gy SRS	Biopsy (11%), tumor debulking (65%)	1-y OS, 37%	9.5	NR
Mehta et al, 1994	31	LINAC	54 Gy RT + 12 Gy (10–20) SRS	Biopsy (39%), STR (55%), near-total resection (6%)	1-y OS, 38%; 2-y OS, 28%	10.5	NR
Nwokedi et al, 2002	33 RT alone; 31 RT + SRS	GKRS	59.7 Gy (28–80) RT + 17.1 Gy (10–28) SRS	Biopsy (30%), maximal safe resection (70%)	For all patients: 1-y OS, 67%; 2-y OS, 40%; 3 y OS, 26%	RT alone, 13; RT + SRS, 25	No patients experienced acute grade 3–4 toxicity that could be attributed to radiotherapy alone; of the patients who received RT + SRS, 2 patients (7%) developed radiation necrosis
Balducci et al, 2010	41 (36 GBM, 5 AA)	LINAC	59.4 Gy or 50.4 Gy RT + 10 or 19 Gy SRS + TMZ	STR (68%), GTR (32%)	2-y OS, 63%	All patients, 30; GBM, 28	12% of patients experienced G1–2 neurologic acute toxicity such as headache, confusion and seizures. G3 toxicity was observed in 1 patient. Hematologic acute toxicity G1–2 was observed in 2% of patients. During adjuvant chemotherapy, 10% of patients experienced G2 hematologic toxicity and G3 toxicity was seen in 7% of patients. Late neurologic toxicity included 2 cases (4.8%) of radionecrosis
Cardinale et al, 1998	12 (9 GBM, 3 AA)	LINAC	44 Gy RT + 36 Gy SRS	Biopsy (17%), STR (83%)	NR	GBM, 16; AA, 33	1 patient required an increase in steroid dose because of headache and neurologic progression. 1 patient with a history of seizures had a seizure 5 wk after completion of radiation with significant edema that was then managed with steroid therapy. Another patient developed new seizures 6 mo after treatment. 4 patients (33%) were diagnosed with radionecrosis
Shrieve et al, 1999	78	LINAC	12 Gy (6–24) SRS	Stereotactic biopsy (27%), STR (64%), GTR (9%)	1-y OS, 88.5%; 2-y OS, 35.9%	19.9	Acute toxicity following SRS showed exacerbation of existing symptoms (eg, seizure activity, aphasia, or paresis). 50% had reoperation for symptomatic necrosis or recurrent tumor. Rate of reoperation at 24 mo after SRS was 54.8%
Floyd et al, 2012	20	CyberKnife	40 Gy RT + SRS (lesions <2 cm, 22 Gy; 2.1–3.0 cm, 18 Gy; 3.1–4.1 cm, 15 Gy; >4.1 cm, 8 Gy) + TMZ	Biopsy (35%), STR (15%), GTR (50%)	NR	13	All patients experienced fatigue and skin reactions (erythema and alopecia) without requiring further treatment (grade I). 4 patients required prolonged dexamethasone for symptomatic cerebral edema, which eventually resolved in all but 2 patients (20% grade II toxicity). Overall, 4 patients (20%) experienced grade III toxicity
Landy et al, 2004	23	GKRS	Estramustine + SRS (tumor maximum diameter ≤20 mm, 21 Gy; 21–30 mm, 18 Gy; 31–40 mm, 15 Gy) + 72 Gy RT for new tumors	NR	2-y OS, 38%	16	7 patients (30%) experienced moderate nausea, with emesis in 4 of these patients (17%). 4 other patients (17%) developed DVT and 1 patient experienced vaginal bleeding
Omuro et al, 2014	40	LINAC	6 Gy × 6 or 4 Gy × 6 FSRS + TMZ + bevacizumab	STR or biopsy (75%), GTR (25%)	1-y OS, 93%	19	1 patient (2.5%) developed grade 4 surgical wound infection without dehiscence; 2 patients (5%) had grade 4 pulmonary embolisms and 1 experienced a late ischemic stroke. 1 patient (2.5%) had a history of difficult to control seizures and died suddenly during sleep while on treatment. 2 patients (5%) had CNS bleeding, both grade 1 and asymptomatic

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Radiographic Detection and Advanced Imaging of Glioblastoma Multimodality Targeting of Glioma Cells Awake Craniotomy for Glioblastoma Brain Plasticity and Reorganization Before, During, and After Glioma Resection Lessons Learned: Clinical Trials and Other Interventions for Glioblastoma Recurrent Glioblastoma

Stay updated, free articles. Join our Telegram channel

Join