Figure 11.1
Typical patient immobilization and field set-up for whole-brain radiotherapy (WBRT) via opposed lateral fields. (a) Custom headholder with field shape outlined on mask, (b) multileaf collimator outline (dark blue lines) and (c) radiation dose distribution – starting from upper right-hand corner and moving clockwise: 3D rendering of dose distribution for sagittal, coronal and axial cross-sections (Reprinted from Kirkpatrick et al. [5]. With Permission from Elsevier)
3D and Intensity-Modulated Radiation Therapy
In 3D treatment of brain tumors, the lesion is drawn on multiple CT or MRI slices to create a three-dimensional structure. This structure may be expanded several millimeters to centimeters in each direction to yield a target volume. The treatment planner then sets up multiple beams in the computer, each of which is sized, shaped and weighted to achieve the desired dose to the target while minimizing dose to the normal brain. During treatment, lead blocks or thin metal leaves in the linear accelerator are used to achieve the desired shape of the radiation beams. In intensity-modulated radiotherapy (IMRT), the shape of the beam is continuously adjusted by adjusting these metal leaves, permitting the dose to be precisely varied within the target volume. This “dose painting” is particularly useful when treating irregularly shaped targets that wrap around critical normal structures, such as the brain stem or optic nerves.
Intracranial Stereotactic Radiosurgery (SRS)
In SRS of brain lesions, a high dose of radiation is delivered in a single fraction or a few fractions with rapid dose fall-off from the periphery of the target lesion into the surrounding normal brain. While a variety of radiotherapy systems, e.g., GammaKnife (Elekta), CyberKnife (AccuRay), Novalis Tx (Varian Medical Systems and BrainLab), are utilized in intracranial SRS, all share some common features [6]. SRS systems exhibit high accuracy (<1 mm deviation) for patient positioning and dose delivery. Typically, a patient is immobilized in a removable, semi-rigid plastic head mask (Fig. 11.2a) or a head ring fixed to the patient’s skull. The target for radiation is precisely identified using fine-cut CT scans fused with MR images and occasionally functional imaging modalities, such as PET.
Figure 11.2
Example of patient immobilization and field set-up for stereotactic radiosurgery (SRS) via dynamic conformal arcs to a left frontal lobe metastasis. (a) Custom U-frame mask, (b) multiple arc paths and (c) radiation dose distribution – starting from upper left-hand corner and moving clockwise: 3D rendering of dose distribution for axial, coronal and sagittal cross-sections (Reprinted from Kirkpatrick et al. [5]. With Permission from Elsevier)
In a collimator-based linear-accelerator system, such as the Novalis Tx, a typical treatment plan for an ellipsoid lesion, such as a small brain metastasis, consists of three to five non-coplanar conformal arcs (as illustrated in Fig. 11.2b) yielding the conformal dose distribution shown in Fig. 11.2c. Multiple intensity-modulated beams are often used for treating irregularly shaped targets and/or those that are immediately next to critical organs, such as the brainstem. The correlation between the patient geometry (and/or immobilization device geometry) and the treatment machine geometry is achieved through two different approaches: (1) matching the geometry of the immobilization device with the machine isocenter through dedicated measurement devices with the assistance of room lasers; (2) matching planning/simulation images with treatment images acquired using an imaging device mounted in the treatment room (or machine) while the patient is on the treatment table. Both approaches are able to achieve localization accuracy of about 1 mm. Radiation delivery consists of multiple beams intersecting at a single point (isocenter), shaped by fixed diameter cones and delivered in multiple arcs, dynamically conformal arcs continuously shaped by a multi-leaf collimator or multiple intensity-modulated beams. In the CyberKnife system, multiple collimated small-diameter beams are delivered to an intracranial lesion using a linear accelerator attached to a highly mobile robotic arm.
In contrast, the GammaKnife system uses hundreds of gamma-ray sources (Co-60) precisely intersecting at a single isocenter. This yields a small spherical or ellipsoid high-dose cloud whose diameter is determined by the size of the collimator opening. Dose fall-off from the cloud into the surrounding tissue is extremely rapid. Treatment of irregular and/or large targets is achieved by “packing” together multiple dose “clouds,” positioned in the target by precisely repositioning the patient over the course of a treatment session.
Brain Metastases
Primary cancer metastatic to the brain (brain metastases) is the most common malignant lesion in the brain, developing in over 200,000 cancer patients in the United States each year [7]. While brain metastases from lung, breast, kidney and skin (melanoma) are most frequently encountered, virtually any histology from any anatomic suite can metastasize to the brain. The optimal management of brain metastases is controversial, given the improved control of extracranial disease and increased longevity after cancer is diagnosed, multiple tumor and patient factors influencing prognosis, and the many treatment options. Treatment typically consists or whole-brain radiotherapy, radiosurgery, surgical resection or some combination of these modalities, as described below. Chemotherapy does not yet play a significant role in the management of brain metastases [8].
WBRT with and Without Surgery
Whole-brain radiotherapy is widely employed for the treatment of patients with brain metastases. WBRT can temporarily halt the growth of brain metastases, gradually reducing mass effect and neurologic deficits and extending life. However, there is a substantial risk of recurrence and neurologic death, and WBRT is typically delivered with palliative intent. Acute side effects of WBRT include complete hair loss and mild scalp erythema and pruritus in nearly all patients, occasional sensation of fullness in the ears and parotid swelling, and mild anorexia and moderate fatigue which can be severe in the debilitated and/or elderly patient [9]. Steroids (primarily dexamethasone) should be given judiciously, using the lowest dose to control symptoms while carefully managing the many potential side effects. Prophylactic anti-epileptic drugs should not be routinely administered [10].
The long-term impact of WBRT on neurocognition and quality-of-life is a common concern of patients and their families. A frequently cited study of patients from Memorial Sloan-Kettering with single brain metastases treated with WBRT reported that “radiation-induced dementia” was observed in 5/47 patients at 1-year (11 % crude rate.) Note that four of the five patients who developed dementia were treated with a high dose per fraction (three 5- to 6-Gy fractions) and that the other received a concurrent radiosensitizer. In contrast, none of the 15 patients treated in ten 300 cGy fractions developed dementia. Today, patients with brain metastases treated with brain metastases typically receive ten 300 cGy, fourteen to fifteen 250 cGy or twenty 200 cGy fractions, though shorter or longer courses can be utilized. While data from low-grade primary tumors suggest that a more protracted course affords better preservation of neurocognition [11, 12], the optimal dose/fractionation regimen for brain metastases has not been established [13].
Studies of single brain metastases treated with WBRT with and without surgery have yielded conflicting results [14–16]. For example, a randomized trial of WBRT alone versus surgery plus WBRT suggests that surgery be considered in all surgical candidates with a single resectable lesion [16]. The rate of recurrence at the original site of metastasis was significantly lower in patients who were resected and irradiated (20 versus 52 %), overall survival was much higher and functional independence longer compared to those who received WBRT alone. In contrast, another randomized study of WBRT with and without surgery in 84 patients with single brain metastases showed no significant difference with the addition of surgery.
Surgery with and Without WBRT
The resection of a brain metastasis can reduce the pressure on adjacent structures, recurrence of disease at the resection cavity and in other areas of the brain occurs frequently. In a trial of patients with a solitary brain metastasis randomized to surgery with or without WBRT, recurrence of tumor anywhere in the brain was far less frequent in the group receiving WBRT (18 % versus 70 % [17]). The addition of WBRT reduced the risk of recurrence at both the original site of the metastasis and at other sites in the brain, and these patients were less likely to die of neurologic causes. However, the study showed no significant difference in overall survival with or without WBRT. A subsequent study from the European Organization for Research and Treatment of Cancer (EORTC) randomized over 300 patients with one to three brain metastases to observation versus WBRT after either surgery or SRS [18]. The primary endpoint was deterioration in performance status. Recurrence at the resection site and the uninvolved areas of the brain was significantly higher when WBRT was omitted, and patients receiving WBRT were less likely to die of intracranial disease. However, the study found no difference in time to deterioration of performance status or in overall survival.
WBRT with and without SRS
The Radiation Therapy Oncology Group randomized 333 adult patients with one to three brain metastases treated with WBRT to SRS within 1 week of completing WBRT versus observation (RTOG 9508 [19].) Local control was significantly improved in the group undergoing SRS (82 versus 71 % at 1 year), though recurrent disease anywhere in the brain was not significantly better. Nonetheless, median overall survival was significantly higher with the addition of SRS in patients with a single brain metastasis patients <65 years old with controlled extracranial disease and Karnofsky performance status ≥70, and patients with brain metastasis ≥2 cm in greatest diameter. In addition, patients receiving treated with SRS exhibited significantly reduced steroid use and less deterioration in Karnofsky performance status than those who did not. Rates of acute and late toxicities were quite similar between the two groups, though SRS carried an approximate 0.5 % monthly rate of radionecrosis.
SRS with or without WBRT
SRS alone with close follow-up to detect and treat recurrent disease has been suggested as an alternative to whole-brain radiotherapy, as it potentially avoids neurocognitive and systemic side effects encountered with treatment of the entire brain. On the other hand, omitting WBRT carries a significantly higher risk of recurrence, which in turn may result in increased neurocognitive deficits. Sneed et al. [20] performed a retrospective analysis of 569 patients from ten institutions treated with SRS alone versus SRS with up-front WBRT. There was no significant difference in the median overall survival time for patients receiving SRS alone versus SRS and WBRT.
In a study from Japan [21], patients with one to three brain metastases were randomized to receive SRS alone versus SRS and WBRT. The addition of WBRT significantly improved both control at the site of the original metastases (89 versus 73 % at 1 year) and at distant sites in the brain (58 versus 36 % at 1 year.) However, overall survival was not different with SRS alone versus SRS and WBRT. As measured by mini-mental status exam (MSE), neurocognition did not differ between these arms [22], though MMSE is admittedly not a sensitive instrument for detecting changes in cognition.
In contrast a study from M. D. Anderson [23] randomized 58 patients with brain metastases to receive SRS alone versus SRS and WBRT, focusing on neurocognitive decline as measured by a comprehensive battery of tests. Four months after SRS, neurocognitive decline was substantially higher in the group receiving WBRT – 52 versus 24 %. Similar to other studies, the 1-year freedom from recurrence anywhere in the brain was 27 % for SRS alone versus 73 % for SRS plus WBRT. However, median overall survival was substantially poorer than expected in patients treated with WBRT. As the neurocognitive decline was measured at a time when many of the patients in the WBRT group were close to death, the results of this study are somewhat difficult to interpret.
SRS with Surgery
Following resection of a single brain metastasis, the surgical cavity alone can be treated with radiosurgery, omitting whole-brain radiotherapy, with the objective of decreasing the high rates of local recurrence observed with surgery alone [17] and avoiding the side effects of WBRT [24]. For example, Choi et al. irradiated 120 resection cavities in 112 patients with brain metastases [25]. At 1 year, the rate of recurrence at the cavity was 9.5 % while the rate of distant failure in the brain was 54 %. They also examined the effect of irradiating only the resection cavity versus the resection cavity expanded by 2 mm and found that the rate of local failure at 1 year was significantly lower in the 2 mm and that no significant difference in toxicity was observed as a function of resection margin.
Decision-Making
All patients with brain metastases should be treated with some form of radiation therapy. In determining which patients should be treated with surgery before or after radiation, there are generally six features to consider, as follows: comorbidities, patient prognosis, size, location and number of metastasis, and patient goals for treatment. In general, patients with a poor prognosis due to fulminant disease outside the brain or other comorbidities should be treated with radiation only, as the time to recover from surgery is generally a minimum of 3–6 weeks and surgery imparts risks that may increase the recovery time. Given increasing tumor burden and decreasing maximum tolerated dose for radiosurgery as tumor diameter increases, many patients with tumors >3 cm and most patients with lesions >4 cm diameter should be considered for surgery. It is also generally accepted that patients with a single metastasis or more than one metastasis that can all be accessed through a reasonable sized craniotomy should be considered for surgical resection. Finally, patient’s preference should always be a factor in the decision given the lack of Level I data to support specific recommendations, particularly with regard to the choice between surgery plus radiation versus radiation alone. This discussion will involve the neurosurgeon, radiation oncologist, the patient and other members of the care team.
Primary Brain Tumors
Malignant Gliomas
Anaplastic astrocytomas and glioblastomas (WHO Grade III and IV malignant gliomas, respectively) account for about two-thirds of primary malignant brain tumors in adults with an annual incidence in the U. S. of approximately six cases/100,000 person-years [26]. While meningiomas are more frequent, these are typically benign tumors [26] and the discussion in this section will focus on the management of the far more aggressive malignant gliomas. Malignant gliomas arise from neuroepithelial tissue and with a peak incidence in the sixth decade of life. The cause of most cases of malignant gliomas is unknown in more than 90 % of cases, though exposure to ionizing radiation and certain genetic syndromes are associated with an increased risk of this disease [27].
Surgery
Maximum safe resection of malignant glioma is a key element in the management of malignant gliomas, as outcomes appear to be more favorable in patients undergoing a gross or near total resection compared to minimal debulking or biopsy alone [28]. However, there are no randomized control studies proving the superiority of a gross total resection and it is unlikely that such a trial would be performed. With surgery alone, median progression-free and overall survival are on the order of only a few months, as tumor cells are present well beyond the gross lesion. Thus, surgery and radiotherapy are typically both utilized, as described below.
Radiotherapy
Radiation therapy following surgical resection of malignant gliomas has been a recommended component of the management strategy since the 1970’s, as the combination of surgery and RT improved overall survival over surgery alone [29, 30]. Subsequent studies suggested that a total dose of around 60 Gy, typically administered at 2 Gy per day, improved survival compared to lower total doses [31, 32]. Trials to improve outcome by dose escalation using conventionally fractionated RT [33], hyperfractionation [34], brachytherapy [29, 35] or a stereotactic radiosurgery [36] boost have not revealed a benefit to increasing dose beyond 60 Gy. Thus, standard RT typically consists of thirty 2.0 or thirty-three 1.8 Gy daily fractions to a total dose of 59.4–60 Gy delivered over a 6–7-week period. However, there is evidence in elderly patients, that treatment at a slightly higher dose per day for a significantly shorter period (e.g., 40 Gy delivered over 3 weeks) may yield a reasonable outcome [37].
Though the entire brain was initially irradiated due to the concern about the invasion of tumor cells throughout the brain, various trials showed no significant differences in outcome when the volume of brain irradiated was reduced [38, 39]. In addition, most failures occur within 2–3 cm of the enhancing lesion on CT or MRI scans and a distant failure is usually associated with a local recurrence [38, 40]. Thus, in order to avoid toxicity associated with whole-brain irradiation to 60 Gy, the current practice is to irradiate only the involved part of the brain. Typically, the initial target for irradiation is the volume of brain exhibiting T2 hyperintensity on MRI expanded by approximately 2 cm, followed by a “boost” of an additional 14–14.4 Gy to the contrast-enhancing residual lesion and/or resection cavity on T1-weighted MRI imaging. In order to minimize the volume of normal brain irradiated and to keep the dose to critical structures within tolerance, multiple shaped, intersecting radiation beams are employed and intensity-modulated radiotherapy is often utilized.
Surgery, Radiotherapy and Chemotherapy
Meta-analyses of the outcome in patients with malignant glioma treated with or without nitrosureas suggested a small, but significant, benefit from the addition of these intravenous agents [41, 42]. However, an EORTC trial in which patients with glioblastoma were randomized to receive RT (60 Gy in 2 Gy daily fractions) with or without temozolomide (TMZ), demonstrated that the addition of TMZ yielded significantly improved overall survival [43]. Patients expressing lower levels of the enzyme responsible for repair of DNA damage, MGMT, exhibited a much more favorable response, though an improvement in survival was noted in the RT/TMZ arm even in those patients with unfavorable MGMT status. Likewise, while younger age, performance status and increased extent if resection were associated with better outcome, the addition of TMZ conveyed improved survival in all prognostic groups. Consequently, the standard of care for adult patients with newly diagnosed glioblastomas includes maximum safe resection followed by conventionally fractionated radiotherapy with concurrent and adjuvant chemotherapy.
Even with the “optimum” combination of surgery, radiotherapy and chemotherapy, the virtually all patients with malignant glioma recur [43]. A variety of novel approaches are under trial to improve outcome in newly diagnosed glioblastoma, and enrollment in these trials is essential to identify more effective treatment. Given the extremely high rates of recurrence in malignant gliomas, improved treatment of recurrent disease is also a matter of great interest. Bevacizumab has been approved by the FDA for treatment of recurrent disease based on the results of phase II trials [44–46] and SRS, alone [47] or, particularly, in combination with bevacizumab [48–50], may offer benefits in this setting. Randomized trials testing the efficacy of SRS and bevacizumab (RTOG 1205) are underway.
Spine and Spinal Cord Tumors
Radiotherapy Techniques
External-Beam Radiotherapy (EBRT)
EBRT for spine tumors are typically utilizes one of three techniques: (1) a single radiation beam entering posteriorly (PA field, Fig. 11.3a), (2) two opposed radiation beams entering anteriorly and posteriorly (AP-PA fields) or (3) three or more radiation beams, often shaped by multi-leaf collimators (conformal 3D beams, Fig. 11.3b) All of these EBRT techniques result in irradiation of entire vertebral body, with the spinal canal/cord receiving the full dose of radiation. If control of the tumor is the primary objective of treatment, multiple modest doses of radiation are used (typically, ranging from five 4 Gy daily fractions up to twenty 2 Gy fractions.) Alternatively, if pain relief is the goal, it may be possible to treat with a single 8 Gy fraction, though this may limit durability of response. Both the PA and AP-PA fields are relatively quick to design and deliver. The PA field may reduce dose to the chest and abdomen, but is limited in the depth of treatment, particularly for lesions located in the lumbar spine. AP-PA fields are capable of treating deep lesions but deliver higher radiation doses to the viscera. In contrast, 3D conformal EBRT plans are more complex to plan and execute but significantly reduce the maximum dose to adjacent organs (see Fig. 11.3b)
Figure 11.3
Typical axial radiation dose distributions for (a) external-beam radiotherapy to the spine via posterior-anterior fields and (b) multiple 3D conformal beams, (c) spinal stereotactic radiosurgery via intensity-modulated radiotherapy (Reprinted from Kirkpatrick et al. [5]. With Permission from Elsevier)
Spinal Radiosurgery
For metastatic disease involving one or a few contiguous vertebral bodies, SRS can be utilized to treat the osseous spine while sparing the spinal cord with one or a few high dose fractions. To do so, it is essential to employ intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) to treat the concave target while minimizing dose to the canal [51–54], as shown in Fig. 11.3c. As in intracranial radiosurgery, key elements of spinal SRS include high-resolution imaging for planning, immobilization and imaging for position verification and adjustment immediately before and during treatment [55, 56].
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