Oncologic outcomes of GKS on sellar and parasellar tumors
Childhood-onset CRPs are prone to recur even after radical resection because of their invasive growth and adhesion to adjacent structures, although the histological diagnosis is benign [10, 11]. Reoperation is often challenging, particularly in pediatric patients, and pose an increased risk of morbidities. SRS has been established as a safe and effective alternative treatment to surgery for residual or recurrent tumors. The proximity of the optic apparatus to the CRP leads to concerns over RION and compels operators to prescribe a lower radiation dose, resulting in a lower tumor control rate. A large cases series of GKS performed on 98 CRPs showed that a mean marginal dose of 11.5 Gy resulted in 5- and 10-year local control rates of 60.8 and 53.8%, respectively . The present study revealed 5- and 10-year tumor control rates of 76.8% and 59.8%, respectively, with a mean marginal dose of 15.3 Gy. The optimal marginal dose and the decisive dosimetric parameters for the long-term control of CRPs remain unclear. Notably, D98%, rather than the marginal dose, was significantly associated with long-term tumor control, with a value of ≥ 10 Gy resulting in 5- and 10-year tumor control rates of 93.3% and 61.3%, respectively. At times, some portion of the tumor is excluded from the prescription isodose line when planning due to safety concerns, more frequently in the sellar and parasellar tumors located near the organ at risk. In such cases, the prescription dose does not reflect the dose irradiated to the tumor site excluded from the prescription isodose line at all. On the other hand, D98% is the minimum dose received by 98% of the tumor volume, informing the actual lowest dose irradiated to the tumor, which is not simply deduced from the prescription dose or tumor coverage (%). Our results indicate that tumor control closely correlates with the suboptimal doses delivered to some of the tumor cells rather than the sufficient dose most of the tumor cells receive. From this point of view, we suggest D98% as a valid indicator of the Maginot Line radiation dose necessary for tumor control, and we recommend D98% ≥ 10 Gy for long-term tumor control of CRPs.
Meanwhile, SRS efficacy has been reported to depend on the properties of the tumor [1, 13]. With a median marginal dose of 13 Gy (range, 9–20), the 5-year local control rates for solid versus mixed CRPs were reported to be 91.6% versus 68%, respectively . In contrast, the nature of the tumor, whether solid or cystic, was not statistically associated with tumor control in this study. The discrepancy in the results might be based on the differences in the nature of the tumor, size of the tumor, and radiation dose; however, large-scale studies exploring the GKS efficacy for CRPs in children are required in the future.
PAs account for less than 3% of all pediatric intracranial tumors and show a higher incidence of functional tumors than adults [14, 15]. The goals of SRS for functioning PAs are to restrain tumor growth, and promote endocrinological remission, so a higher dose is recommended than that for nonfunctioning PA (NFPA) [5, 16]. In general, greater biochemical control was achieved in patients with Cushing’s disease and acromegaly than in those with prolactinomas . Marginal dose of 25 Gy was reported to play a critical role in the endocrinological remission rate: 52% (range, 25–70%) versus 63.5% (35–83%) in Cushing’s disease; 49% (17– 82%) versus 40% (17–65%) in acromegaly; and 26% (23–27%) versus 37% (18–50%) in prolactinoma [17-30]. Meanwhile, the optimal marginal dose for the local control of NFPA remains controversial. A multicenter study reported that a median marginal dose of 16 Gy resulted in 5- and 10-year tumor control rates of 95% and 85%, respectively . A recent meta-analysis reported that with a median dose of 15 Gy, the 5- and 10-year random effects local tumor control rates after SRS were estimated to be 94% and 83%, respectively . However, it seems that favorable tumor control may be achievable with a marginal dose of only 12 Gy, yielding a 95% control rate [33, 34].
In the present study, among the patients with functioning PAs, one patient with Cushing’s disease who received 12.5 Gy and one patient with acromegaly who received 18.3 Gy experienced tumor progression despite undergoing GKS. None achieved endocrine remission, which was ascribable to an insufficient dose (mean, 19.6 Gy) delivered to the tumors in most patients due to the proximity of the optic apparatus. On the other hand, all NFPA cases were stationary after GKS with a marginal dose of 14 Gy during the 96-months follow-up. As NFPA itself is not life-threatening, we recommend prescribing the minimum dose effective to arrest tumor growth while preserving hormone function.
Visual outcome of GKS in patients with sellar and parasellar tumors
The anterior visual pathway is believed to be one of the structures most vulnerable to radiation . Traditionally, the tolerable dose to prevent RION is less than 8 Gy delivered to the optic apparatus [35, 36]. However, excessive constraints on the dose to the optic apparatus may limit the prescription of a sufficient marginal dose to the tumor or lead to less coverage of the target, which is associated with poor tumor control. Therefore, careful attention to treatment planning, considering both RION risk and long-term tumor control, is required. The risk of RION has been reported to range from 0 to 3 % for maximum doses to the optic apparatus of less than 8–10 Gy [36-38]. Some authors have asserted that a maximum dose of 12 Gy is safe, although a dose > 12 Gy has been associated with RION [37, 38]. However, in the present study, post-GKS visual deterioration occurred in two patients who received maximum point doses to the optic apparatus of 10.1 Gy and 10.6 Gy, respectively. Therefore, we recommend keeping a conservative cutoff value for the maximum point dose to the optic apparatus to avoid RION.
Achievement of long-term tumor control with preservation of visual and hormonal functions is worth pursuing, particularly in pediatric patients. For sellar and parsellar tumors, the proximity of the tumor to the optic apparatus and pituitary gland often restricts the dose that can be delivered to the tumor due to safety concerns. It also compels physicians to exclude a portion of the tumor from the prescription dose, leaving some tumor cells to be irradiated with a dose that is below that prescribed. However, insufficiently irradiated tumor cells can lead to progression. Therefore, it is imperative to clarify the dose window, ranging from a minimally effective dose for tumor control to a maximally safe dose to prevent RION, and plan for the delivery of proper radiation within that window while thoroughly covering the entire tumor. Many authors have sought to elucidate the relationship between the marginal dose and tumor control rates; however, the clear-cut association between them has not been statistically proven. We anticipate that this could be caused by discrepancies between the marginal dose and the actual dose delivered to the tumor cells. In this study, we revealed that D98% is significantly associated with tumor control rather than the marginal dose. D98% represents the actual minimum dose irradiated to the tumors in the volume, and thus, it may be a reliable index of the minimum required dose for long-term tumor control. There may still be a dose gradient between the D98% value for long-term tumor control and the tolerable maximum point dose to the optic apparatus. The tumors apart > 2 mm from the optic apparatus usually meet the required dose gradient due to the steep dose fall-off of GKS at the margin of the target; otherwise, fractionated radiosurgery may help lower the dose gradient . These results are based on data derived from heterogeneous tumors with different biological behaviors, as well as a small sample size for each tumor type. Therefore, the relevant dosimetric factors and the optimal D98% value for long-term tumor control for each kind of pathology need to be elucidated by prospective, large-scale studies in the future.