Craniopharyngiomas develop and grow in a narrow anatomic space wherein lies structures that critically affect quality of life – the pituitary stalk and gland, the optic nerve and chiasm, and critical vascular structures that affect the hypothalamus and basal ganglia.(12) Gross total resection as the first line management option confirms the pathological diagnosis and facilitates visual recovery in patients with symptomatic optic neuropathy related to tumor compression. The rate of gross total resection varies between 59-90%.(2, 13–16) Many patients require either additional resection, radiosurgery, intracavitary radiation for cyst progression, or in rare cases fractionated radiation therapy to achieve long tumor control.(2, 17)
Overall survival
Previous studies reported overall survival for craniopharyngioma ranging from 91.5% to 97.1% at 5 years and from 82.0% to 91.0% at 10 years after SRS(4–6, 18). Most long survival patients had multimodality management. Such strategies should continue to focus on methods to improve quality of life, including visual, hormonal, and neurocognitive preservation. The use of SRS is an important option that can improve tumor control with reduced risks compared to additional surgical resection.(15, 19)
Tumor control
In previous reports of craniopharyngioma patients who underwent SRS, tumor control rates varied from 73.1-84.8% at 3 years, 60.8-73.6% at 5 years, and 42.6-60.2% at 10 years.(4–8, 18) Results of the current study are similar to prior publications. In previous reports, an adequate distance between the tumor and the optic nerve, smaller tumor volume, higher margin dose, and normal vision were reported as predictors for better tumor control.(4, 6–8, 20) In our univariate analysis, a greater percent of the tumor receiving at least 12 Gy, greater distance between the optic nerve and the tumor , and purely solid or cystic tumors were factors associated with better tumor control. In the multivariate analysis, greater percent receiving 12 Gy coverage and pure solid or cystic tumors again were significant. An increased distance between the tumor and the optic nerve was not significant in the multivariate analysis because a small number of patients who were blind at the time of SRS were treated with complete coverage and long-term tumor control. Of note a single patient whose tumor margin dose was 18 Gy and the 100 % of the tumor received >12 Gy had a late progression at 164 months after SRS. This single example emphasizes the importance of long-term vigilance of such tumors.
Enhanced 12 Gy coverage improved tumor control
In order to prevent tumor growth while reducing the risk of optic neuropathy, we have advocated a prescribed margin dose of 12 Gy for better tumor control. Because of the anatomic location of craniopharyngiomas, including those that are in contact with the optic system, dose reduction near such critical structures are needed to reduce the risk of further optic neuropathy. This is the first study to suggest that strict conformity (100% of the tumor receives at least 12 Gy) may not be necessary. Instead we found that when ≥85% of the tumor volume receives 12 Gy or greater, tumor control can be maximized while reducing the risk of optic nerve injury. Risk in radiosurgery does not come from what the target gets but rather from what adjacent brain, cranial nerves, or pituitary gland receive. The cutoff value for tumor control that maximized the Youden index was 0.85 for the 12 Gy coverage. Higher margin dose (>12 Gy, p <0.001) and greater distance from optic system (>3 mm, p <0.001) also were significant. For the tumors near the optic nerve, it is necessary to reduce the tumor margin dose so that the optic nerve receives a tolerance dose.(21) Although this study had only 24 tumors that were near the optic nerve, higher 12 Gy coverage rate was significantly associated with improved tumor control (>85%, p=0.027). Even if the craniopharyngioma is close to the optic nerve, the tumor control was improved by ensuring that ≥ 85% received at least 12 Gy. Dose fall off (selectivity) using the Gamma knife also is improved by using small isocenters with selective beam blockage.
SRS Conformity and Selectivity Concepts
Since the advent of advanced dose planning strategies, various authors have emphasized two critical aspects of SRS. First the tumor must be precisely defined (contouring) after which using either prospective or inverse dose planning, the tumor must have 100% conformity of the dose delivery.(9) Secondly, the dose outside the tumor must fall off as rapidly as possible to reduce injury to nearby critical structures (selectivity). Paddick et al have developed conformity indices that are helpful guides to dose planning especially in less experienced planners(9). As yet no data shows that both tumor response and risk reduction are improved by conformity concepts. It is important to understand that risk comes from what adjacent critical structures outside the target receive, not from what the target itself receives. The conformity index does not take into account the location of critical structures in relation to the tumor. In a study of brain metastases SRS, Aiyama et al. had reported that tumor control actually was reduced as the conformity index was increased.(22)
The present study found that for tumors such as craniopharyngioma the conformity index had no relationship to tumor control or to adverse radiation effect. Instead when deliberately reducing the tumor dose near the optic system while at the same time ensuring that at least 85% of the tumor received ≥12 Gy, tumor control was improved and risk was low (Fig. 3). This finding parallels the report of Kano et al. who demonstrated that AVM obliteration results can be improved significantly when at least 63% of the AVM receives a dose >20 Gy; this also confirmed that margin dose critical predictor of successful obliteration.(23) Using the Gamma knife, we can increase the percent volume receiving higher dose by adding low weighted isocenters within the target volume while not changing the prescription margin dose or conformity.(23)
Adverse radiation effect
In a previous large SRS craniopharyngioma series, the rate of visual field deterioration without tumor progression was 0-2.2%(4, 5, 7). In the present study, a single patient had visual field deterioration unrelated to tumor progression. The patient was treated with a margin dose of 9 Gy and the dose reduction to the optic nerve was performed by selective beam channel blocking of isocenters closer to the optic nerve. The cause of this presumed radiation related optic neuropathy is unclear. If the maximum point dose delivered to the optic nerve is 10 Gy and the average dose is < 8 Gy, the risk of optic neuropathy is < 1 % in patients without prior radiation therapy.(24, 25) This is achieved by enhancing selectivity using only small isocenters near the target periphery and by selective beam channel blocking. Margin doses can be reduced to assist, as long as 85 % of the tumor receives a dose of 12 Gy. This same concept applies to pituitary gland and stalk radiation dose.
In the current study, a single patient at 24 months developed additional hormone loss in the absence of tumor progression. This patient was treated with a margin dose of 11 Gy.
Study limitations
This is a retrospective study. Since the clinical course of patients with craniopharyngioma is complex and their incidence is rare, it is difficult to have a homogenous cohort. Both selection bias and prior treatment bias may interact. Since no patient in this study also had fractionated radiation therapy, we cannot assess the benefit or the risks of this alternative strategy.