Main findings

This review aimed to determine whether the success of stereotactic radiosurgery for vestibular schwannomas is compromised in those showing a fast-growing tumour prior to treatment. The overall success rate of stereotactic radiosurgery was between 88 and 91 per cent (Figures 3 and 4), with a lower success rate, 79 per cent, in fast-growing vestibular schwannomas (Figure 5). Such results should be interpreted with caution, as they do not imply that fast-growing vestibular schwannomas do not respond to stereotactic radiosurgery, as the studies examined growth rates of vestibular schwannomas following stereotactic radiosurgery, and the results seen immediately post treatment may not be a unifying concept to be directly correlated with long-term outcomes. However, the ability of stereotactic radiosurgery to induce stabilisation or a reduction in tumour size appeared to be lower in the fast-growing vestibular schwannoma group. These results should therefore be taken into account when stereotactic radiosurgery is being considered as a management option in this sub-group. It is also vital to recognise that most tumours will show a degree of size increment in the first year following stereotactic radiosurgery, with further involution in the second year.^{Reference Ton, Sheldon, Tikka, Locke, Crowther and Kontorinis27}

Langenhuizen et al. concluded that fast-growing tumours are less radiosensitive.^{Reference Langenhuizen, Zinger, Hanssens, Kunst, Mulder and Leenstra24} Their study postulates that this is secondary to a superior DNA repair system or potentially secondary to the indirect effects of radiotherapy, such as decreased tumour vascularity.^{Reference Langenhuizen, Zinger, Hanssens, Kunst, Mulder and Leenstra24} Stereotactic radiosurgery was, however, efficacious for slow-growing tumours. This resulted in the conclusion that treatment strategies in vestibular schwannomas should be determined by the rate of tumour growth.^{Reference Langenhuizen, Zinger, Hanssens, Kunst, Mulder and Leenstra24} A similar conclusion was reached by Marston et al., who concluded that pre-treatment tumour growth was a strong predictor of tumour control.^{Reference Marston, Jacob, Carlson, Pollock, Driscoll and Link16}

On the contrary, Larjani et al. did not identify a significant difference between the outcomes of fast- and slow-growing tumours following stereotactic radiosurgery based on tumour volume.^{Reference Larjani, Monsalves, Pebdani, Krischek, Gentili and Cusimano23} This was also the outcome displayed in our meta-analysis (Figure 5). Larjani et al. argued that the reason for continued growth post treatment may be the variability in intrinsic molecular properties between tumours, thus resulting in varying degrees of radio-resistance.^{Reference Larjani, Monsalves, Pebdani, Krischek, Gentili and Cusimano23} Furthermore, Larjani et al. observed that fast-growing vestibular schwannomas experienced the greatest change in growth following stereotactic radiosurgery, with those that continued to grow at significant rates post treatment being associated with adverse radiation effects.^{Reference Larjani, Monsalves, Pebdani, Krischek, Gentili and Cusimano23} Conversely, Varughese et al. did observe a relationship between tumour size at treatment and the rates of successful control in terms of tumour size reduction or stabilisation following stereotactic radiosurgery.^{Reference Varughese, Wentzel-Larsen, Pedersen, Mahesparan and Lund-Johansen19}

The studies by Larjani et al. and Varughese et al. did examine tumour growth as a covariate, but failed to show any statistical correlation between the pre-treatment growth rate and response to stereotactic radiosurgery.^{Reference Varughese, Wentzel-Larsen, Pedersen, Mahesparan and Lund-Johansen19,Reference Larjani, Monsalves, Pebdani, Krischek, Gentili and Cusimano23} However, as mentioned previously, Larjani et al. noted greater post-treatment changes in fast-growing tumours.^{Reference Larjani, Monsalves, Pebdani, Krischek, Gentili and Cusimano23} This relationship was also partly mirrored in the retrospective study by Killeen et al., where it was concluded that smaller pre-treatment tumour volume and greater linear tumour growth rates pre-treatment were associated with greater changes to tumour size post stereotactic radiosurgery.^{Reference Killeen, Tolisano, Isaacson, Kutz, Barnett and Wardak28} Overall, from the literature it can be concluded that faster-growing tumours are less radiosensitive.

Limitations

The principal challenge in assessing the literature was the methodological inconsistencies among the individual studies, which subsequently made the task of drawing comparisons and coming to conclusions based on their evidence somewhat challenging, particularly because of the variability in the definition of fast-growing vestibular schwannomas and treatment failure (Table 1). Only three of the studies explored the ‘retreatment-free survival rate’, all with different tumour volumes, with Marston et al. having the largest range (Table 2).^{Reference Marston, Jacob, Carlson, Pollock, Driscoll and Link16,Reference Varughese, Wentzel-Larsen, Pedersen, Mahesparan and Lund-Johansen19,Reference Langenhuizen, Zinger, Hanssens, Kunst, Mulder and Leenstra24}

The studies in our analysis also lacked a comparative (control) arm, therefore it was not possible to perform a more rigorous effect size estimator such as an odds ratio.^{Reference Marston, Jacob, Carlson, Pollock, Driscoll and Link16,Reference Varughese, Wentzel-Larsen, Pedersen, Mahesparan and Lund-Johansen19,Reference Larjani, Monsalves, Pebdani, Krischek, Gentili and Cusimano23,Reference Langenhuizen, Zinger, Hanssens, Kunst, Mulder and Leenstra24,Reference Murad, Sultan, Haffar and Bazerbachi26} For maximum value to be achieved in any future research, there is a requirement for greater consistency in definitions and classifications, particularly in the method of assessing and describing tumour growth. Prospective studies with standardised methods of reporting growth rates and responses to treatment are required to better assess the exact success rates of stereotactic radiosurgery in the management of fast-growing vestibular schwannomas.

Additionally, the measurement methodology of vestibular schwannomas was not standardised across the studies, which may impact both the accuracy of individual measurements and the comparison between the studies (Table 1). A short follow-up period post treatment was identified as a limitation by two of the studies, which limits the clinical applicability of their results.^{Reference Marston, Jacob, Carlson, Pollock, Driscoll and Link16,Reference Varughese, Wentzel-Larsen, Pedersen, Mahesparan and Lund-Johansen19}

Further limitations specific to individual studies include the retrospective nature of the study by Langenhuizen et al., alongside the variability in the imaging modalities being used.^{Reference Langenhuizen, Zinger, Hanssens, Kunst, Mulder and Leenstra24} A potential treatment selection bias was identified in Marston et al.^{Reference Marston, Jacob, Carlson, Pollock, Driscoll and Link16} Arbitrary cut-off points between the slow-, medium- and fast-growing categories by Larjani et al., without clear definitions of these parameters to enable external validation of their findings, was also an issue when attempting to draw conclusions.^{Reference Larjani, Monsalves, Pebdani, Krischek, Gentili and Cusimano23}

Given the large variability in the methodology and definitions of the studies (Table 1), it was extremely difficult to combine the results in a meaningful way. None of the selected studies in our analysis had standardised the ‘success’ criteria definition, thus limiting the data pooling for the meta-analysis to a proportional method only. Post-treatment tumour size was not recorded by all the selected studies, which limits mean-difference analysis for effect size. As a result of the weaknesses highlighted, the limitation of our review arises from the lack of rigour between the selected studies.^{Reference Marston, Jacob, Carlson, Pollock, Driscoll and Link16,Reference Varughese, Wentzel-Larsen, Pedersen, Mahesparan and Lund-Johansen19,Reference Larjani, Monsalves, Pebdani, Krischek, Gentili and Cusimano23,Reference Langenhuizen, Zinger, Hanssens, Kunst, Mulder and Leenstra24} However, we utilised a blinded review strategy and independent data extraction to overcome this limitation. Here, the proportionate meta-analysis to determine the success rate as the effect size estimator with arcsine transformation enabled the best information pooling for translation. This was due to the differences in the study definitions as noted by the I ² indexes and vestibular schwannoma rarity.^{Reference Murad, Sultan, Haffar and Bazerbachi26}